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Sjöholm Å, Bennet L, Nilsson PM. Cognitive dysfunction in diabetes - the 'forgotten' diabetes complication: a narrative review. Scand J Prim Health Care 2025; 43:448-454. [PMID: 39876043 PMCID: PMC12090258 DOI: 10.1080/02813432.2025.2455136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/10/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND In addition to peripheral neuropathy of various kinds, diabetes can also cause central neuropathy, which among other things can manifest itself as premature cognitive dysfunction, often linked to vascular dysfunction. Although the link between diabetes and cognitive dysfunction was discovered more than 100 years ago and has important clinical implications, this diabetes complication remains relatively unknown. Recent years have seen research that has clarified cerebral insulin resistance and defective insulin signaling as examples of pathogenic factors behind this cognitive impairment in diabetes. METHOD We provide a narrative review of select and contemporary publications with relevance for the interface between diabetes/prediabetes and cognitive function. RESULTS Recently published studies show that physical activity can reverse insulin resistance in the brain as well as cognitive impairment and pathological appetite regulation. Pharmacological interventions with, for example, nasal insulin, GLP-1 receptor agonists, SGLT-2 inhibitors, or PPAR-γ agonists have also shown promising results. CONCLUSION Optimization of lifestyle factors (e.g. physical activity), as well as several pharmaceutical agents already in clinical use against diabetes, have shown promising results in improving cognitive function in diabetic patients. An important task for primary health care, where most patients with type 2 diabetes are diagnosed, treated, and followed, is to increase awareness and early detection of cognitive dysfunction in these patients for optimizing risk factor control.
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Affiliation(s)
- Åke Sjöholm
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Gävle Hospital and University of Gävle, Gävle, Sweden
| | - Louise Bennet
- Department of Clinical Sciences, Lund University, Clinical Studies Sweden, Forum South, Skåne University Hospital, Lund, Sweden
| | - Peter M. Nilsson
- Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
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Chiang PC, Hsieh CY, Sung SF. Comparative risk of dementia in diabetic stroke patients prescribed SGLT2 vs. DPP-4 inhibitors: A propensity-matched retrospective cohort study. J Stroke Cerebrovasc Dis 2025; 34:108276. [PMID: 40049567 DOI: 10.1016/j.jstrokecerebrovasdis.2025.108276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/08/2025] [Accepted: 03/03/2025] [Indexed: 03/30/2025] Open
Abstract
OBJECTIVE Diabetes is a significant risk factor for both stroke and dementia. This study aimed to compare the risk of incident dementia between sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in diabetic patients with a history of ischemic stroke. MATERIALS We conducted a propensity-matched retrospective cohort study using observational data from the TriNetX global federated health research network. Patients aged 18 years or older with type 2 diabetes (T2D) and a history of ischemic stroke, newly prescribed either an SGLT2 or DPP-4 inhibitor from July 1, 2013, to June 30, 2024, were included. Propensity score matching was employed to balance baseline characteristics between treatment groups. The primary outcome was incident dementia, with secondary outcomes including degenerative and vascular dementia. RESULTS After propensity score matching, each group consisted of 15901 patients. Over a mean follow-up of 2.52 years, SGLT2 inhibitor use was associated with lower risks of overall dementia (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.59-0.74), degenerative dementia (HR 0.68; 95% CI 0.60-0.76), and vascular dementia (HR 0.59, 95% CI 0.49-0.70) compared to DPP-4 inhibitor use. These findings remained consistent across various sensitivity and subgroup analyses. CONCLUSIONS In diabetic patients with a history of ischemic stroke, initiating SGLT2 inhibitors, compared to DPP-4 inhibitors, is associated with a lower risk of incident dementia. This association was observed for both degenerative and vascular dementias. These findings support the preferential use of SGLT2 inhibitors in this high-risk population, warranting further investigation through randomized clinical trials.
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Affiliation(s)
- Pei-Chun Chiang
- Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan
| | - Cheng-Yang Hsieh
- Department of Neurology, Tainan Sin Lau Hospital, Tainan, Taiwan; School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Sheng-Feng Sung
- Division of Neurology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539 Zhongxiao Road, East District, Chiayi City 60002, Taiwan; Department of Nursing, Fooyin University, Kaohsiung, Taiwan.
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Hou Y, Chen Z, Cheng J, Li G, Yin L, Gao J. The Mechanism and Treatment of Cognitive Dysfunction in Diabetes: A Review. Exp Clin Endocrinol Diabetes 2025; 133:64-72. [PMID: 39572247 DOI: 10.1055/a-2480-7826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2025]
Abstract
Diabetes mellitus (DM) is one of the fastest growing diseases in terms of global incidence and seriously affects cognitive function. The incidence rate of cognitive dysfunction is up to 13% in diabetes patients aged 65-74 years and reaches 24% in those aged >75 years. The mechanisms and treatments of cognitive dysfunction associated with diabetes mellitus are complicated and varied. Previous studies suggest that hyperglycemia mainly contributes to cognitive dysfunction through mechanisms involving inflammation, autophagy, the microbial-gut-brain axis, brain-derived neurotrophic factors, and insulin resistance. Antidiabetic drugs such as metformin, liraglutide, and empagliflozin and other drugs such as fingolimod and melatonin can alleviate diabetes-induced cognitive dysfunction. Self-management, intermittent fasting, and repetitive transverse magnetic stimulation can also ameliorate cognitive impairment. In this review, we discuss the mechanisms linking diabetes mellitus with cognitive dysfunction and propose a potential treatment for cognitive decline associated with diabetes mellitus.
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Affiliation(s)
- Yangbo Hou
- Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhen Chen
- Department of Encephalopathy, Suqian Hospital of Chinese Medicine , Nanjing University of Traditional Chinese Medicine, Suqian, China
| | - Jiwei Cheng
- Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guoyi Li
- Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lu Yin
- Department of Rehabilitation, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jie Gao
- Department of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Abdullah Z, Cui Y, Platt RW, Renoux C, Azoulay L, Xia C, Yu OHY. Association between use of sodium-glucose co-transporter-2 inhibitor and the risk of incident dementia: a population-based cohort study. BMJ Open Diabetes Res Care 2025; 13:e004541. [PMID: 39842866 PMCID: PMC11751778 DOI: 10.1136/bmjdrc-2024-004541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 12/22/2024] [Indexed: 01/24/2025] Open
Abstract
OBJECTIVES To assess the association between sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use and the risk of incident dementia compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) use among individuals with type 2 diabetes. DESIGN A population-based retrospective cohort study. SETTING The Clinical Practice Research Datalink (CPRD) Aurum database from the UK. PARTICIPANTS Individuals with type 2 diabetes, aged 40 years or older, newly prescribed SGLT-2i or DPP-4i on or after 2013-2021, registered in the CPRD Aurum database. MAIN OUTCOME MEASURE The primary outcome was incident dementia, and the secondary outcome was incident mild cognitive impairment (MCI). Cox proportional hazard models were used to estimate the HR and corresponding 95% CI for the primary and secondary outcomes. Propensity score fine stratification weights were used to adjust for confounding. RESULTS Among a cohort of 118 006 individuals, the incident rate (IR) of dementia was 0.56/1000 person-years over a median follow-up period of 1.54 years among SGLT-2i users compared with 2.67/1000 person-years in DPP-4i users, over a median follow-up period of 1.79 years. The adjusted HR for SGLT-2i use compared with DPP-4i use for dementia was 0.78 (95% CI 0.55 to 1.12), while for MCI was 0.86 (95% CI 0.80 to 0.92). The age-specific stratified analysis demonstrated the adjusted HR for SGLT-2i use compared with DPP-4i use for the risk of incident dementia among elderly, aged ≥65 years, was 0.50 (95% CI 0.31 to 0.80). CONCLUSION Primary findings did not yield conclusive evidence to infer an association between SGLT-2i use and the risk of incident dementia.
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Affiliation(s)
- Zarin Abdullah
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
| | - Ying Cui
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
| | - Robert W Platt
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
| | - Christel Renoux
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada
| | - Laurent Azoulay
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
| | - Chenjie Xia
- Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada
| | - Oriana Hoi Yun Yu
- Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Montreal, Québec, Canada
- Department of Medicine, McGill University, Montreal, Québec, Canada
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Wang X, Chen L, Li W, He Z, Jiang H. Association of dipeptidyl peptidase-4 with Alzheimer's disease: A new therapeutic prospect. J Alzheimers Dis 2025; 103:319-332. [PMID: 39773090 DOI: 10.1177/13872877241304673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Alzheimer's disease (AD) is the most common disease associated with cognitive dysfunction, which is closely associated with type 2 diabetes mellitus (T2DM) in clinical manifestations, pathological changes and prevention. Inhibition of dipeptidyl peptidase 4 (DPP-4) can lower blood glucose levels by stimulating insulin secretion. Besides, it can affect cognitive function through the neuroprotective effect of DPP-4 substrates, such as glucose-dependent insulin peptide and glucagon-like peptide-1, the proteolytic effect on amyloid-β and the protective effect on neuronal structure. This review discusses the relationship between cognitive impairment in T2DM and in AD, summarizes the effect of DPP-4 inhibitor (DPP-4i) on improving cognitive impairment in these two diseases based on the current studies. Given the lack of clinical randomized trials that evaluate the effect of DPP-4i on AD, this review is expected to provide preclinical evidence for DPP-4i as a potential therapy for the treatment and prevention of AD.
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Affiliation(s)
- Xinyi Wang
- Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Li Chen
- Department of Pathology, Northeast Yunnan Regional Central Hospital, Zhaotong, China
| | - Weijian Li
- Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China
| | - Zhi He
- Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China
| | - Haiying Jiang
- Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, China
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Piatkowska-Chmiel I, Gawronska-Grzywacz M, PawLowski K, Dudka J, Slaska B, Tkaczyk-Wlizlo A, Kowal K, Herbet M. Restoring Brain Pathways Involved in Diabetes-Associated Neurocognitive Disorders: The Potential of Dipeptidyl Peptidase 4 Inhibitors as a Therapeutic Strategy. Curr Neuropharmacol 2025; 23:426-438. [PMID: 38860903 DOI: 10.2174/1570159x22666240517094428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 06/12/2024] Open
Abstract
BACKGROUND Diabetes, a widespread chronic metabolic disease, is projected to affect 783 million people globally by 2045. Recent studies emphasize the neuroprotective potential of dipeptidyl peptidase 4 (DPP4i) inhibitors, pointing toward a promising avenue for intervention in addressing cognitive challenges associated with diabetes. Due to limited data on the effect of DPP4i on brain pathways involvedin diabetes-related neurocognitive disorders, the decision was made to conduct this study to fill existing knowledge gaps on this topic. METHODS The primary aim of our study was to evaluate the potential of DPP4 inhibitors (DPP4i) in preventing cognitive decline in mice with type 2 diabetes (T2D), placing special emphasis on gaining insight into the complex molecular mechanisms underlying this action. RESULTS We examined drug efficacy in modulating neurotrophic factors, calcium levels, and the expression of key genes (HIF1α, APP, Arc) crucial for neural plasticity. Conducting cognitive assessments with the hole board and passive avoidance tests, we discerned a remarkable influence of shortterm gliptin usage on the limiting progress of cognitive dysfunction in diabetic mice. The administration of DPP4 inhibitors ledto heightened neurotrophin levels, increased HIF1α in the prefrontal cortex, and a significant elevation in Arc mRNA levels. CONCLUSION Our findings reveal that DPP4 inhibitors effectively limit the progression of diabetesrelated cognitive disorders. This breakthrough discovery not only opens new research avenues but also constitutes a potential starting point for creating innovative strategies for the treatment of central nervous system disorders focused on improving cognitive abilities.
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Affiliation(s)
- Iwona Piatkowska-Chmiel
- Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 20-090 Lublin, Poland
| | | | - Kamil PawLowski
- Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 20-090 Lublin, Poland
| | - Jaroslaw Dudka
- Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 20-090 Lublin, Poland
| | - Brygida Slaska
- Institute of Biological Bases of Animal Production, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Angelika Tkaczyk-Wlizlo
- Institute of Biological Bases of Animal Production, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Krzysztof Kowal
- Institute of Biological Bases of Animal Production, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Mariola Herbet
- Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 20-090 Lublin, Poland
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Pai YW, Chen IC, Lin JF, Chen XH, Chen HH, Chang MH, Huang JA, Lin CH. Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks. Diabetes Obes Metab 2024; 26:5420-5430. [PMID: 39248211 DOI: 10.1111/dom.15918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/08/2024] [Accepted: 08/15/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors is associated with a lower risk of incident dementia and all-cause mortality, relative to dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). METHODS In this retrospective, active-comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged ≥50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan-Meier survival analysis to estimate the incidence of dementia and all-cause mortality in our cohort after they had used glucose-lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT-2 inhibitor, DPP-4 inhibitor and GLP-1 RA cohorts. Subgroup analyses for sex and age were also conducted. RESULTS Our first cohort comprised 193 948 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and DPP-4 inhibitors. In this cohort, the risk of dementia and all-cause mortality was lower in patients treated with SGLT-2 inhibitors than in those treated with DPP-4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59-0.65, for dementia; HR: 0.54, 95% CI: 0.52-0.56, for all-cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and GLP-1 RAs. In this cohort, the risk of dementia and all-cause mortality was lower in those treated with SGLT-2 inhibitors than in those treated with GLP-1 RAs (HR: 0.92, 95% CI: 0.87-0.98, for dementia; HR: 0.88, 95% CI: 0.85-0.91, for all-cause mortality). CONCLUSIONS The use of SGLT-2 inhibitor was associated with a lower risk of incident dementia and all-cause mortality in older adults with T2D compared to DPP-4 inhibitor and GLP-1 RA.
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Affiliation(s)
- Yen-Wei Pai
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - I-Chieh Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jun-Fu Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Xiao-Hui Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hsin-Hua Chen
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ming-Hong Chang
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jin-An Huang
- Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Health Business Administration, Hungkuang University, Taichung, Taiwan
| | - Ching-Heng Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan
- Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Hong B, Lee H, Choi A, Kim WJ, Cho YM, Yon DK, Shin JY. Sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase IV inhibitors and risk of dementia among patients with type 2 diabetes and comorbid mental disorders: A population-based cohort study. DIABETES & METABOLISM 2024; 50:101581. [PMID: 39349097 DOI: 10.1016/j.diabet.2024.101581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 09/04/2024] [Accepted: 09/10/2024] [Indexed: 10/02/2024]
Abstract
AIM To evaluate whether the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors which have shown potential neuroprotective effects, is associated with lower risk of dementia in patients with type 2 diabetes (T2D) and comorbid mental disorders, who are considerably more susceptible to dementia. METHODS Using the nationwide healthcare data of South Korea between 2010 and 2022, we conducted a retrospective cohort study among patients with T2D and comorbid mental disorders initiating SGLT2 inhibitors versus active comparator (Dipeptidyl Peptidase IV (DPP4) inhibitors). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years of incident dementia were estimated after weighting by propensity score fine stratification method. RESULTS Over a 4.8-year median follow-up, SGLT2 inhibitors were associated with a 12 % lower risk of dementia compared with DPP4 inhibitors (11.31 vs. 12.86 events per 1000 person years; HR 0.88, 95 % CI 0.84 to 0.92; RD -1.55, -2.13 to -0.97). The results were consistent when stratified by age, sex, individual component, severe mental disorders, presence of insulin, history of cardiovascular disease, or history of hypertension. CONCLUSIONS SGLT2 inhibitors versus DPP4 inhibitors were associated with a lower risk of incident dementia in patients with T2D and comorbid mental disorders. Further randomized controlled trials are required to confirm our findings.
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Affiliation(s)
- Bin Hong
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Hyesung Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea
| | - Ahhyung Choi
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Woo Jung Kim
- Department of Psychiatry, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea; Institute of Behavioral Sciences in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute for Innovation in Digital Healthcare, Yonsei University, Seoul, Republic of Korea
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Dong Keon Yon
- Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea
| | - Ju-Young Shin
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea; Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
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Mok VCT, Cai Y, Markus HS. Vascular cognitive impairment and dementia: Mechanisms, treatment, and future directions. Int J Stroke 2024; 19:838-856. [PMID: 39283037 PMCID: PMC11490097 DOI: 10.1177/17474930241279888] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 08/17/2024] [Indexed: 10/21/2024]
Abstract
Worldwide, around 50 million people live with dementia, and this number is projected to triple by 2050. It has been estimated that 20% of all dementia cases have a predominant cerebrovascular pathology, while perhaps another 20% of vascular diseases contribute to a mixed dementia picture. Therefore, the vascular contribution to dementia affects 20 million people currently and will increase markedly in the next few decades, particularly in lower- and middle-income countries.In this review, we discuss the mechanisms of vascular cognitive impairment (VCI) and review management. VCI refers to the spectrum of cerebrovascular pathologies that contribute to any degree of cognitive impairment, ranging from subjective cognitive decline, to mild cognitive impairment, to dementia. While acute cognitive decline occurring soon after a stroke is the most recognized form of VCI, chronic cerebrovascular disease, in particular cerebral small-vessel disease, can cause insidious cognitive decline in the absence of stroke. Moreover, cerebrovascular disease not only commonly co-occurs with Alzheimer's disease (AD) and increases the probability that AD pathology will result in clinical dementia, but may also contribute etiologically to the development of AD pathologies.Despite its enormous health and economic impact, VCI has been a neglected research area, with few adequately powered trials of therapies, resulting in few proven treatments. Current management of VCI emphasizes prevention and treatment of stroke and vascular risk factors, with most evidence for intensive hypertension control. Reperfusion therapies in acute stroke may attenuate the risk of VCI. Associated behavioral symptoms such as apathy and poststroke emotionalism are common. We also highlight novel treatment strategies that will hopefully lead to new disease course-modifying therapies. Finally, we highlight the importance of including cognitive endpoints in large cardiovascular prevention trials and the need for an increased research focus and funding for this important area.
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Affiliation(s)
- Vincent Chung Tong Mok
- Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Lui Che Woo Institute of Innovative Medicine, Gerald Choa Neuroscience Institute, Li Ka Shing Institute of Health Science, Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Yuan Cai
- Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Lui Che Woo Institute of Innovative Medicine, Gerald Choa Neuroscience Institute, Li Ka Shing Institute of Health Science, Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Hugh S Markus
- Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
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Hong B, Bea S, Ko HY, Kim WJ, Cho YM, Shin JY. Sodium-Glucose Cotransporter-2 Inhibitors, Dulaglutide, and Risk for Dementia : A Population-Based Cohort Study. Ann Intern Med 2024; 177:1319-1329. [PMID: 39186787 DOI: 10.7326/m23-3220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/28/2024] Open
Abstract
BACKGROUND Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes (T2D). However, their comparative effectiveness in preventing dementia remains uncertain. OBJECTIVE To compare the risk for dementia between SGLT2 inhibitors and dulaglutide (a GLP-1 RA). DESIGN Target trial emulation study. SETTING Nationwide health care data of South Korea obtained from the National Health Insurance Service between 2010 and 2022. PATIENTS Patients aged 60 years or older who have T2D and are initiating treatment with SGLT2 inhibitors or dulaglutide. MEASUREMENTS The primary outcome was the presumed clinical onset of dementia. The date of onset was defined as the year before the date of dementia diagnosis, assuming that the time between the onset of dementia and diagnosis was 1 year. The 5-year risk ratios and risk differences comparing SGLT2 inhibitors with dulaglutide were estimated in a 1:2 propensity score-matched cohort adjusted for confounders. RESULTS Overall, 12 489 patients initiating SGLT2 inhibitor treatment (51.9% dapagliflozin and 48.1% empagliflozin) and 1075 patients initiating dulaglutide treatment were included. In the matched cohort, over a median follow-up of 4.4 years, the primary outcome event occurred in 69 participants in the SGLT2 inhibitor group and 43 in the dulaglutide group. The estimated risk difference was -0.91 percentage point (95% CI, -2.45 to 0.63 percentage point), and the estimated risk ratio was 0.81 (CI, 0.56 to 1.16). LIMITATION Residual confounding is possible; there was no adjustment for hemoglobin A1c levels or duration of diabetes; the study is not representative of newer drugs, including more effective GLP-1 RAs; and the onset of dementia was not measured directly. CONCLUSION Under conventional statistical criteria, a risk for dementia between 2.5 percentage points lower and 0.6 percentage point greater for SGLT2 inhibitors than for dulaglutide was estimated to be highly compatible with the data from this study. However, whether these findings generalize to newer GLP-1 RAs is uncertain. Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required. PRIMARY FUNDING SOURCE Ministry of Food and Drug Safety of South Korea.
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Affiliation(s)
- Bin Hong
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea (B.H., H.Y.K.)
| | - Sungho Bea
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea, and Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (S.B.)
| | - Hwa Yeon Ko
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea (B.H., H.Y.K.)
| | - Woo Jung Kim
- Department of Psychiatry, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin; Institute of Behavioral Sciences in Medicine, Yonsei University College of Medicine, Seoul; and Institute for Innovation in Digital Healthcare, Yonsei University, Seoul, South Korea (W.J.K.)
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea (Y.M.C.)
| | - Ju-Young Shin
- School of Pharmacy and Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, and Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea (J.-Y.S.)
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11
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Shin A, Koo BK, Lee JY, Kang EH. Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in adults aged 40-69 years with type 2 diabetes: population based cohort study. BMJ 2024; 386:e079475. [PMID: 39197881 PMCID: PMC11350613 DOI: 10.1136/bmj-2024-079475] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2024] [Indexed: 09/01/2024]
Abstract
OBJECTIVE To compare the risk of dementia associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors in adults aged 40-69 years with type 2 diabetes. DESIGN Population based cohort study. SETTING Korean National Health Insurance Service data, 2013-21. PARTICIPANTS 110 885 propensity score matched pairs of adults with type 2 diabetes aged 40-69 years who were initiators of either an SGLT-2 inhibitor or a DPP-4 inhibitor. MAIN OUTCOME MEASURES The primary outcome was new onset dementia. Secondary outcomes were dementia requiring drug treatment and individual types of dementia, including Alzheimer's disease and vascular dementia. Control outcomes were genital infections (positive), and osteoarthritis related clinical encounters and cataract surgery (negative). Hazard ratios and 95% confidence intervals (CIs) were estimated using Cox models. Follow-up time stratified analyses (>2 years and ≤2 years) and subgroup analyses by age, sex, concomitant use of metformin, and baseline cardiovascular risk were performed. RESULTS 110 885 propensity score matched pairs of initiators of an SGLT-2 inhibitor or a DPP-4 inhibitor were followed-up for a mean 670 (standard deviation 650) days, generating 1172 people with newly diagnosed dementia: incidence rate 0.22 per 100 person years in initiators of SGLT-2 inhibitors and 0.35 per 100 person years in initiators of DPP-4 inhibitors, with hazard ratios of 0.65 (95% CI 0.58 to 0.73) for dementia, 0.54 (0.46 to 0.63) for dementia requiring drugs, 0.61 (0.53 to 0.69) for Alzheimer's disease, and 0.48 (0.33 to 0.70) for vascular dementia. The hazard ratios for the control outcomes were 2.67 (2.57 to 2.77) for genital infections, 0.97 (0.95 to 0.98) for osteoarthritis related encounters, and 0.92 (0.89 to 0.96) for cataract surgery. When calibrated for residual confounding measured by cataract surgery, the hazard ratio for dementia was 0.70 (0.62 to 0.80). The association was greater for more than two years of treatment (hazard ratio of dementia 0.57, 95% CI 0.46 to 0.70) than for two years or less (0.52, 0.41 to 0.66) and persisted across subgroups. CONCLUSION SGLT-2 inhibitors might prevent dementia, providing greater benefits with longer treatment. As this study was observational and therefore prone to residual confounding and informative censoring, the effect size could have been overestimated. Randomised controlled trials are needed to confirm these findings.
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Affiliation(s)
- Anna Shin
- Medical Research Collaborating Centre, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Bo Kyung Koo
- Division of Endocrinology, Department of Internal Medicine, Seoul National University College of Medicine, SMG-SNU Boramae Medical Centre, Seoul, Korea
| | - Jun Young Lee
- Department of Psychiatrics, Seoul National University College of Medicine, SMG-SNU Boramae Medical Centre, Seoul, Korea
| | - Eun Ha Kang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
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12
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Ciardullo S, Morieri ML, Daniele G, Fiorentino TV, Mezza T, Tricò D, Consoli A, Del Prato S, Giorgino F, Piro S, Solini A, Avogaro A. GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes. Acta Diabetol 2024; 61:941-950. [PMID: 38831203 PMCID: PMC11329401 DOI: 10.1007/s00592-024-02300-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 05/04/2024] [Indexed: 06/05/2024]
Abstract
Type 2 diabetes represents a growing challenge for global public health. Its prevalence is increasing worldwide, and, like obesity, it affects progressively younger populations compared to the past, with potentially greater impact on chronic complications. Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. In this context, the aim of the present document is to summarize, in the form of a narrative literature review, the currently available data on the main mechanisms of action of GIP/GLP-1 co-agonists and the clinical effects of tirzepatide evaluated in various clinical trials.
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Affiliation(s)
- Stefano Ciardullo
- Department of Medicine and Surgery, Università degli Studi di Milano Bicocca, Milan, Italy.
- Department of Medicine and Rehabilitation, Policlinico di Monza, Via Modigliani 10, 20900, Monza, Italy.
| | | | - Giuseppe Daniele
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- CISUP, Center for Instrument Sharing, University of Pisa, 56124, Pisa, Italy
| | - Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy
| | - Teresa Mezza
- Department of Medicine and Translational Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Agostino Consoli
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST, Ex CeSIMet) G. d'Annunzio University Chieti-Pescara, Chieti, Italy
- Endocrinology and Metabolism Unit, Pescara Health Service, Pescara, Italy
| | | | - Francesco Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, 70124, Bari, Italy
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Angelo Avogaro
- Unit of Metabolic Disease, University Hospital of Padua, Padua, Italy
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13
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van Sloten TT, Luchsinger JA, Launer LJ, Strachan M, Cukierman-Yaffe T, Gerstein HC, Sattar N, Biessels GJ. Call for effective therapies for preventing dementia in people with type 2 diabetes. Lancet Diabetes Endocrinol 2024; 12:510-513. [PMID: 38901446 DOI: 10.1016/s2213-8587(24)00158-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 05/23/2024] [Indexed: 06/22/2024]
Affiliation(s)
- Thomas T van Sloten
- Department of Vascular Medicine and Diabetology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
| | - José A Luchsinger
- Department of Medicine, Columbia University Medical Center, New York, NY, USA; Department of Epidemiology, Columbia University Medical Center, New York, NY, USA
| | | | - Mark Strachan
- Metabolic Unit, Western General Hospital, Edinburgh, UK
| | - Tali Cukierman-Yaffe
- Division of Endocrinology and Metabolism, Sheba Medical Center, Epidemiology Department, School of Public Health, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Hertzel C Gerstein
- Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
| | - Naveed Sattar
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Geert Jan Biessels
- Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, Netherlands
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14
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Tang B, Sjölander A, Wastesson JW, Maura G, Blotiere PO, Szilcz M, Mak JK, Qin C, Alvarsson M, Religa D, Johnell K, Hägg S. Comparative effectiveness of glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes in Sweden: an emulated trial study. EClinicalMedicine 2024; 73:102689. [PMID: 39429814 PMCID: PMC11490655 DOI: 10.1016/j.eclinm.2024.102689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/25/2024] [Accepted: 05/30/2024] [Indexed: 10/22/2024] Open
Abstract
Background The comparative effectiveness of glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes mellitus (T2DM) is unknown. Methods We conducted a sequential trial emulation from 1st January 2010 to 30th June 2020 using data from Swedish national registers. Swedish residents who were aged 65 or older, had type 2 diabetes (T2DM), and initiated GLP-1 agonists, DPP-4 inhibitors, or sulfonylureas were followed for up to 10 years to assess the risk of dementia. Participants who had dementia, used the three drug classes, or had contraindications were excluded from enrollment. The characteristics between arms were balanced through the application of propensity scores estimated from predefined covariates. Intention-to-treat effects were analysed with all enrolled participants, while the per-protocol effects were analysed with participants who adhered to the assigned treatment. Findings The pooled trial included 88,381 participants who received prescriptions for GLP-1 agonists (n = 12,351), DPP-4 inhibitors (n = 43,850), or sulfonylureas (n = 32,216) at baseline and were followed for an average of 4.3 years. A total of 4607 dementia cases developed during follow-up: 278 for the GLP-1 agonist initiators (incidence rate: 6.7 per 1000 person years), 1849 for DPP-4 inhibitor initiators (IR: 11.8), and 2480 for sulfonylurea initiators (IR: 13.7). In an intention-to-treat analysis, GLP-1 agonist initiation was associated with a reduced risk of dementia compared to sulfonylureas (hazard ratio: 0.69, 95% CI: 0.60-0.79, p < 0.0001) and DPP-4 inhibitors (HR: 0.77, 95% CI: 0.68-0.88, p < 0.0001), after adjusting for age, enrollment year, sex, socioeconomic factors, health conditions, and past medication uses. These findings were consistent in several sensitivity analyses, including a per-protocol analysis (HR for sulfonylureas: 0.41, 95% CI: 0.32-0.53, p < 0.0001; HR for DPP-4 inhibitors: 0.38, 95% CI: 0.30-0.49, p < 0.0001). Interpretation Our research suggested that GLP-1 agonists were associated with a lower risk of dementia compared to sulfonylureas and DPP-4 inhibitors in older individuals with T2DM. Further clinical trials are needed to validate these findings. Funding Swedish Research Council, Karolinska Institutet, the National Institute on Aging, the National Institutes of Health, and Riksbankens Jubileumsfond.
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Affiliation(s)
- Bowen Tang
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Arvid Sjölander
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jonas W. Wastesson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Géric Maura
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Pierre-Olivier Blotiere
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Máté Szilcz
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jonathan K.L. Mak
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
| | - Chenxi Qin
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Michael Alvarsson
- Division of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Dorota Religa
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden
| | - Kristina Johnell
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Sara Hägg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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15
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Cukierman-Yaffe T, Ramasundarahettige C, Bosch J, Gerstein HC. Effect of basal insulin and omega 3 fatty acids on cognitive impairment in dysglycaemia: An exploratory analysis of the ORIGIN trial. Diabetes Obes Metab 2024; 26:1180-1187. [PMID: 38204215 DOI: 10.1111/dom.15412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/03/2023] [Accepted: 12/04/2023] [Indexed: 01/12/2024]
Abstract
AIM The outcomes reduction with an initial glargine intervention (ORIGIN) trial reported that, allocation to insulin glargine-mediated normoglycaemia versus standard care, and to omega 3 fatty acids versus placebo had a neutral effect on cognitive test scores when analysed as continuous variables. Analyses of these scores as standardized categorical variables using a previously validated strategy may yield different results. MATERIALS AND METHODS The ORIGIN trial recruited participants with dysglycaemia and additional cardiovascular risk factors from 573 sites in 40 countries. They completed a mini mental state examination and a subset completed the digit symbol substitution test at baseline and up to three subsequent visits. The effect of the interventions on country-standardized substantive cognitive impairment, defined as the first occurrence of a baseline-adjusted follow-up mini mental state examination or digit symbol substitution test score ≥1.5 standard deviations below the baseline mean score in each participant's country was assessed using Cox proportional hazards models. RESULTS During a median follow-up of 6.2 years, 2627 of 11 682 people (22.5%) developed country-standardized substantive cognitive impairment. The hazard of this outcome was reduced by 9% (hazard ratio 0.91, 95% confidence interval 0.85, 0.99; p = .023) in participants assigned to insulin glargine (21.6%) versus standard care (23.3%). Conversely, the hazard of this outcome was not affected by assignment to omega 3 fatty acid versus placebo (hazard ratio 0.93, 95% confidence interval 0.86, 1.01; p = .074). CONCLUSIONS In this post hoc exploratory analysis, insulin glargine-mediated normoglycaemia but not omega 3 fatty acids reduced the hazard of substantive cognitive impairment in people with dysglycaemia and additional cardiovascular risk factors.
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Affiliation(s)
- Tali Cukierman-Yaffe
- Division of Endocrinology & Metabolism, Sheba Medical Center, Ramat Gan, Israel
- Epidemiology Department, School of Public Health, Faculty of Medicine, Herczeg Institute of Aging, Tel-Aviv University, Tel Aviv, Israel
- Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Chinthanie Ramasundarahettige
- Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
- School of Rehabilitation Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Jackie Bosch
- Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
- School of Rehabilitation Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Hertzel C Gerstein
- Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
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16
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Zhuge F, Zheng L, Pan Y, Ni L, Fu Z, Shi J, Ni Y. DPP-4 inhibition by linagliptin ameliorates age-related mild cognitive impairment by regulating microglia polarization in mice. Exp Neurol 2024; 373:114689. [PMID: 38199510 DOI: 10.1016/j.expneurol.2024.114689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/29/2023] [Accepted: 01/06/2024] [Indexed: 01/12/2024]
Abstract
Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.
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Affiliation(s)
- Fen Zhuge
- Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Liujie Zheng
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Yuxiang Pan
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Liyang Ni
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
| | - Zhengwei Fu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Junping Shi
- Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Yinhua Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
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Yuan Y, Zhang Y, Lei M, Guo X, Yang X, Ouyang C, Liu C, Chen Q. Effects of DPP4 Inhibitors as Neuroprotective Drug on Cognitive Impairment in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review. Int J Endocrinol 2024; 2024:9294113. [PMID: 38379936 PMCID: PMC10878760 DOI: 10.1155/2024/9294113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/07/2023] [Accepted: 01/28/2024] [Indexed: 02/22/2024] Open
Abstract
Purpose Type 2 diabetes mellitus is considered as one of the risk factors for cognitive impairment. DPP4 inhibitors are effective drugs for the treatment of type 2 diabetes mellitus. However, the relationship between DPP4 inhibitors and cognitive dysfunction remains unclear. Therefore, we used a meta-analysis to determine the association between DPP4 inhibitors and cognitive impairment in type 2 diabetes mellitus. Methods We systematically searched PubMed, CNKI, and the Cochrane Library at the time of establishment, 2022, and then made inclusion criteria and screened strategies to identify studies with more precise correlations. Results We included 10 studies with 5,583 participants. The data showed that DPP4 inhibitors significantly reduced the incidence rate of cognitive impairment in type 2 diabetes mellitus (SMD: 0.99; 95% CI [0.59, 1.38]). Furthermore, there was a linear correlation found between cognitive impairment in type 2 diabetes mellitus and fasting blood glucose, 2-hour postprandial blood glucose, and glycosylated hemoglobin. DPP4 inhibitors decreased fasting blood glucose (FPG) (SMD: 0.52; 95% CI [-0.68, -0.37]), blood glucose (2hPPG) at 2 hours after the meal (SMD: 0.82; 95% CI, [-1.2, -0.43]), and HbA1c (SMD: 0.34; 95% CI [-0.48, -0.21]). All data were statistically significant (P < 0.0001). Furthermore, we conducted subgroup analyses of the following measures at various treatment durations and ages: cognitive scores, fasting blood glucose, glycosylated hemoglobin, and two-hour postprandial blood glucose. Conclusion DPP4 inhibitors significantly improved type 2 diabetic mellitus individuals' cognitive impairment and reduced fasting blood glucose, 2-hour postprandial blood glucose, and glycosylated hemoglobin. Subgroup analysis showed that people aged 60 to 70 years had better treatment effects at 0-180 days. This trial is registered with CRD42023399473.
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Affiliation(s)
- Yuting Yuan
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Yue Zhang
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Min Lei
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Xiying Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Xiaosong Yang
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Changhan Ouyang
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Chao Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Qingjie Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
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Jiang X, Li J, Yao X, Ding H, Gu A, Zhou Z. Neuroprotective effects of dipeptidyl peptidase 4 inhibitor on Alzheimer's disease: a narrative review. Front Pharmacol 2024; 15:1361651. [PMID: 38405664 PMCID: PMC10884281 DOI: 10.3389/fphar.2024.1361651] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 01/30/2024] [Indexed: 02/27/2024] Open
Abstract
Insulin resistance in brain and amyloidogenesis are principal pathological features of diabetes-related cognitive decline and development of Alzheimer's disease (AD). A growing body of evidence suggests that maintaining glucose under control in diabetic patients is beneficial for preventing AD development. Dipeptidyl peptidase 4 inhibitors (DDP4is) are a class of novel glucose-lowering medications through increasing insulin excretion and decreasing glucagon levels that have shown neuroprotective potential in recent studies. This review consolidates extant evidence from earlier and new studies investigating the association between DPP4i use, AD, and other cognitive outcomes. Beyond DPP4i's benefits in alleviating insulin resistance and glucose-lowering, underlying mechanisms for the potential neuroprotection with DPP4i medications were categorized into the following sections: (Ferrari et al., Physiol Rev, 2021, 101, 1,047-1,081): the benefits of DPP4is on directly ameliorating the burden of β-amyloid plaques and reducing the formation of neurofibrillary tangles; DPP4i increasing the bioactivity of neuroprotective DPP4 substrates including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and stromal-derived factor-1α (SDF-1α) etc.; pleiotropic effects of DPP4is on neuronal cells and intracerebral structure including anti-inflammation, anti-oxidation, and anti-apoptosis. We further revisited recently published epidemiological studies that provided supportive data to compliment preclinical evidence. Given that there remains a lack of completed randomized trials that aim at assessing the effect of DPP4is in preventing AD development and progression, this review is expected to provide a useful insight into DPP4 inhibition as a potential therapeutic target for AD prevention and treatment. The evidence is helpful for informing the rationales of future clinical research and guiding evidence-based clinical practice.
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Affiliation(s)
- Xin Jiang
- Baoying People’s Hospital, Yangzhou, China
| | | | | | - Hao Ding
- Baoying People’s Hospital, Yangzhou, China
| | - Aihong Gu
- Baoying People’s Hospital, Yangzhou, China
| | - Zhen Zhou
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
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Lee KJ, Bae HJ. What have clinical trials taught us about brain health? CEREBRAL CIRCULATION - COGNITION AND BEHAVIOR 2023; 6:100199. [PMID: 38235315 PMCID: PMC10792690 DOI: 10.1016/j.cccb.2023.100199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 12/26/2023] [Accepted: 12/27/2023] [Indexed: 01/19/2024]
Abstract
The Global Burden of Disease Study projects an almost tripling of dementia cases worldwide in the next 30 years making it important to recognize and understand modifiable risks and preventatives for cognitive impairment. Recent studies suggest that prevention or treatment of cardiovascular risks may be an important strategy to prevent or slow the progression of cognitive impairment. In 2017, the American Heart Association and American Stroke Association introduced metrics for "optimal brain health". These metrics defined brain health in terms of ideal health behaviors and factors. Since then and leading up to 2017, a number of clinical trials have been conducted to investigate the potential of modification of cardiovascular risks on prevention of dementia or cognitive impairment and thus, enhancement of brain health. This discussion is a review of findings from clinical trials focusing on interventions, including antihypertensive agents, glycemic control and lipid-lowering therapies, multidomain approaches, and antithrombotic medications. Notably, the results highlight the promise of intensive blood pressure lowering strategies and multidomain approaches, as evidenced by the FINGER trial. The review also discusses the potential of treatment or prevention of cerebral small vessel disease (cSVD) and the application of Mendelian randomization as a strategy to preserve brain structure and function.
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Affiliation(s)
- Keon-Joo Lee
- Department of Neurology, Korea University Guro Hospital, Seoul, South Korea
| | - Hee-Joon Bae
- Department of Neurology and Cerebrovascular Center, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
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Meng J, Yan R, Zhang C, Bai X, Yang X, Yang Y, Feng T, Liu X. Dipeptidyl peptidase-4 inhibitors alleviate cognitive dysfunction in type 2 diabetes mellitus. Lipids Health Dis 2023; 22:219. [PMID: 38082288 PMCID: PMC10712048 DOI: 10.1186/s12944-023-01985-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 12/04/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) are commonly at high risk for developing cognitive dysfunction. Antidiabetic agents might be repurposed for targeting cognitive dysfunction in addition to modulation on glucose homeostasis. This study aimed to evaluate the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on cognitive function in T2DM. METHODS PubMed, Embase, Cochrane Library and Web of Science were systematically searched from inception to September 30, 2023. Weighted mean differences were calculated using the Mantel-Haenszel (M-H) fixed or random effects model based on the degree of heterogeneity among studies. Heterogeneity was evaluated using a Chi-squared test and quantified with Higgins I2. Sensitivity analysis was performed with the leave-one-out method, and publication bias was evaluated according to Begg's and Egger's tests. RESULTS Six clinical trials involving 5,178 participants were included in the pooled analysis. Administration of DPP-4i generally correlated with an increase of Mini-Mental State Examination (MMSE) scores (1.09, 95% CI: 0.22 to 1.96). DPP-4i alleviated cognitive impairment in the copying skill subdomain of MMSE (0.26, 95% CI: 0.12 to 0.40). Treatment with DPP-4i also resulted in an increase of Instrumental Activities of Daily Living (IADL) scores (0.82, 95% CI: 0.30 to 1.34). However, DPP-4i produced no significant effects on Barthel Activities of Daily Living (BADL) scores (0.37, 95% CI: -1.26 to 1.99) or other test scores. CONCLUSIONS DPP-4i treatment favourably improved cognitive function in patients with T2DM. Further trials with larger samples should be performed to confirm these estimates and investigate the association of different DPP-4i with cognitive function among diabetic patients. TRIAL REGISTRATION IN PROSPERO CRD42023430873.
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Affiliation(s)
- Jie Meng
- Department of Pathology, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Rui Yan
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chen Zhang
- National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xueyan Bai
- Department of Hemotology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xingsheng Yang
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yu Yang
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Tao Feng
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
- National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Xin Liu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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21
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Slouha E, Ibrahim F, Rezazadah A, Esposito S, Clunes LA, Kollias TF. Anti-diabetics and the Prevention of Dementia: A Systematic Review. Cureus 2023; 15:e49515. [PMID: 38152822 PMCID: PMC10752751 DOI: 10.7759/cureus.49515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2023] [Indexed: 12/29/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide epidemic that is only increasing as the years progress, and as of 2019, affecting over 37 million. T2DM is a chronic condition caused by reduced insulin secretion and increased insulin resistance. Due to insulin not operating at optimal conditions, blood glucose rises and remains high, thus disturbing metabolic hemostasis. Many complications can arise from T2DM, such as coronary vascular disease, kidney damage, eye damage, and, quite significantly, dementia. It is theorized that dementia from T2DM stems from the fact that the brain is susceptible to hyperglycemic conditions, which are promoted by the increase in insulin resistance of target cells in the central nervous system. This directly affects cognitive processes and memory, which correlates to decreased temporal and front lobes volume. The risk of diabetic complications can be minimized with therapeutic interventions such as oral-antidiabetic (OAD) agents and insulin. Several OADs are on the market, but the first-line agent is metformin, a biguanide that decreases glucose production and increases insulin sensitivity. This paper aims to determine if currently prescribed OADs can help slow cognitive decline and reduce the risk and incidence of dementia as a complication of T2DM. Studies found that, for the most part, all OADs except sulfonylureas (SU) significantly slowed the decline of cognitive function and reduced the risk and incidence of dementia. SU's were shown to increase the risk of dementia in most studies. Of all the OADs, thiazolidinediones may be the most beneficial drug class for reducing the risk of dementia in T2DM patients. Future research should focus on whether early intervention with specific classes of OADs can not only improve glycemic control, leading to decreased hyperglycemia but also prevent the build-up of damaged brain tissue and help to reduce the risk and incidence of dementia in patients with T2DM.
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Affiliation(s)
- Ethan Slouha
- Anatomical Sciences, St. George's University School of Medicine, True Blue, GRD
| | - Fadi Ibrahim
- Pharmacology, St. George's University School of Medicine, True Blue, GRD
| | - Atbeen Rezazadah
- Pharmacology, St. George's University School of Medicine, True Blue, GRD
| | - Sarah Esposito
- Pharmacology, St. George's University School of Medicine, True Blue, GRD
| | - Lucy A Clunes
- Pharmacology, St. George's University, St George's, GRD
| | - Theofanis F Kollias
- Microbiology, Immunology and Pharmacology, St. George's University School of Medicine, True Blue, GRD
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22
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Chai S, Liu F, Yu S, Yang Z, Sun F. Cognitive protection of incretin-based therapies in patients with type 2 diabetes mellitus: A systematic review and meta-analysis based on clinical studies. J Diabetes Investig 2023; 14:864-873. [PMID: 37147888 PMCID: PMC10286783 DOI: 10.1111/jdi.14015] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/23/2023] [Accepted: 03/26/2023] [Indexed: 05/07/2023] Open
Abstract
AIMS/INTRODUCTION Cognitive dysfunction, including mild cognitive impairment and dementia, is increasingly recognized as an important complication of type 2 diabetes mellitus. The aims of the preset study was to investigate the cognitive protection of incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, in patients with type 2 diabetes mellitus. MATERIALS AND METHODS PubMed, EMBASE, Cochrane library, Web of Science and PsycINFO were searched from the inception through 17 January 2023 for randomized controlled trials and cohort studies on the association between incretin-based therapies and cognitive function. A total of 15 studies were finally included in our systematic review, and eight of which were incorporated into our meta-analysis. RESULTS Pooled results showed that the Mini-Mental State Examination score in incretin-based therapy groups was increased by 1.20 compared with the control group (weighted mean difference 1.20, 95% confidence interval 0.39-2.01). The results of eight studies assessed by the Newcastle Ottawa Quality Assessment Scale and the Cochrane Collaboration's tool, and the quality of the eight studies were at a relatively high level. Egger's regression did not show significant publication bias. CONCLUSIONS Current evidence shows that incretin-based therapies might be more effective, when compared with the other hypoglycemic drugs, for cognitive improvement in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Sanbao Chai
- Department of Endocrinology and MetabolismPeking University International HospitalBeijingChina
| | - Fengqi Liu
- Department of Epidemiology and Biostatistics, School of Public HealthPeking University Health Science CenterBeijingChina
| | - Shuqing Yu
- Department of Epidemiology and Biostatistics, School of Public HealthPeking University Health Science CenterBeijingChina
| | - Zhirong Yang
- Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina
| | - Feng Sun
- Department of Epidemiology and Biostatistics, School of Public HealthPeking University Health Science CenterBeijingChina
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23
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Li J, Hui Y, Xu Z, Tan J, Yin K, Kuang L, Tang Y, Wei J, Zhong Q, Zheng T. Non-canonical function of DPP4 promotes cognitive impairment through ERp29-associated mitochondrial calcium overload in diabetes. iScience 2023; 26:106271. [PMID: 36936785 PMCID: PMC10014273 DOI: 10.1016/j.isci.2023.106271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 01/15/2023] [Accepted: 02/19/2023] [Indexed: 03/02/2023] Open
Abstract
DPP4 has been shown to induce diabetes-associated mitochondrial dysfunction and cognitive impairment through its non-canonical function. Here, we report that enhanced DPP4 expression in diabetes contributes to IP3R2-mediated mitochondria-associated ER membrane (MAM) formation, mitochondria calcium overload, and cognitive impairment, and its knockdown showed opposite effects. Mechanistically, DPP4 binds to PAR2 in hippocampal neurons and activates ERK1/2/CEBPB signaling, which upregulates ERp29 expression and promotes its binding to IP3R2, thereby inhibiting IP3R2 degradation and promoting MAM formation, mitochondria calcium overload, and cognitive impairment. Meanwhile, targeting DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling achieved satisfactory therapeutic effects on MAM formation, mitochondria calcium overload, and cognitive impairment. Notably, DPP4 activates this pathway in an enzymatic activity-independent manner, suggesting the non-canonical role of DPP4 in the pathogenesis of mitochondria calcium overload and cognitive impairment in diabetes. Together, these results identify DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling as a promising therapeutic target for the treatment of cognitive impairment in type 2 diabetes.
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Affiliation(s)
- Jiaxiu Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Ya Hui
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Zhiqiang Xu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Jie Tan
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Kai Yin
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Liuyu Kuang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Yunyun Tang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Junjie Wei
- Lingui Clinical Medical College, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Qiongsui Zhong
- Lingui Clinical Medical College, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
| | - Tianpeng Zheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P. R. China
- Corresponding author
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24
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Dybjer E, Kumar A, Nägga K, Engström G, Mattsson-Carlgren N, Nilsson PM, Melander O, Hansson O. Polygenic risk of type 2 diabetes is associated with incident vascular dementia: a prospective cohort study. Brain Commun 2023; 5:fcad054. [PMID: 37091584 PMCID: PMC10118265 DOI: 10.1093/braincomms/fcad054] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/28/2022] [Accepted: 03/02/2023] [Indexed: 03/09/2023] Open
Abstract
Type 2 diabetes and dementia are associated, but it is unclear whether the two diseases have common genetic risk markers that could partly explain their association. It is also unclear whether the association between the two diseases is of a causal nature. Furthermore, few studies on diabetes and dementia have validated dementia end-points with high diagnostic precision. We tested associations between polygenic risk scores for type 2 diabetes, fasting glucose, fasting insulin and haemoglobin A1c as exposure variables and dementia as outcome variables in 29 139 adults (mean age 55) followed for 20-23 years. Dementia diagnoses were validated by physicians through data from medical records, neuroimaging and biomarkers in cerebrospinal fluid. The dementia end-points included all-cause dementia, mixed dementia, Alzheimer's disease and vascular dementia. We also tested causal associations between type 2 diabetes and dementia through two-sample Mendelian randomization analyses. Seven different polygenic risk scores including single-nucleotide polymorphisms with different significance thresholds for type 2 diabetes were tested. A polygenic risk score including 4891 single-nucleotide polymorphisms with a P-value of <5e-04 showed the strongest association with different outcomes, including all-cause dementia (hazard ratio 1.11; Bonferroni corrected P = 3.6e-03), mixed dementia (hazard ratio 1.18; Bonferroni corrected P = 3.3e-04) and vascular dementia cases (hazard ratio 1.28; Bonferroni corrected P = 9.6e-05). The associations were stronger for non-carriers of the Alzheimer's disease risk gene APOE ε4. There was, however, no significant association between polygenic risk scores for type 2 diabetes and Alzheimer's disease. Furthermore, two-sample Mendelian randomization analyses could not confirm a causal link between genetic risk markers of type 2 diabetes and dementia outcomes. In conclusion, polygenic risk of type 2 diabetes is associated with an increased risk of dementia, in particular vascular dementia. The findings imply that certain people with type 2 diabetes may, due to their genetic background, be more prone to develop diabetes-associated dementia. This knowledge could in the future lead to targeted preventive strategies in clinical practice.
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Affiliation(s)
- Elin Dybjer
- Department of Clinical Sciences Malmö, Lund University, Jan Waldenströms gata 35, SE-21428 Malmö, Sweden
| | - Atul Kumar
- MultiPark: Multidisciplinary Research focused on Parkinson's disease, Lund University, Box 117, SE-22100 Lund, Sweden
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Skånes universitetssjukhus, VE Minnessjukdomar, SE-20502 Malmö, Sweden
| | - Katarina Nägga
- Department of Clinical Sciences Malmö, Lund University, Jan Waldenströms gata 35, SE-21428 Malmö, Sweden
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Skånes universitetssjukhus, VE Minnessjukdomar, SE-20502 Malmö, Sweden
- Department of Acute Internal Medicine and Geriatrics, Linköping University, SE-58183 Linköping, Sweden
| | - Gunnar Engström
- Department of Clinical Sciences Malmö, Lund University, Jan Waldenströms gata 35, SE-21428 Malmö, Sweden
| | - Niklas Mattsson-Carlgren
- MultiPark: Multidisciplinary Research focused on Parkinson's disease, Lund University, Box 117, SE-22100 Lund, Sweden
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Skånes universitetssjukhus, VE Minnessjukdomar, SE-20502 Malmö, Sweden
- Brain Injury After Cardiac Arrest Research Group, Lund University, Box 117, SE-22100 Lund, Sweden
- WCMM – Wallenberg Centre for Molecular Medicine, Lund University, Sölvegatan 19, BMC D11, SE-22184 Lund, Sweden
| | - Peter M Nilsson
- Department of Clinical Sciences Malmö, Lund University, Jan Waldenströms gata 35, SE-21428 Malmö, Sweden
- EpiHealth: Epidemiology for Health Strategic Research Area, Lund University, SUS Malmö, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden
| | - Olle Melander
- Department of Clinical Sciences Malmö, Lund University, Jan Waldenströms gata 35, SE-21428 Malmö, Sweden
- EpiHealth: Epidemiology for Health Strategic Research Area, Lund University, SUS Malmö, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden
- Department of Emergency and Internal Medicine, Skåne University Hospital, SE-20502 Malmö, Sweden
- EXODIAB: Excellence in Diabetes Research in Sweden, Lund University, Box 117, SE-22100 Lund, Sweden
| | - Oskar Hansson
- MultiPark: Multidisciplinary Research focused on Parkinson's disease, Lund University, Box 117, SE-22100 Lund, Sweden
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Skånes universitetssjukhus, VE Minnessjukdomar, SE-20502 Malmö, Sweden
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25
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Wu CY, Iskander C, Wang C, Xiong LY, Shah BR, Edwards JD, Kapral MK, Herrmann N, Lanctôt KL, Masellis M, Swartz RH, Cogo-Moreira H, MacIntosh BJ, Rabin JS, Black SE, Saskin R, Swardfager W. Association of Sodium-Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study. Diabetes Care 2023; 46:297-304. [PMID: 36508692 DOI: 10.2337/dc22-1705] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/31/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium-glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) inhibitors was associated with lower dementia risk. RESEARCH DESIGN AND METHODS Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP-4 inhibitor from 1 July 2016 to 31 March 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer's disease and related dementias. Propensity score-weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and CIs for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed. RESULTS Among 106,903 individuals, SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risk of dementia (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71-0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53-0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69-0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80-1.16]). The as-treated analysis observed a larger association (aHR 0.66 [95% CI 0.57-0.76]) than the intention-to-treat analysis. CONCLUSIONS SGLT2 inhibitors showed an association with lower dementia risk in older people with T2D. Randomized controlled trials are warranted.
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Affiliation(s)
- Che-Yuan Wu
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | | | | | - Lisa Y Xiong
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Baiju R Shah
- ICES, Toronto, Ontario, Canada
- Divisions of Endocrinology and Obstetric Medicine, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Jodi D Edwards
- University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- ICES, Ottawa, Ontario, Canada
| | - Moira K Kapral
- ICES, Toronto, Ontario, Canada
- Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Division of General Internal Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Nathan Herrmann
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Krista L Lanctôt
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
- KITE University Health Network Toronto Rehabilitation Institute, Toronto, Ontario, Canada
- Toronto Dementia Research Alliance, Toronto, Ontario, Canada
| | - Mario Masellis
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Richard H Swartz
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- ICES, Toronto, Ontario, Canada
- Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Hugo Cogo-Moreira
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Faculty of Education, ICT, and Learning, Østfold University College, Halden, Norway
| | - Bradley J MacIntosh
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Computational Radiology & Artificial Intelligence, Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Jennifer S Rabin
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
- Harquail Centre for Neuromodulation, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Rehabilitation Sciences Institute, University of Toronto, Toronto, Ontario, Canada
| | - Sandra E Black
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Toronto Dementia Research Alliance, Toronto, Ontario, Canada
- Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | | | - Walter Swardfager
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- KITE University Health Network Toronto Rehabilitation Institute, Toronto, Ontario, Canada
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26
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Andrew NE, Srikanth V. Plasma Soluble Dipeptidyl Peptidase-4: A Possible Mechanism for Identifying and Managing Poststroke Cognitive Impairment. Stroke 2023; 54:122-123. [PMID: 36475463 DOI: 10.1161/strokeaha.122.041522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Nadine E Andrew
- Department of Medicine, Peninsula Clinical School, Central Clinical School, Monash University, Frankston, Victoria, Australia (N.E.A., V.S.).,National Centre for Healthy Ageing, Frankston, Victoria, Australia (N.E.A., V.S.)
| | - Velandai Srikanth
- Department of Medicine, Peninsula Clinical School, Central Clinical School, Monash University, Frankston, Victoria, Australia (N.E.A., V.S.).,National Centre for Healthy Ageing, Frankston, Victoria, Australia (N.E.A., V.S.).,Department of Medicine & Geriatric Medicine, Frankston Hospital, Peninsula Health, Melbourne, Australia (V.S.)
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27
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Hui Y, Xu Z, Li J, Kuang L, Zhong Y, Tang Y, Wei J, Zhou H, Zheng T. Nonenzymatic function of DPP4 promotes diabetes-associated cognitive dysfunction through IGF-2R/PKA/SP1/ERp29/IP3R2 pathway-mediated impairment of Treg function and M1 microglia polarization. Metabolism 2023; 138:155340. [PMID: 36302455 DOI: 10.1016/j.metabol.2022.155340] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/16/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Impairment of regulatory T (Treg) cells function is implicated in the pathogenesis of immune imbalance-mediated cognitive impairment. A complete understanding of whether and how this imbalance affect cognitive function in type 2 diabetes is lacking, and the driver affecting this imbalance remains unknown. METHODS We examined the impact of enzymatic and non-enzymatic function of DPP4 on Treg cell impairment, microglia polarization and diabetes-associated cognitive defects and identified its underlying mechanism in type 2 diabetic patients with cognitive impairment and in db/db mice. RESULTS We report that DPP4 binds to IGF2-R on Treg cell surface and activates PKA/SP1 signaling, which upregulate ERp29 expression and promote its binding to IP3R2, thereby inhibiting IP3R2 degradation and promoting mitochondria-associated ER membrane formation and mitochondria calcium overload in Tregs. This, in turn, impairs Tregs function and polarizes microglia toward a pro-inflammatory phenotype in the hippocampus and finally leads to neuroinflammation and cognitive impairment in type 2 diabetes. Importantly, inhibiting DPP4 enzymatic activity in type 2 diabetic patients or mutating DPP4 enzymatic active site in db/db mice did not reverse these changes. However, IGF-2R knockdown or blockade ameliorated these effects both in vivo and in vitro. CONCLUSION These findings highlight the nonenzymatic role of DPP4 in impairing Tregs function, which may facilitate the design of novel immunotherapies for diabetes-associated cognitive impairment.
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Affiliation(s)
- Ya Hui
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, PR China; Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Zhiqiang Xu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, PR China; Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Jiaxiu Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, PR China; Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, PR China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Liuyu Kuang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Yuanmei Zhong
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Yunyun Tang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Junjie Wei
- Lingui Clinical Medical College, Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Huimin Zhou
- Department of General Medicine, Guilin Medical University, Guilin, Guangxi 541199, PR China
| | - Tianpeng Zheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, PR China; Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199, PR China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541199, PR China; Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, PR China.
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28
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Coley N, Giulioli C, Aisen PS, Vellas B, Andrieu S. Randomised controlled trials for the prevention of cognitive decline or dementia: A systematic review. Ageing Res Rev 2022; 82:101777. [PMID: 36336171 DOI: 10.1016/j.arr.2022.101777] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 09/02/2022] [Accepted: 10/30/2022] [Indexed: 11/06/2022]
Abstract
Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in pharmacological interventions, notably for individuals with Alzheimer's disease biomarkers, warranting an updated review of results and methodology. We identified 112 completed trials testing the efficacy of single-domain pharmacological (n = 33, 29%), nutritional (n = 27, 24%), physical activity (n = 18, 16%) and cognitive stimulation (n = 13, 12%), or multidomain (n = 22, 20%) interventions on incident dementia, or a relevant intermediate marker (e.g. cognitive function, biomarkers or dementia risk scores) in people without dementia. The earliest trials tested pharmacological interventions or nutritional supplements, but lifestyle interventions predominated in the last decade. In total, 21 (19%) trials demonstrated a clear beneficial effect on the pre-specified primary outcome (or all co-primary outcomes), but only two (10%) were large-scale (testing blood pressure lowering (Syst-Eur) or multidomain (FINGER) interventions on incident dementia and cognitive change in cognitive function, respectively). Of the 116 ongoing trials, 40% (n = 46) are testing multidomain interventions. Recent methodological shifts concern target populations, primary outcome measures, and intervention design, but study design remains constant (parallel group randomised controlled trial). Future trials may consider using adaptive trials or interventions, and more targeted approaches, since certain interventions may be more effective in certain subgroups of the population, and at specific times in the life-course. Efforts should also be made to increase the representativeness and diversity of prevention trial populations.
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Affiliation(s)
- Nicola Coley
- Center for Epidemiology and Research in Population Health (CERPOP), University of Toulouse, INSERM UMR1295, UPS, Toulouse, France; Department of Epidemiology and Public Health, Toulouse University Hospital, Toulouse, France.
| | - Caroline Giulioli
- Center for Epidemiology and Research in Population Health (CERPOP), University of Toulouse, INSERM UMR1295, UPS, Toulouse, France; Department of Epidemiology and Public Health, Toulouse University Hospital, Toulouse, France
| | - Paul S Aisen
- Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, CA, USA
| | - Bruno Vellas
- Center for Epidemiology and Research in Population Health (CERPOP), University of Toulouse, INSERM UMR1295, UPS, Toulouse, France; Department of Epidemiology and Public Health, Toulouse University Hospital, Toulouse, France; Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital, France
| | - Sandrine Andrieu
- Center for Epidemiology and Research in Population Health (CERPOP), University of Toulouse, INSERM UMR1295, UPS, Toulouse, France; Department of Epidemiology and Public Health, Toulouse University Hospital, Toulouse, France; Department of Internal Medicine, Division of General Internal and Geriatric Medicine, University of New Mexico, USA
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29
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Decourt B, Noorda K, Noorda K, Shi J, Sabbagh MN. Review of Advanced Drug Trials Focusing on the Reduction of Brain Beta-Amyloid to Prevent and Treat Dementia. J Exp Pharmacol 2022; 14:331-352. [PMID: 36339394 PMCID: PMC9632331 DOI: 10.2147/jep.s265626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 10/14/2022] [Indexed: 11/21/2022] Open
Abstract
Alzheimer disease (AD) is the most common neurodegenerative disease and typically affects patients older than age 65. Around this age, the number of neurons begins to gradually decrease in healthy brains, but brains of patients with AD show a marked increase in neuron death, often resulting in a significant loss of cognitive abilities. Cognitive skills affected include information retention, recognition capabilities, and language skills. At present, AD can be definitively diagnosed only through postmortem brain biopsies via the detection of extracellular amyloid beta (Aβ) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles. Because the levels of both Aβ plaques and tau tangles are increased, these 2 proteins are thought to be related to disease progression. Although relatively little is known about the cause of AD and its exact pathobiological development, many forms of treatment have been investigated to determine an effective method for managing AD symptoms by targeting Aβ. These treatments include but are not limited to using small molecules to alter the interactions of Aβ monomers, reducing hyperactivation of neuronal circuits altering Aβ's molecular pathway of synthesis, improving degradation of Aβ, employing passive immunity approaches, and stimulating patients' active immunity to target Aβ. This review summarizes the current therapeutic interventions in Phase II/III of clinical development or higher that are capable of reducing abnormal brain Aβ levels to determine which treatments show the greatest likelihood of clinical efficacy. We conclude that, in the near future, the most promising therapeutic interventions for brain Aβ pathology will likely be passive immunotherapies, with aducanumab and donanemab leading the way, and that these drugs may be combined with antidepressants and acetylcholine esterase inhibitors, which can modulate Aβ synthesis.
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Affiliation(s)
- Boris Decourt
- Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA
| | | | | | - Jiong Shi
- Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA
| | - Marwan N Sabbagh
- Alzheimer’s and Memory Disorders Division, Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA
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30
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Verhagen C, Janssen J, Minderhoud CA, van den Berg E, Wanner C, Passera A, Johansen OE, Biessels GJ. Chronic kidney disease and cognitive decline in patients with type 2 diabetes at elevated cardiovascular risk. J Diabetes Complications 2022; 36:108303. [PMID: 36116359 DOI: 10.1016/j.jdiacomp.2022.108303] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/24/2022] [Accepted: 08/27/2022] [Indexed: 11/18/2022]
Abstract
AIMS We addressed the question whether chronic kidney disease (CKD) may contribute to cognitive decline in type 2 diabetes. METHODS Participants with type 2 diabetes with elevated cardiovascular risk or CKD from cognition substudies of two large trials were studied prospectively (CARMELINA: n = 2666, mean ± SD age 68.1 ± 8.7 years, CAROLINA: n = 4296; 64.7 ± 9.4 years). Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) at baseline were related to cognitive performance (Mini-Mental State Examination (MMSE) and attention and executive functioning score (A&E)) in linear regression analyses, adjusted for demographics, cardiovascular risk factors and treatment, at baseline and follow-up. RESULTS CKD at baseline was more common in CARMELINA than CAROLINA (eGFR<60 in 72.6 % and 19.6 %, macroalbuminuria in 35.0 % and 4.1 %, respectively). Baseline eGFR was related to A&E in CARMELINA (b = 0.02 per 10 ml/min/1.73m2, 95%CI [0.01,0.03]). Baseline UACR was related to A&E in CAROLINA (b = -0.01 per doubling of UACR mg/g, 95%CI [-0.02,-0.002]). Baseline UACR predicted decline in A&E in CAROLINA (median 6.1 years follow-up; b = -0.01, 95%CI [-0.03,-0.0001] per doubling of UACR mg/g). CONCLUSIONS eGFR and UACR were associated with A&E in two cohorts with type 2 diabetes, enriched for CKD and cardiovascular disease. The small effect size estimates indicate limited impact of kidney dysfunction on cognition in this setting. GOV IDENTIFIERS NCT01897532 NCT01243424.
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Affiliation(s)
- Chloë Verhagen
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, the Netherlands.
| | - Jolien Janssen
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, the Netherlands.
| | - Crista A Minderhoud
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, the Netherlands.
| | - Esther van den Berg
- Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
| | - Christoph Wanner
- Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg, Germany.
| | - Anna Passera
- Clinical Development & Analytics, Novartis Pharma, Basel, Switzerland.
| | - Odd Erik Johansen
- Cardiometabolic Clinical Development, Nestlé Health Science, Vevey, Switzerland.
| | - Geert Jan Biessels
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, the Netherlands.
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31
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Ogura J, Yamaguchi H. The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties. Int J Mol Sci 2022; 23:6542. [PMID: 35742986 PMCID: PMC9223777 DOI: 10.3390/ijms23126542] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 12/04/2022] Open
Abstract
Dementia dramatically affects the activities of daily living and quality of life; thus, many therapeutic approaches for overcoming dementia have been developed. However, an effective treatment regimen is yet to be developed. As diabetes is a well-known risk factor for dementia, drug repositioning and repurposing of antidiabetic drugs are expected to be effective dementia treatments. Several observational studies have been useful for understanding the effectiveness of antidiabetic drugs in treating dementia, but it is difficult to conclusively analyze the association between antidiabetic drug treatment and the risk of developing dementia after correcting for potential confounding factors. Mechanism-based approaches may provide a better understanding of the effectiveness of antidiabetic drugs for treating dementia. Since the peripheral circulation and the central nerve system are separated by the blood-brain barrier, it is important to understand the regulation of the central glucose metabolism. In this review, we discuss the pharmacological and pharmacokinetic properties of antidiabetic drugs in relation to treating dementia.
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Affiliation(s)
- Jiro Ogura
- Department of Pharmacy, Yamagata University Hospital, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan;
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32
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Wu CY, Shapiro L, Ouk M, MacIntosh BJ, Black SE, Shah BR, Swardfager W. Glucose-lowering drugs, cognition, and dementia: The clinical evidence. Neurosci Biobehav Rev 2022; 137:104654. [PMID: 35398114 DOI: 10.1016/j.neubiorev.2022.104654] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 11/19/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is an important risk factor for dementia. The possibility to mitigate this risk by controlling T2DM is compelling; however, different glucose-lowering drugs have different effects on the brain by virtue of their different mechanisms of action. The clinical and epidemiological data appear mixed, warranting careful critical evaluation of the human studies. Here we examine the evidence in the context of dementia prevention and treatment, both for people with and without T2DM. We discuss the evidence on this scaffold of research directions, identifying methodological complexities in the extant literature (e.g. comparator discrepancies, changes in the therapeutic landscape), and the implications of different outcome measures (e.g. neuropsychological). We consider possible implications of cerebrovascular protection vs. effects on progression of neurodegenerative proteinopathy, and we present a research roadmap for glucose-lowering drugs in cognitive neurology, including neuroimaging, and fluid biomarkers. We conclude that there is great potential to advance personalized strategies to prevent and treat dementia with glucose-lowering drugs.
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Affiliation(s)
- Che-Yuan Wu
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Lila Shapiro
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Michael Ouk
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Bradley J MacIntosh
- Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Sandra E Black
- Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Toronto Dementia Research Alliance, Toronto, Ontario, Canada
| | - Baiju R Shah
- ICES, Toronto, Ontario, Canada; Divisions of Endocrinology and Obstetric Medicine, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Walter Swardfager
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Ontario, Canada; KITE UHN Toronto Rehabilitation Institute, Toronto, Ontario, Canada
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33
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Yin R, Xu Y, Wang X, Yang L, Zhao D. Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment. Molecules 2022; 27:3055. [PMID: 35630534 PMCID: PMC9147686 DOI: 10.3390/molecules27103055] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/02/2022] [Accepted: 05/07/2022] [Indexed: 02/07/2023] Open
Abstract
In recent years, important changes have occurred in the field of diabetes treatment. The focus of the treatment of diabetic patients has shifted from the control of blood glucose itself to the overall management of risk factors, while adjusting blood glucose goals according to individualization. In addition, regulators need to approve new antidiabetic drugs which have been tested for cardiovascular safety. Thus, the newest class of drugs has been shown to reduce major adverse cardiovascular events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they have a prominent place in the hyperglycemia treatment algorithms. In recent years, the role of DPP4 inhibitors (DPP4i) has been modified. DPP4i have a favorable safety profile and anti-inflammatory profile, do not cause hypoglycemia or weight gain, and do not require dose escalation. In addition, it can also be applied to some types of chronic kidney disease patients and elderly patients with diabetes. Overall, DPP4i, as a class of safe oral hypoglycemic agents, have a role in the management of diabetic patients, and there is extensive experience in their use.
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Affiliation(s)
| | | | | | | | - Dong Zhao
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China; (R.Y.); (Y.X.); (X.W.); (L.Y.)
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34
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Moran C, Than S, Callisaya M, Beare R, Srikanth V. New Horizons-Cognitive Dysfunction Associated With Type 2 Diabetes. J Clin Endocrinol Metab 2022; 107:929-942. [PMID: 34788847 DOI: 10.1210/clinem/dgab797] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Indexed: 11/19/2022]
Abstract
The prevalence of type 2 diabetes (T2D) and cognitive dysfunction increases with age. As society ages, clinicians will be increasingly tasked with managing older people who have both T2D and cognitive dysfunction. T2D is associated with an increased risk of cognitive dysfunction and hence there is increasing interest in whether T2D is a causal factor in the pathogenesis of cognitive decline and dementia. Recent advances in the use of sensitive measures of in vivo brain dysfunction in life-course studies can help understand potential mechanistic pathways and also help guide recommendations for clinical practice. In this article we will describe new horizons in the understanding of cognitive dysfunction associated with T2D. Coming from a clinical perspective, we discuss potential mechanisms and pathways linking the 2 conditions and the contribution of multimodal neuroimaging and study designs to advancing understanding in the field. We also highlight the important issues on the horizon that will need addressing in clinical identification, management, and risk reduction for people with coexistent T2D and cognitive dysfunction.
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Affiliation(s)
- Chris Moran
- Academic Unit, Peninsula Clinical School, Central Clinical School, Monash University, Melbourne, 3199 Victoria, Australia
- Department of Geriatric Medicine, Peninsula Health, Melbourne, 3199 Victoria, Australia
- Department of Geriatric Medicine, Alfred Health, Melbourne, 3004 Victoria, Australia
| | - Stephanie Than
- Academic Unit, Peninsula Clinical School, Central Clinical School, Monash University, Melbourne, 3199 Victoria, Australia
- Department of Geriatric Medicine, Peninsula Health, Melbourne, 3199 Victoria, Australia
| | - Michele Callisaya
- Academic Unit, Peninsula Clinical School, Central Clinical School, Monash University, Melbourne, 3199 Victoria, Australia
- Menzies Institute for Medical Research, University of Tasmania, Hobart, 7000 Tasmania, Australia
| | - Richard Beare
- Academic Unit, Peninsula Clinical School, Central Clinical School, Monash University, Melbourne, 3199 Victoria, Australia
- Developmental Imaging, Murdoch Children's Research Institute, Melbourne, 3052 Victoria, Australia
| | - Velandai Srikanth
- Academic Unit, Peninsula Clinical School, Central Clinical School, Monash University, Melbourne, 3199 Victoria, Australia
- Department of Geriatric Medicine, Peninsula Health, Melbourne, 3199 Victoria, Australia
- Menzies Institute for Medical Research, University of Tasmania, Hobart, 7000 Tasmania, Australia
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35
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Secnik J, Xu H, Schwertner E, Hammar N, Alvarsson M, Winblad B, Eriksdotter M, Garcia-Ptacek S, Religa D. The association of antidiabetic medications and Mini-Mental State Examination scores in patients with diabetes and dementia. Alzheimers Res Ther 2021; 13:197. [PMID: 34857046 PMCID: PMC8641148 DOI: 10.1186/s13195-021-00934-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/09/2021] [Indexed: 02/06/2023]
Abstract
Background The effect of antidiabetic medication on cognitive function is unclear. We analyzed the association between five antidiabetic drugs and change in Mini-Mental State Examination (MMSE) scores in patients with diabetes and dementia. Methods Using the Swedish Dementia Registry and four supplementary Swedish registers/databases, we identified 1873 patients (4732 observations) with diagnosis of type 2 diabetes (diabetes) and Alzheimer’s disease or mixed-pathology dementia who were followed up at least once after dementia diagnosis. Use of metformin, insulin, sulfonylurea, thiazolidinediones (TZD), and dipeptidyl-peptidase-4 inhibitors (DPP-4i) was identified at baseline. Prevalent-user, incident-user, and drug-drug cohorts were sampled, and propensity-score matching was used to analyze comparable subjects. Beta coefficients with 95% confidence intervals (CI) from the random intercept and slope linear mixed-effects models determined the association between the use of antidiabetic medications and decline in MMSE score points between the follow-ups. Inverse-probability weighting was used to account for patient dropout. Results Compared to non-users, prevalent users of metformin (beta 0.89, 95% CI 0.44; 1.33) and DPP-4i (0.72, 0.06; 1.37) experienced a slower cognitive decline with time. Secondly, compared to DPP-4i, the use of insulin (−1.00, −1.95; −0.04) and sulfonylureas (−1.19; −2.33; −0.04) was associated with larger point-wise decrements in MMSE with annual intervals. Conclusions In this large cohort of patients with diabetes and dementia, the use of metformin and DPP-4i was associated with a slower decline in MMSE scores. Further examination of the cognitive effects of metformin and incretin-based medications is warranted. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-021-00934-0.
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Affiliation(s)
- Juraj Secnik
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagången 16, 14152, Huddinge, Sweden. .,Department of Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic.
| | - Hong Xu
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagången 16, 14152, Huddinge, Sweden.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Emilia Schwertner
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagången 16, 14152, Huddinge, Sweden
| | - Niklas Hammar
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michael Alvarsson
- Growth and Metabolism, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Bengt Winblad
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
| | - Maria Eriksdotter
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagången 16, 14152, Huddinge, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
| | - Sara Garcia-Ptacek
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagången 16, 14152, Huddinge, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
| | - Dorota Religa
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagången 16, 14152, Huddinge, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
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van Gennip ACE, Stehouwer CDA, van Boxtel MPJ, Verhey FRJ, Koster A, Kroon AA, Köhler S, van Greevenbroek MMJ, Wesselius A, Eussen SJPM, Backes WH, Jansen JF, Schram MT, Henry RMA, Singh-Manoux A, van Sloten TT. Association of Type 2 Diabetes, According to the Number of Risk Factors Within Target Range, With Structural Brain Abnormalities, Cognitive Performance, and Risk of Dementia. Diabetes Care 2021; 44:2493-2502. [PMID: 34588209 PMCID: PMC9612883 DOI: 10.2337/dc21-0149] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 06/15/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, according to the number of risk factors on target, compared with control subjects without diabetes. RESEARCH DESIGN AND METHODS Prospective data were from UK Biobank of 87,856 individuals (n = 10,663 diabetes, n = 77,193 control subjects; baseline 2006-2010), with dementia follow-up until February 2018. Individuals with diabetes were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking; guideline-recommended levels of glycated hemoglobin, blood pressure, BMI, albuminuria, physical activity, and diet). Outcomes were incident dementia, domain-specific cognitive performance, white matter hyperintensities, and total brain volume. RESULTS After a mean follow-up of 9.0 years, 147 individuals (1.4%) with diabetes and 412 control subjects (0.5%) had incident dementia. Among individuals with diabetes, excess dementia risk decreased stepwise for a higher number of risk factors on target. Compared with control subjects (incidence rate per 1,000 person-years 0.62 [95% CI 0.56; 0.68]), individuals with diabetes who had five to seven risk factors on target had no significant excess dementia risk (absolute rate difference per 1,000 person-years 0.20 [-0.11; 0.52]; hazard ratio 1.32 [0.89; 1.95]). Similarly, differences in processing speed, executive function, and brain volumes were progressively smaller for a higher number of risk factors on target. These results were replicated in the Maastricht Study. CONCLUSIONS Among individuals with diabetes, excess dementia risk, lower cognitive performance, and brain abnormalities decreased stepwise for a higher number of risk factors on target.
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Affiliation(s)
- April C E van Gennip
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.,School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, the Netherlands
| | - Coen D A Stehouwer
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.,School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, the Netherlands
| | - Martin P J van Boxtel
- School for Mental Health and Neuroscience MHENS, Maastricht University, Maastricht, the Netherlands.,Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Frans R J Verhey
- School for Mental Health and Neuroscience MHENS, Maastricht University, Maastricht, the Netherlands.,Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Annemarie Koster
- Care and Public Health Research Institute CAPHRI, Maastricht University, Maastricht, the Netherlands.,Department of Social Medicine, Maastricht University, Maastricht, the Netherlands
| | - Abraham A Kroon
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.,School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, the Netherlands
| | - Sebastian Köhler
- School for Mental Health and Neuroscience MHENS, Maastricht University, Maastricht, the Netherlands.,Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Marleen M J van Greevenbroek
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.,School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, the Netherlands
| | - Anke Wesselius
- School of Nutrition and Translational Research in Metabolism NUTRIM, Maastricht University, Maastricht, the Netherlands.,Department of Genetics and Cell Biology, Complex Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Simone J P M Eussen
- School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, the Netherlands.,Department of Epidemiology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Walter H Backes
- School for Mental Health and Neuroscience MHENS, Maastricht University, Maastricht, the Netherlands.,Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Jacobus F Jansen
- School for Mental Health and Neuroscience MHENS, Maastricht University, Maastricht, the Netherlands.,Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.,Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Miranda T Schram
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.,School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, the Netherlands.,School for Mental Health and Neuroscience MHENS, Maastricht University, Maastricht, the Netherlands.,Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Ronald M A Henry
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.,School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, the Netherlands
| | - Archana Singh-Manoux
- Epidemiology of Ageing and Neurodegenerative Diseases, Université de Paris, INSERM U1153, Paris, France.,Department of Epidemiology and Public Health, University College London, London, U.K
| | - Thomas T van Sloten
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands .,School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, the Netherlands
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Sun C, Xiao Y, Li J, Ge B, Chen X, Liu H, Zheng T. Nonenzymatic function of DPP4 in diabetes-associated mitochondrial dysfunction and cognitive impairment. Alzheimers Dement 2021; 18:966-987. [PMID: 34374497 DOI: 10.1002/alz.12437] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/27/2021] [Accepted: 07/05/2021] [Indexed: 12/25/2022]
Abstract
Dipeptidyl peptidase-4 (DPP4) has been proven to exert its functions by both enzymatic and nonenzymatic pathways. The nonenzymatic function of DPP4 in diabetes-associated cognitive impairment remains unexplored. We determined DPP4 protein concentrations or its enzymatic activity in type 2 diabetic patients and db/db mice and tested the impact of the non-enzymatic function of DPP4 on mitochondrial dysfunction and cognitive impairment both in vivo and in vitro. The results show that increased DPP4 activity was an independent risk factor for incident mild cognitive impairment (MCI) in type 2 diabetic patients. In addition, DPP4 was highly expressed in the hippocampus of db/db mice and contributed to mitochondria dysfunction and cognitive impairment. Mechanistically, DPP4 might bind to PAR2 in the hippocampus and trigger GSK-3β activation, which downregulates peroxisome proliferator-activated receptor gamma coactivator 1 alpha expression and leads to mitochondria dysfunction, thereby promoting cognitive impairment in diabetes. Our findings indicate that the nonenzymatic function of DPP4 might promote mitochondrial dysfunction and cognitive impairment in diabetes.
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Affiliation(s)
- Cunwei Sun
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P. R. China.,Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, P. R. China.,Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi, P. R. China
| | - Yanhua Xiao
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P. R. China.,Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, P. R. China
| | - Jiaxiu Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P. R. China.,Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, P. R. China
| | - Bo Ge
- Department of Urology, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P. R. China
| | - Xu Chen
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, P. R. China
| | - Hongbo Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P. R. China
| | - Tianpeng Zheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P. R. China.,Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, P. R. China.,Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi, P. R. China.,Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P. R. China
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Li Q, Jia M, Yan Z, Li Q, Sun F, He C, Li Y, Zhou X, Zhang H, Liu X, Bu X, Gao P, He H, Zhao Z, Zhu Z. Activation of Glucagon-Like Peptide-1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism-Independent Pathway. J Am Heart Assoc 2021; 10:e020734. [PMID: 34250817 PMCID: PMC8483500 DOI: 10.1161/jaha.120.020734] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background Patients with hypertension and diabetes mellitus are susceptible to dementia, but regular therapy fails to reduce the risk of dementia. Glucagon‐like peptide‐1 receptor agonists have neuroprotective effects in experimental studies. We aimed to assess the effect of liraglutide, a glucagon‐like peptide‐1 receptor agonist, on cognitive function and whether its effect was associated with metabolic changes in patients with type 2 diabetes mellitus. Methods and Results Fifty patients with type 2 diabetes mellitus were recruited in this prospective study. All patients underwent cognitive assessment and brain activation monitoring by functional near‐infrared spectroscopy. At 12 weeks, patients in the glucagon‐like peptide‐1 group acquired better scores in all cognitive tests and showed remarkable improvement in memory and attention (P=0.040) test compared with the control group after multivariable adjustment. Compared with the control group, liraglutide significantly increased activation of the dorsolateral prefrontal cortex and orbitofrontal cortex brain regions (P=0.0038). After liraglutide treatment, cognitive scores were significantly correlated with changes in these activating brain regions (P<0.05), but no correlation was observed between the changes in cognitive function and changes of body mass index, blood pressure, and glycemic levels. Conclusions We concluded that liraglutide improves cognitive decline in patients with type 2 diabetes mellitus. This beneficial effect is independent of its hypoglycemic effect and weight loss. The optimal intervention should be targeted to cognitive decline in the early stages of dementia. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT03707171.
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Affiliation(s)
- Qiang Li
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Mengxiao Jia
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Zhencheng Yan
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Qiang Li
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Fang Sun
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Chengkang He
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Yingsha Li
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Xunmei Zhou
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Hexuan Zhang
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Xiaoli Liu
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Xiaona Bu
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Peng Gao
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Hongbo He
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Zhigang Zhao
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
| | - Zhiming Zhu
- Center for Hypertension and Metabolic Diseases Department of Hypertension and Endocrinology Daping Hospital Army Medical University Chongqing China
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Secnik J, Xu H, Schwertner E, Hammar N, Alvarsson M, Winblad B, Eriksdotter M, Garcia-Ptacek S, Religa D. Dementia Diagnosis Is Associated with Changes in Antidiabetic Drug Prescription: An Open-Cohort Study of ∼130,000 Swedish Subjects over 14 Years. J Alzheimers Dis 2021; 76:1581-1594. [PMID: 32741836 PMCID: PMC7504989 DOI: 10.3233/jad-200618] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Care individualization dominates in clinical guidelines for cognitively impaired patients with diabetes; however, few studies examined such adaptations. OBJECTIVE Describe long-term pharmacological changes in diabetes treatment in subjects with and without dementia. METHODS We performed a registry-based cohort study on 133,318 Swedish subjects (12,284 [9.2%] with dementia) with type 2 or other/unspecified diabetes. Dementia status originated from the Swedish Dementia Registry, while the National Patient Register, Prescribed Drug Register, and Cause of Death Register provided data on diabetes, comorbidities, drug dispensation, and mortality. Drug dispensation interval comprised years between 2005 and 2018 and the dispensation was assessed relative to index date (dementia diagnosis) in full cohort and propensity-score (PS) matched cohorts. Annual changes of drug dispensation were analyzed by linear regression, while Cox and competing-risk regression were used to determine the probability of drug dispensation after index date in naïve subjects. Studied medications included insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 agonists (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). RESULTS Dementia patients had higher probability of insulin dispensation (hazard ratio 1.21 [95% CI 1.11-1.31] and lower probability of DPP-4i (0.72 [0.66-0.79]), GLP-1a (0.51 [0.41-0.63]), and SGLT-2i dispensation (0.44 [0.36-0.54]) after index date. PS-matched analyses showed increased annual insulin dispensation (β difference 0.97%) and lower increase in DPP-4i (-0.58%), GLP-1a (-0.13%), and SGLT-2i (-0.21%) dispensation in dementia patients compared to dementia-free controls. CONCLUSION Dementia patients had lower probability of receiving newer antidiabetic drugs, with simultaneous higher insulin dispensation compared to dementia-free subjects.
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Affiliation(s)
- Juraj Secnik
- Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden
| | - Hong Xu
- Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Emilia Schwertner
- Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden
| | - Niklas Hammar
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michael Alvarsson
- Department of Molecular Medicine and Surgery, Growth and Metabolism, Karolinska Institutet, Stockholm, Sweden
| | - Bengt Winblad
- Department of Neurobiology, Center for Alzheimer Research, Division of Neurogeriatrics, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
| | - Maria Eriksdotter
- Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
| | - Sara Garcia-Ptacek
- Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.,Department of Internal Medicine, Södersjukhuset, Section for Neurology, Stockholm, Sweden
| | - Dorota Religa
- Department of Neurobiology, Center for Alzheimer Research, Division of Clinical Geriatrics, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.,Theme Aging, Karolinska University Hospital, Huddinge, Sweden
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Biessels GJ, Verhagen C, Janssen J, van den Berg E, Wallenstein G, Zinman B, Espeland MA, Johansen OE. Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study. Diabetologia 2021; 64:1235-1245. [PMID: 33559704 PMCID: PMC8099814 DOI: 10.1007/s00125-021-05393-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 12/11/2020] [Indexed: 01/27/2023]
Abstract
AIMS/HYPOTHESIS Type 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes. METHODS The CAROLINA-COGNITION study was part of the randomised, double-blind, active-controlled CAROLINA trial that evaluated the cardiovascular safety of linagliptin vs glimepiride in individuals with age ≥40 and ≤85 years and HbA1c 48-69 mmol/mol (6.5-8.5%) receiving standard care, excluding insulin therapy. Participants were randomised 1:1 using an interactive telephone- and web-based system and treatment assignment was determined by a computer-generated random sequence with stratification by center. The primary cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression-based index score ≤16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning, in participants with a baseline MMSE score ≥24. Prespecified additional analyses included effects on ACD at week 160, in subgroups (sex, age, race, ethnicity, depressive symptoms, cardiovascular risk, duration of type 2 diabetes, albuminuria), and absolute changes in cognitive performance. Participants, caregivers, and people involved in measurements, examinations or adjudication, were all masked to treatment assignment. RESULTS Of 6033 participants recruited from hospital and primary care sites, 3163 (38.0% female, mean age/diabetes duration 64/7.6 years, MMSE score 28.5, HbA1c 54 mmol/mol [7.1%]) represent the CAROLINA-COGNITION cohort. Over median 6.1 years, ACD occurred in 27.8% (449/1618, linagliptin) vs 27.6% (426/1545, glimepiride), OR 1.01 (95% CI 0.86, 1.18). Also, no differences in ACD were observed at week 160 (OR 1.07 [0.91, 1.25]), between treatments across subgroups, or for absolute cognitive changes. CONCLUSIONS/INTERPRETATION In a large, international outcome trial in people with relatively early type 2 diabetes at elevated cardiovascular risk, no difference in risk for ACD was observed between linagliptin and glimepiride over 6.1 years. FUNDING This study was sponsored by Boehringer Ingelheim. TRIAL REGISTRATION ClinicalTrials.gov NCT01243424.
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Affiliation(s)
- Geert Jan Biessels
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.
| | - Chloë Verhagen
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Jolien Janssen
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Esther van den Berg
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands
- Department of Neurology, Erasmus MC - University Medical Center, Rotterdam, the Netherlands
| | - Gudrun Wallenstein
- Biostatistics and Data Sciences, Boehringer Ingelheim, Ingelheim, Germany
| | - Bernard Zinman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada
| | - Mark A Espeland
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Odd Erik Johansen
- Therapeutic Area Cardiometabolism, Boehringer Ingelheim, Asker, Norway.
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Shao JW, Wang JD, He Q, Yang Y, Zou YY, Su W, Xiang ST, Li JB, Fang J. Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat. World J Diabetes 2021; 12:499-513. [PMID: 33889293 PMCID: PMC8040076 DOI: 10.4239/wjd.v12.i4.499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/12/2021] [Accepted: 03/07/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia. The mechanisms of diabetes-associated cognitive dysfunction (DACD) have not been fully elucidated to date. Some studies proved lower cerebral blood flow (CBF) in the hippocampus was associated with poor executive function and memory in T2DM. Increasing evidence showed that diabetes leads to abnormal vascular endothelial growth factor (VEGF) expression and CBF changes in humans and animal models. In this study, we hypothesized that DACD was correlated with CBF alteration as measured by three-dimensional (3D) arterial spin labeling (3D-ASL) and VEGF expression in the hippocampus. AIM To assess the correlation between CBF (measured by 3D-ASL and VEGF expression) and DACD in a rat model of T2DM. METHODS Forty Sprague-Dawley male rats were divided into control and T2DM groups. The T2DM group was established by feeding rats a high-fat diet and glucose to induce impaired glucose tolerance and then injecting them with streptozotocin to induce T2DM. Cognitive function was assessed using the Morris water maze experiment. The CBF changes were measured by 3D-ASL magnetic resonance imaging. VEGF expression was determined using immunofluorescence. RESULTS The escape latency time significantly reduced 15 wk after streptozotocin injection in the T2DM group. The total distance traveled was longer in the T2DM group; also, the platform was crossed fewer times. The percentage of distance in the target zone significantly decreased. CBF decreased in the bilateral hippocampus in the T2DM group. No difference was found between the right CBF value and the left CBF value in the T2DM group. The VEGF expression level in the hippocampus was lower in the T2DM group and correlated with the CBF value. The escape latency negatively correlated with the CBF value. The number of rats crossing the platform positively correlated with the CBF value. CONCLUSION Low CBF in the hippocampus and decreased VEGF expression might be crucial in DACD. CBF measured by 3D-ASL might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2DM.
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Affiliation(s)
- Ju-Wei Shao
- Department of Radiology, The Second People’s Hospital of Yunnan Province, The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
- College of Public Health, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Jin-De Wang
- College of Clinical Medicine, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Qian He
- Department of Radiology, The Second People’s Hospital of Yunnan Province, The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Ying Yang
- Department of Endocrinology and Metabolism, The Second People’s Hospital of Yunnan Province, The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Ying-Ying Zou
- Department of Pathology and Pathophysiology, Kunming Medical University, Kunming 650021, Yunnan Province, China
| | - Wei Su
- Department of Radiology, The Second People’s Hospital of Yunnan Province, The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Shu-Tian Xiang
- Department of Radiology, The Second People’s Hospital of Yunnan Province, The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Jian-Bo Li
- Department of Radiology, The Second People’s Hospital of Yunnan Province, The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Jing Fang
- Institute for Health Sciences, Kunming Medical University, Kunming 650500, Yunnan Province, China
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Zanon Zotin MC, Sveikata L, Viswanathan A, Yilmaz P. Cerebral small vessel disease and vascular cognitive impairment: from diagnosis to management. Curr Opin Neurol 2021; 34:246-257. [PMID: 33630769 PMCID: PMC7984766 DOI: 10.1097/wco.0000000000000913] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW We present recent developments in the field of small vessel disease (SVD)-related vascular cognitive impairment, including pathological mechanisms, updated diagnostic criteria, cognitive profile, neuroimaging markers and risk factors. We further address available management and therapeutic strategies. RECENT FINDINGS Vascular and neurodegenerative pathologies often co-occur and share similar risk factors. The updated consensus criteria aim to standardize vascular cognitive impairment (VCI) diagnosis, relying strongly on cognitive profile and MRI findings. Aggressive blood pressure control and multidomain lifestyle interventions are associated with decreased risk of cognitive impairment, but disease-modifying treatments are still lacking. Recent research has led to a better understanding of mechanisms leading to SVD-related cognitive decline, such as blood-brain barrier dysfunction, reduced cerebrovascular reactivity and impaired perivascular clearance. SUMMARY SVD is the leading cause of VCI and is associated with substantial morbidity. Tackling cardiovascular risk factors is currently the most effective approach to prevent cognitive decline in the elderly. Advanced imaging techniques provide tools for early diagnosis and may play an important role as surrogate markers for cognitive endpoints in clinical trials. Designing and testing disease-modifying interventions for VCI remains a key priority in healthcare.
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Affiliation(s)
- Maria Clara Zanon Zotin
- J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Center for Imaging Sciences and Medical Physics. Department of Medical Imaging, Hematology and Clinical Oncology. Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Lukas Sveikata
- J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Cardiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Anand Viswanathan
- J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Pinar Yilmaz
- J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Departments of Epidemiology and Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
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Huang Y, Xu Y, Liu A. Increased Levels of Serum Glycosylated Hemoglobin are Associated with Depressive Symptoms in a Population with Cancer (≥49 Years): An Antidepressant-Stratified Analysis. Clin Interv Aging 2021; 16:205-212. [PMID: 33564231 PMCID: PMC7866938 DOI: 10.2147/cia.s294704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 01/14/2021] [Indexed: 01/09/2023] Open
Abstract
Purpose Patients with cancer tend to have a high prevalence of depressive symptoms. The direct relationship between serum glycosylated hemoglobin (GHb) levels and depressive symptoms in cancer patients is still uncertain. We aimed to evaluate the association with serum GHb levels with depressive symptoms in the population (aged ≥49 years) with cancer. Patients and Methods Longitudinal data in 204 participants with cancer obtained from The Irish LongituDinal Study on Ageing (TILDA) were used to investigate the association of serum GHb levels with depressive symptoms. Results Our results suggested a positive and significant association between serum GHb levels and depression score, independent of age, gender, body mass index (BMI), currently married, education, smoking status, drink alcohol, systolic and diastolic blood pressure (BP), physical activity, self-reported cardiovascular diseases and laboratory measurement in participants with cancer (coefficient =0.141, P<0.001; Model 2) at baseline (wave 1). Higher GHb levels did associate with higher prevalence of depressive symptoms in participants with cancer (OR=2.100, 95% CI 1.105–5.036, P=0.004; Model 2) after adjustment for these same confounding factors in wave 1 was made. Stratified analysis further showed that these significant associations were interfered by antidepressants. Sensitivity analysis showed that higher serum GHb levels in subjects with cancer were linked to higher prevalence of depression events during a follow-up of 4 years. Conclusion Our results found a significant association between elevated serum GHb levels and increased risk of depressive symptoms in the population aged ≥49 years with cancer after confounding factors were adjusted.
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Affiliation(s)
- Ying Huang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Yilin Xu
- Oncology Department, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China.,Jiangxi Key Laboratory of Clinical Translational Cancer Research, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Anwen Liu
- Oncology Department, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China.,Jiangxi Key Laboratory of Clinical Translational Cancer Research, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
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Espeland MA, Pratley RE, Rosenstock J, Kadowaki T, Seino Y, Zinman B, Marx N, McGuire DK, Andersen KR, Mattheus M, Keller A, Weber M, Johansen OE. Cardiovascular outcomes and safety with linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulphonylurea glimepiride in older people with type 2 diabetes: A subgroup analysis of the randomized CAROLINA trial. Diabetes Obes Metab 2021; 23:569-580. [PMID: 33185002 PMCID: PMC7839453 DOI: 10.1111/dom.14254] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/29/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022]
Abstract
AIM To compare the cardiovascular (CV) safety of linagliptin with glimepiride in older and younger participants in the CAROLINA trial in both prespecified and post hoc analyses. MATERIALS AND METHODS People aged 40 to 85 years with relatively early type 2 diabetes, inadequate glycaemic control and elevated CV risk were randomly assigned to linagliptin 5 mg or glimepiride 1 to 4 mg. The primary endpoint was time to first occurrence of three-point major adverse CV events (MACE: CV death, non-fatal myocardial infarction, or non-fatal stroke). We evaluated clinical and safety outcomes across age groups. RESULTS Of 6033 participants, 50.7% were aged <65 years, 35.3% were aged 65 to 74 years, and 14.0% were aged ≥75 years. During the 6.3-year median follow-up, CV/mortality outcomes did not differ between linagliptin and glimepiride overall (hazard ratio [HR] for three-point MACE 0.98, 95.47% confidence interval [CI] 0.84, 1.14) or across age groups (interaction P >0.05). Between treatment groups, reductions in glycated haemoglobin were comparable across age groups but moderate-to-severe hypoglycaemia was markedly reduced with linagliptin (HR 0.18, 95% CI 0.15, 0.21) with no differences among age groups (P = 0.23). Mean weight was -1.54 kg (95% CI -1.80, -1.28) lower for linagliptin versus glimepiride. Adverse events increased with age, but were generally balanced between treatment groups. Significantly fewer falls or fractures occurred with linagliptin. CONCLUSIONS Linagliptin and glimepiride were comparable for CV/mortality outcomes across age groups. Linagliptin had significantly lower risk of hypoglycaemia and falls or fractures than glimepiride, including in "older-old" individuals for whom these are particularly important treatment considerations.
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Affiliation(s)
- Mark A. Espeland
- Division of Gerontology and Geriatric MedicineWake Forest School of MedicineWinston‐SalemNorth Carolina
| | | | | | | | - Yutaka Seino
- Kansai Electric Power Medical Research InstituteKobeJapan
- Kansai Electric Power HospitalOsakaJapan
| | - Bernard Zinman
- Lunenfeld‐Tanenbaum Research Institute, Mount Sinai HospitalUniversity of TorontoTorontoOntarioCanada
| | - Nikolaus Marx
- Department of Internal Medicine I, University Hospital AachenRWTH Aachen UniversityAachenGermany
| | - Darren K. McGuire
- Division of CardiologyDepartment of Internal Medicine, University of Texas Southwestern Medical Center, and Parkland Health and Hospital SystemDallasTexas
| | | | | | - Annett Keller
- Boehringer Ingelheim Pharma GmbH & Co. KGIngelheimGermany
| | - Maria Weber
- Boehringer Ingelheim International GmbHIngelheimGermany
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Tyagi A, Pugazhenthi S. Targeting Insulin Resistance to Treat Cognitive Dysfunction. Mol Neurobiol 2021; 58:2672-2691. [PMID: 33483903 DOI: 10.1007/s12035-021-02283-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
Dementia is a devastating disease associated with aging. Alzheimer's disease is the most common form of dementia, followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus, characterized by chronic hyperglycemia and insulin resistance, as a risk factor for Alzheimer's disease and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported by recent clinical and preclinical studies. The findings from these studies suggest that antidiabetic drugs have the potential to be used to treat dementia. In this review, we discuss the physiological functions of insulin in the brain, studies on the evaluation of cognitive function under conditions of insulin resistance, and reports on the beneficial actions of antidiabetic drugs in the brain. This review covers clinical studies as well as investigations in animal models and will further highlight the emerging link between insulin resistance and neurodegenerative disorders.
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Affiliation(s)
- Anit Tyagi
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.,Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.,University of Denver, Denver, CO, USA
| | - Subbiah Pugazhenthi
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA. .,Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.
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Krivanek TJ, Gale SA, McFeeley BM, Nicastri CM, Daffner KR. Promoting Successful Cognitive Aging: A Ten-Year Update. J Alzheimers Dis 2021; 81:871-920. [PMID: 33935078 PMCID: PMC8293659 DOI: 10.3233/jad-201462] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2021] [Indexed: 02/07/2023]
Abstract
A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.
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Affiliation(s)
- Taylor J. Krivanek
- Center for Brain/Mind Medicine, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Hale Building for Transformative Medicine, Boston, MA, USA
| | - Seth A. Gale
- Center for Brain/Mind Medicine, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Hale Building for Transformative Medicine, Boston, MA, USA
| | - Brittany M. McFeeley
- Center for Brain/Mind Medicine, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Hale Building for Transformative Medicine, Boston, MA, USA
| | - Casey M. Nicastri
- Center for Brain/Mind Medicine, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Hale Building for Transformative Medicine, Boston, MA, USA
| | - Kirk R. Daffner
- Center for Brain/Mind Medicine, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Hale Building for Transformative Medicine, Boston, MA, USA
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Jin Y, Zhao H, Hou Y, Song G. The effects of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists on cognitive functions in adults with type 2 diabetes mellitus: a systematic review and meta-analysis. Acta Diabetol 2020; 57:1129-1144. [PMID: 32300876 DOI: 10.1007/s00592-020-01529-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 03/27/2020] [Indexed: 12/30/2022]
Abstract
AIMS The effects of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors/DPP-4I) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) on cognition in patients with type 2 diabetes mellitus (T2DM) remain controversial. We aimed to explore this clinical issue through a systematic review and meta-analysis. METHODS PubMed, EMBASE and the Cochrane Library were searched, and data were expressed as mean difference (MD) or hazard ratio (HR)/odds ratio (OR) with a 95% confidence interval (CI). Heterogeneity was assessed using the Chi-squared test and the I2 statistic. The study was registered with PROSPERO (ID: CRD42019138777). RESULTS Eleven studies (n = 304,258 T2DM patients) were included in our review. In the DPP-4I group, six studies were enrolled to estimate ΔMini-Mental State Examination (MMSE) scores from baseline to the final evaluations after DPP-4I treatment, which showed no statistical difference (MD 0.20; 95% CI - 0.75 to 1.15, p = 0.68). ΔMMSE scores in the DPP-4I group and the other antidiabetic groups were compared, revealing no statistical difference (MD 0.57; 95% CI - 0.05 to 1.19, p = 0.07). Two cohort studies were pooled to determine the HRs for dementia, showing a lower risk of dementia after DPP-4I treatment (HR 0.52; 95% CI 0.29-0.93, p = 0.03). In the GLP-1 analogs group, two studies were included, one of which revealed a downward trend in the risk of dementia after GLP-1 analog treatment, while the other revealed no significant difference after incretins treatment. CONCLUSIONS Currently there is not enough irrefutable evidence to support the hypothesis of positive effects of incretins on cognition. Further clinical studies need to be performed.
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Affiliation(s)
- Yuxin Jin
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China
- Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China
| | - Hang Zhao
- Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China
| | - Yilin Hou
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China
- Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China
| | - Guangyao Song
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, People's Republic of China.
- Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China.
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Verhagen C, Janssen J, Exalto LG, van den Berg E, Johansen OE, Biessels GJ. Diabetes-specific dementia risk score (DSDRS) predicts cognitive performance in patients with type 2 diabetes at high cardio-renal risk. J Diabetes Complications 2020; 34:107674. [PMID: 32723590 DOI: 10.1016/j.jdiacomp.2020.107674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/19/2020] [Accepted: 07/08/2020] [Indexed: 12/23/2022]
Abstract
AIM To investigate the relationship between the diabetes-specific dementia risk score (DSDRS) and concurrent and future cognitive impairment (CI) in type 2 diabetes (T2D). METHODS DSDRS were calculated for participants with T2D aged ≥60 years from the CARMELINA-cognition substudy (ClinicalTrials.gov Identifier: NCT01897532). Cognitive assessment included Mini-Mental State Examination (MMSE) and a composite attention and executive functioning score (A&E). The relation between baseline DSDRS and probability of CI (MMSE < 24) and variation in cognitive performance was assessed at baseline (n = 2241) and after 2.5 years follow-up in patients without baseline CI (n = 1312). RESULTS Higher DSDRS was associated with a higher probability of CI at baseline (OR = 1.17 per point, 95% CI 1.12-1.22) and follow-up (OR = 1.24 per point, 95% CI 1.14-1.35). Moreover, in patients without baseline CI, higher DSDRS was also associated with lower baseline cognitive performance (MMSE: F(1, 1930) = 47.07, p < .0001, R2 = 0.02); A&E z-score: (F(1, 1871) = 33.44 p < .0001, R2 = 0.02) and faster cognitive decline at follow-up (MMSE: F(3, 1279) = 38.41, p < .0001; A&E z-score: F(3, 1206) = 148.48, p < .0001). CONCLUSIONS The DSDRS identifies patients with T2D at risk of concurrent as well as future CI. The DSDRS may thus be a supportive tool in screening strategies for cognitive dysfunction in patients with T2D.
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Affiliation(s)
- Chloë Verhagen
- Department of Neurology, UMCU Brain Centre, University Medical Center Utrecht, the Netherlands.
| | - Jolien Janssen
- Department of Neurology, UMCU Brain Centre, University Medical Center Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands.
| | - Lieza G Exalto
- Department of Neurology, UMCU Brain Centre, University Medical Center Utrecht, the Netherlands.
| | - Esther van den Berg
- Department of Neurology, UMCU Brain Centre, University Medical Center Utrecht, the Netherlands; Department of Neurology, Erasmus MC - University Medical Center, Rotterdam, the Netherlands.
| | - Odd Erik Johansen
- Clinical Development, Therapeutic Area Cardio Metabolism, Boehringer Ingelheim, Asker, Norway.
| | - Geert Jan Biessels
- Department of Neurology, UMCU Brain Centre, University Medical Center Utrecht, the Netherlands.
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Dybjer E, Engström G, Helmer C, Nägga K, Rorsman P, Nilsson PM. Incretin hormones, insulin, glucagon and advanced glycation end products in relation to cognitive function in older people with and without diabetes, a population-based study. Diabet Med 2020; 37:1157-1166. [PMID: 32020688 DOI: 10.1111/dme.14267] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/03/2020] [Indexed: 12/23/2022]
Abstract
AIM The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting. METHODS Cross-sectional data were obtained from the Swedish population-based Malmö Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. RESULTS Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found. CONCLUSIONS Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain.
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Affiliation(s)
- E Dybjer
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - G Engström
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - C Helmer
- University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
| | - K Nägga
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Department of Acute Internal Medicine and Geriatrics, Linköping University, Linköping, Sweden
| | - P Rorsman
- Metabolic Research, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - P M Nilsson
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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Biessels GJ. A first lead in dementia prevention in people with diabetes. Lancet Neurol 2020; 19:559-560. [DOI: 10.1016/s1474-4422(20)30174-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 05/11/2020] [Indexed: 12/23/2022]
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