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Tura A, Göbl C, El-Tanani M, Rizzo M. In-silico modelling of insulin secretion and pancreatic beta-cell function for clinical applications: is it worth the effort? FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2024; 5:1452400. [PMID: 39559404 PMCID: PMC11570995 DOI: 10.3389/fcdhc.2024.1452400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 08/29/2024] [Indexed: 11/20/2024]
Affiliation(s)
- Andrea Tura
- CNR Institute of Neuroscience, Padova, Italy
| | - Christian Göbl
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
- Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Manfredi Rizzo
- School of Medicine, Mohammed Bin Rashid University, Dubai, United Arab Emirates
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, Palermo, Italy
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Rabbani N, Thornalley PJ. Unraveling the impaired incretin effect in obesity and type 2 diabetes: Key role of hyperglycemia-induced unscheduled glycolysis and glycolytic overload. Diabetes Res Clin Pract 2024; 217:111905. [PMID: 39447679 DOI: 10.1016/j.diabres.2024.111905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/01/2024] [Accepted: 10/21/2024] [Indexed: 10/26/2024]
Abstract
Glucagon-like peptide-1 (GLP-1) agonists and GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) co-agonists are major treatment options for subjects with obesity and patients with type 2 diabetes mellitus (T2DM). They counter without addressing the mechanistic cause of the impaired incretin effect associated with obesity and T2DM. Incretin effect impairment is characterized by decreased secretion of incretins from enteroendocrine cells and incretin resistance of pancreatic β-cells. It is linked to hyperglycemia. We present evidence that subversion of the gating of glucose entry into glycolysis, mainly by glucokinase (hexokinase-4), during persistent hyperglycemia in enteroendocrine cells, pancreatic β- and α-cells and appetite-regulating neurons contributes to the biochemical mechanism of the impaired incretin effect. Unscheduled glycolysis and glycolytic overload thereby produced decreases cell signalling of incretin secretion to glucose and other secretion stimuli and incretin receptor responses. This mechanism provides a guide for development of alternative therapies targeting recovery of the impaired incretin effect.
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Affiliation(s)
- Naila Rabbani
- QU Health, Qatar University, University Street, PO Box 2713, Doha, Qatar
| | - Paul J Thornalley
- College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, PO Box 34110, Doha, Qatar.
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Shibib L, Al-Qaisi M, Guess N, Miras AD, Greenwald SE, Pelling M, Ahmed A. Manipulation of Post-Prandial Hyperglycaemia in Type 2 Diabetes: An Update for Practitioners. Diabetes Metab Syndr Obes 2024; 17:3111-3130. [PMID: 39206417 PMCID: PMC11350065 DOI: 10.2147/dmso.s458894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
This review paper explores post-prandial glycemia in type 2 diabetes. Post-prandial glycemia is defined as the period of blood glucose excursion from immediately after the ingestion of food or drink to 4 to 6 hours after the end of the meal. Post-prandial hyperglycemia is an independent risk factor for cardiovascular disease with glucose "excursions" being more strongly associated with markers of oxidative stress than the fasting or pre-prandial glucose level. High blood glucose is a major promoter of enhanced free radical production and is associated with the onset and progression of type 2 diabetes. Oxidative stress impairs insulin action creating a vicious cycle where repeated post-prandial glucose spikes are key drivers in the pathogenesis of the vascular complications of type 2 diabetes, both microvascular and macrovascular. Some authors suggest post-prandial hyperglycemia is the major cause of death in type 2 diabetes. Proper management of post-prandial hyperglycemia could yield up to a 35% cut in overall cardiovascular events, and a 64% cut in myocardial infarction. The benefits of managing post-prandial hyperglycemia are similar in magnitude to those seen in type 2 diabetes patients receiving secondary prevention with statins - prevention which today is regarded as fundamental by all practitioners. Given all the evidence surrounding the impact of post-prandial glycemia on overall outcome, it is imperative that any considered strategy for the management of type 2 diabetes should include optimum dietary, pharma, and lifestyle interventions that address glucose excursion. Achieving a low post-prandial glucose response is key to prevention and progression of type 2 diabetes and cardiometabolic diseases. Further, such therapeutic interventions should be sustainable and must benefit patients in the short and long term with the minimum of intrusion and side effects. This paper reviews the current literature around dietary manipulation of post-prandial hyperglycemia, including novel approaches. A great deal of further work is required to optimize and standardize the dietary management of post-prandial glycemia in type 2 diabetes, including consideration of novel approaches that show great promise.
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Affiliation(s)
- Lina Shibib
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Mo Al-Qaisi
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Nicola Guess
- Nuffield Department of Primary Care Health Sciences, Oxford University, Oxford, UK
| | | | - Steve E Greenwald
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Marc Pelling
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Ahmed Ahmed
- Department of Surgery and Cancer, Imperial College London, London, UK
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Nielsen ST, Kweka B, Praygod G, Filteau S, Olsen MF, Friis H, Faurholt-Jepsen D, Krogh-Madsen R. The incretin effect in type 2 diabetes in a Sub-Saharan African population. Clin Diabetes Endocrinol 2024; 10:20. [PMID: 39049087 PMCID: PMC11271029 DOI: 10.1186/s40842-024-00178-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 03/01/2024] [Indexed: 07/27/2024] Open
Abstract
AIM Type 2 diabetes is increasing in Sub-Saharan Africa, but the pathophysiology in this population is poorly investigated. In Western populations, the incretin effect is reduced in type 2 diabetes, leading to lowered insulin secretion. The aim of this study was to investigate the incretin effect in a group of Sub-Saharan Africans with type 2 diabetes. METHODS Twenty adults diagnosed with type 2 diabetes, based on either an oral glucose tolerance test (n = 10) or on glycated hemoglobin A1c (n = 10), and 10 non-diabetic controls were included in an interventional study in Tanzania. We investigated the incretin effect as the difference between the plasma insulin area under the curve during an oral glucose tolerance test and that obtained during an intravenous glucose infusion. Differences between diabetes groups were analyzed by Kruskal-Wallis one-way analysis of variance. RESULTS The incretin effect did not differ between groups (p = 0.45), and there was no difference in plasma concentrations of the incretin hormones during the OGTT. CONCLUSION A reduced incretin effect appears not to contribute to hyperglycemia in type 2 diabetes in this Tanzanian population. More research is needed to explain the diabetes phenotype often seen in Sub-Saharan Africa. TRIAL REGISTRATION Clinicaltrials.gov: NCT03106480 , date of registration: 04/10/2017.
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Affiliation(s)
- Signe Tellerup Nielsen
- Department of Anesthesia Surgery and Intensive Care, Copenhagen University Hospital - Herlev, Herlev, Denmark.
- Department of Anesthesiology and Intensive Care, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark.
| | - Belinda Kweka
- National Institute for Medical Research, Mwanza, Tanzania
| | - George Praygod
- National Institute for Medical Research, Mwanza, Tanzania
| | - Suzanne Filteau
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Mette Frahm Olsen
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Henrik Friis
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Daniel Faurholt-Jepsen
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Rikke Krogh-Madsen
- Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
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Liu QK. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol (Lausanne) 2024; 15:1431292. [PMID: 39114288 PMCID: PMC11304055 DOI: 10.3389/fendo.2024.1431292] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.
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Affiliation(s)
- Qiyuan Keith Liu
- MedStar Medical Group, MedStar Montgomery Medical Center, Olney, MD, United States
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Hamasaki A, Harada N, Muraoka A, Yamane S, Joo E, Suzuki K, Inagaki N. The integrated incretin effect is reduced by both glucose intolerance and obesity in Japanese subjects. Front Endocrinol (Lausanne) 2024; 15:1301352. [PMID: 38966210 PMCID: PMC11222327 DOI: 10.3389/fendo.2024.1301352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 03/18/2024] [Indexed: 07/06/2024] Open
Abstract
Introduction Incretin-based drugs are extensively utilized in the treatment of type 2 diabetes (T2D), with remarkable clinical efficacy. These drugs were developed based on findings that the incretin effect is reduced in T2D. The incretin effect in East Asians, whose pancreatic β-cell function is more vulnerable than that in Caucasians, however, has not been fully examined. In this study, we investigated the effects of incretin in Japanese subjects. Methods A total of 28 Japanese subjects (14 with normal glucose tolerance [NGT], 6 with impaired glucose tolerance, and 8 with T2D) were enrolled. Isoglycemic oral (75 g glucose tolerance test) and intravenous glucose were administered. The numerical incretin effect and gastrointestinally-mediated glucose disposal (GIGD) were calculated by measuring the plasma glucose and entero-pancreatic hormone concentrations. Results and discussion The difference in the numerical incretin effect among the groups was relatively small. The numerical incretin effect significantly negatively correlated with the body mass index (BMI). GIGD was significantly lower in participants with T2D than in those with NGT, and significantly negatively correlated with the area under the curve (AUC)-glucose, BMI, and AUC-glucagon. Incretin concentrations did not differ significantly among the groups. We demonstrate that in Japanese subjects, obesity has a greater effect than glucose tolerance on the numerical incretin effect, whereas GIGD is diminished in individuals with both glucose intolerance and obesity. These findings indicate variances as well as commonalities between East Asians and Caucasians in the manifestation of incretin effects on pancreatic β-cell function and the integrated capacity to handle glucose.
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Affiliation(s)
- Akihiro Hamasaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Diabetes and Endocrinology, Medical Research Institute Kitano Hospital, PIIF Tazuke-Kofukai, Osaka, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Muraoka
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Erina Joo
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuyo Suzuki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Rakha A, Rasheed H, Altemimi AB, Tul-Muntaha S, Fatima I, Butt MS, Hussain S, Bhat ZF, Mousavi Khaneghah A, Aadil RM. Tapping the nutraceutical potential of industrial hemp against arthritis and diabetes - A comprehensive review. FOOD BIOSCI 2024; 59:104195. [DOI: 10.1016/j.fbio.2024.104195] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Rangwala HS, Fatima H, Ali M, Mustafa MS, Shafique MA, Rangwala BS, Abbas SR. Evaluating the effectiveness and safety of various Tirzepatide dosages in the management of Type 2 diabetes mellitus: a network meta-analysis of randomized controlled trials. J Diabetes Metab Disord 2024; 23:1199-1222. [PMID: 38932909 PMCID: PMC11196572 DOI: 10.1007/s40200-024-01412-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 02/22/2024] [Indexed: 06/28/2024]
Abstract
Purpose Excess body fat, insulin resistance, and abnormal lipid levels signal type 2 diabetes mellitus (DM2). Globally, 536.6 million people suffer from DM2, projected to rise to 783.2 million by 2045. Obesity fuels insulin resistance and DM2 development, with weight loss significantly improving glycemic control. Titrzepatide (TZP), a dual GIP and GLP-1 receptor agonist, proves highly effective in controlling hyperglycemia, stimulating insulin secretion, and promoting weight loss. TZP, holds promise as a treatment for DM2, surpassing insulin and GLP-1. The study aimed to meticulously assess the safety and efficacy of various doses, offering insights into optimal therapeutic strategies for managing DM2. Methods This study aimed to comprehensively evaluate the safety and efficacy of TZP in treating DM2. The primary focus of the inclusion criteria was on trials comparing TZP with a placebo until November 23, 2023, excluding patients with certain comorbidities. Data extraction included key parameters, and outcomes were assessed for HbA1c levels, weight changes, fasting serum glucose levels, and various adverse events. Quality assessment utilized the Cochrane Collaboration's risk-of-bias tool, and a network meta-analysis explored outcomes across different TZP dosages. Results This meta-analysis systematically reviewed ten studies on TZP for DM2. Results revealed significant reductions in HbA1c with TZP 10 mg (19%) and TZP 15 mg (31%) compared to TZP 5 mg (MD: -0.19 and MD: -0.32, respectively). Additionally, weight reduction was notable for TZP 10 mg (MD: -1.96) and TZP 15 mg (MD: -3.31). Fasting serum glucose showed improvement with TZP 15 mg (MD:-6.71). Gastrointestinal events increased with higher doses, yet without statistical significance. Death, nausea, diarrhea, vomiting, dyspepsia, decreased appetite, injection site reaction, hypoglycemia, treatment discontinuation, and serious adverse events showed no significant differences across doses. Conclusion TZP effectively lowers HbA1c and induces weight loss across its three doses for type 2 diabetes management. The higher dose (15 mg) significantly reduces fasting serum glucose, with increased adverse events observed at higher doses. Dose-specific patterns for adverse effects emphasize the need to balance therapeutic benefits and risks. Further research is crucial for refining clinical applications and understanding TZP's role in DM2 management across doses. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-024-01412-8.
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Affiliation(s)
- Hussain Sohail Rangwala
- Department of Medicine, Jinnah Sindh Medical University, Iqbal Shaheed Rd, Karachi, Pakistan
| | - Hareer Fatima
- Department of Medicine, Jinnah Sindh Medical University, Iqbal Shaheed Rd, Karachi, Pakistan
| | - Mirha Ali
- Department of Medicine, Jinnah Sindh Medical University, Iqbal Shaheed Rd, Karachi, Pakistan
| | | | - Muhammad Ashir Shafique
- Department of Medicine, Jinnah Sindh Medical University, Iqbal Shaheed Rd, Karachi, Pakistan
| | | | - Syed Raza Abbas
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
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Kawaguchi Y, Hajika Y, Rinka M, Masumoto K, Sawa J, Hamazaki K, Kumeda Y. Comparison of efficacy and safety of insulin degludec/liraglutide and insulin glargine U-100/lixisenatide in individuals with type 2 diabetes mellitus using professional continuous glucose monitoring. J Diabetes Investig 2024; 15:598-607. [PMID: 38258482 PMCID: PMC11060164 DOI: 10.1111/jdi.14151] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/22/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
AIM/INTRODUCTION Insulin glargine U100/lixisenatide and insulin degludec/liraglutide are fixed-ratio combinations containing basal insulin and a glucagon-like peptide-1 receptor agonist capable of reducing both fasting and postprandial blood glucose levels with a single formulation. This study aimed to compare the time in range (TIR) and the time below range (TBR) level 1 using professional continuous glucose monitoring and to establish criteria for the differential use of the fixed-ratio combinations. MATERIALS AND METHODS Thirty-six outpatients with type 2 diabetes mellitus (24 men and 12 women; average age, 62.1 years) were randomly assigned to the groups. At 0 and 18 weeks, a device was worn to compare the TIR and TBR level 1. The correlation between the C-peptide index at baseline and TIR at 18 weeks was assessed. RESULTS The TIR and TBR level 1 showed no significant differences between the two groups. Both groups showed significant positive correlations between the C-peptide index and the TIR (P = 0.002, r = 0.679; P = 0.002, r = 0.681, respectively). The changes in glycemic variability, therapeutic indices, and body mass index were not significantly different among the groups (P > 0.05). The receiver operating curve analysis revealed that the cut-off values of the C-peptide index to achieve TIR of >70% at 18 weeks were 1.258 (sensitivity, 77.8%; specificity, 100%) and 1.099 (sensitivity, 57.1%; specificity, 90.9%) in the insulin glargine U100/lixisenatide and insulin degludec/liraglutide groups, respectively. CONCLUSIONS A TIR of >70% was achieved for both fixed-ratio combinations without significant differences.
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Affiliation(s)
- Yuji Kawaguchi
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Yuriko Hajika
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Maho Rinka
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Koji Masumoto
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Jun Sawa
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Kenji Hamazaki
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Yasuro Kumeda
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
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Prajapati A, Rana D, Rangra S, Jindal AB, Benival D. Current Status of Therapeutic Peptides for the Management of Diabetes Mellitus. Int J Pept Res Ther 2024; 30:13. [DOI: 10.1007/s10989-024-10590-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/14/2024] [Indexed: 01/04/2025]
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Szczerbinski L, Florez JC. Precision medicine in diabetes - current trends and future directions. Is the future now? COMPREHENSIVE PRECISION MEDICINE 2024:458-483. [DOI: 10.1016/b978-0-12-824010-6.00021-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Chaiyakul S, Ketkham N, Chaichana C, Khumkhana N, Deekum W, Wongshaya P, Suwanmalai T, Hutchinson C, Pramyothin P. Effects of a novel rice-based diabetes-specific formula on postprandial glucose and gastrointestinal hormones: a double-blinded multi-arm randomized crossover trial. Front Endocrinol (Lausanne) 2023; 14:1141497. [PMID: 37293492 PMCID: PMC10244629 DOI: 10.3389/fendo.2023.1141497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/27/2023] [Indexed: 06/10/2023] Open
Abstract
Introduction We developed a novel rice-based medical food for diabetes (MFDM) powder formula, using locally available ingredients in Thailand, which can potentially improve patient access to diabetes-specific formula (DSF) by reducing cost and improving availability. Purpose The goals of our studies were to 1) measure the glycemic index (GI) and glycemic load (GL) of the MFDM powder formula in healthy individuals, and 2) assess postprandial glucose, insulin, satiety, hunger, and gastrointestinal (GI) hormone responses in adults with prediabetes or early type 2 diabetes after consuming MFDM in comparison with a commercially available standard formula (SF) and a DSF. Methods In Study 1, glycemic responses were assessed using the area under the curve (AUC), which was used to calculate GI and GL. Study 2 was a double-blinded multi-arm randomized crossover trial enrolling participants with either prediabetes or type 2 diabetes of ≤6 years. At each study visit, participants consumed either MFDM, SF, or DSF which contained 25 g of carbohydrates. Hunger and satiety were assessed using a visual analog scale (VAS). Glucose, insulin, and GI hormones were assessed using AUC. Results All participants tolerated the MFDM well with no adverse events. In Study 1, the measured GI was 39 ± 6 (low GI) and GL was 11 ± 2 (medium GL). In Study 2, glucose and insulin responses were significantly lower after MFDM compared with SF (p-value<0.01 for both), however, those responses were similar between MFDM and DSF. MFDM suppressed hunger, promoted satiety, stimulated active GLP-1, GIP, and PYY, and suppressed active ghrelin although these changes were similar to SF and DSF. Conclusions MFDM had a low GI and a low-to-medium GL. In people with prediabetes or early type 2 diabetes, MFDM elicited reduced glucose and insulin responses when compared with SF. Rice-based MFDM may be an option for patients who are at risk for postprandial hyperglycemia. Clinical Trial Registration https://www.thaiclinicaltrials.org/show/TCTR20210731001, identifier TCTR20210731001; https://www.thaiclinicaltrials.org/show/TCTR20210730007, identifier TCTR20210730007.
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Affiliation(s)
- Supat Chaiyakul
- Department of Nutrition, Faculty of Public Health, Mahidol University, Bangkok, Thailand
| | - Narong Ketkham
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chartchai Chaichana
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nanta Khumkhana
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wanjan Deekum
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pakwuan Wongshaya
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Thaniya Suwanmalai
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Carol Hutchinson
- Department of Nutrition, Faculty of Public Health, Mahidol University, Bangkok, Thailand
| | - Pornpoj Pramyothin
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Wibawa IDN, Mariadi IK, Somayana G, Krisnawardani Kumbara CIY, Sindhughosa DA. Diabetes and fatty liver: Involvement of incretin and its benefit for fatty liver management. World J Diabetes 2023; 14:549-559. [PMID: 37273247 PMCID: PMC10237000 DOI: 10.4239/wjd.v14.i5.549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 02/02/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
Fatty liver disease is defined as liver condition characterized by hepatic steatosis, closely related to pathological conditions in type 2 diabetes and obesity. The high prevalence of fatty liver disease in obese patients with type 2 diabetes reached 70%, reflecting the importance of these conditions with fatty liver. Although the exact pathological mechanism of fatty liver disease, specifically non-alcoholic fatty liver disease (NAFLD) remains not completely revealed, insulin resistance is suggested as the major mechanism that bridged the development of NAFLD. Indeed, loss of the incretin effect leads to insulin resistance. Since incretin is closely related to insulin resistance and the resistance of insulin associated with the development of fatty liver disease, this pathway suggested a potential me-chanism that explains the association between type 2 diabetes and NAFLD. Furthermore, recent studies indicated that NAFLD is associated with impaired glucagon-like peptide-1, resulting in decreased incretin effect. Nevertheless, improving the incretin effect becomes a reasonable approach to manage fatty liver disease. This review elucidates the involvement of incretin in fatty liver disease and recent studies of incretin as the management for fatty liver disease.
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Affiliation(s)
- I Dewa Nyoman Wibawa
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | - I Ketut Mariadi
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | - Gde Somayana
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | | | - Dwijo Anargha Sindhughosa
- Internal Medicine Resident, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
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Nauck MA, D'Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol 2022; 21:169. [PMID: 36050763 PMCID: PMC9438179 DOI: 10.1186/s12933-022-01604-7] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/19/2022] [Indexed: 11/29/2022] Open
Abstract
Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1-5) have shown that tirzepatide at 5-15 mg per week reduces both HbA1c (1.24 to 2.58%) and body weight (5.4-11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA1c of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA1c and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.
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Affiliation(s)
- Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Medical Department I, Katholisches Klinikum Bochum gGmbH, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.
| | - David A D'Alessio
- Division of Endocrinology and Metabolism, Department of Medicine, Duke University Medical Center, Durham, NC, 27701, USA
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Dorsey-Trevino EG, Kaur V, Mercader JM, Florez JC, Leong A. Association of GLP1R Polymorphisms With the Incretin Response. J Clin Endocrinol Metab 2022; 107:2580-2588. [PMID: 35723666 PMCID: PMC9387717 DOI: 10.1210/clinem/dgac374] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Polymorphisms in the gene encoding the glucagon-like peptide-1 receptor (GLP1R) are associated with type 2 diabetes but their effects on incretin levels remain unclear. OBJECTIVE We evaluated the physiologic and hormonal effects of GLP1R genotypes before and after interventions that influence glucose physiology. DESIGN Pharmacogenetic study conducted at 3 academic centers in Boston, Massachusetts. PARTICIPANTS A total of 868 antidiabetic drug-naïve participants with type 2 diabetes or at risk for developing diabetes. INTERVENTIONS We analyzed 5 variants within GLP1R (rs761387, rs10305423, rs10305441, rs742762, and rs10305492) and recorded biochemical data during a 5-mg glipizide challenge and a 75-g oral glucose tolerance test (OGTT) following 4 doses of metformin 500 mg over 2 days. MAIN OUTCOMES We used an additive mixed-effects model to evaluate the association of these variants with glucose, insulin, and incretin levels over multiple timepoints during the OGTT. RESULTS During the OGTT, the G-risk allele at rs761387 was associated with higher total GLP-1 (2.61 pmol/L; 95% CI, 1.0.72-4.50), active GLP-1 (2.61 pmol/L; 95% CI, 0.04-5.18), and a trend toward higher glucose (3.63; 95% CI, -0.16 to 7.42 mg/dL) per allele but was not associated with insulin. During the glipizide challenge, the G allele was associated with higher insulin levels per allele (2.01 IU/mL; 95% CI, 0.26-3.76). The other variants were not associated with any of the outcomes tested. CONCLUSIONS GLP1R variation is associated with differences in GLP-1 levels following an OGTT load despite no differences in insulin levels, highlighting altered incretin signaling as a potential mechanism by which GLP1R variation affects T2D risk.
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Affiliation(s)
- Edgar G Dorsey-Trevino
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Varinderpal Kaur
- Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Josep M Mercader
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jose C Florez
- Correspondence: Jose C. Florez, MD, PhD, Endocrine Division and Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, CPZN 5.250, Boston, MA 02114, USA.
| | - Aaron Leong
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Grespan E, Guolo A, Muscelli E, Ferrannini E, Mari A. Loss of the Incretin Effect in Type 2 Diabetes: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab 2022; 107:2092-2100. [PMID: 35397169 DOI: 10.1210/clinem/dgac213] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear. OBJECTIVE To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach. METHODS PubMed, Scopus, and Web-of-Science were searched. Studies measuring IE by the gold-standard protocol employing an oral glucose tolerance test (OGTT) and an intravenous glucose infusion at matched glucose levels were selected. We extracted IE, sex, age, body mass index (BMI), and hemoglobin A1c, fasting values, and area under curve (AUC) of glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). In subjects with T2D, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications. RESULTS The IE weighted mean difference between subjects with T2D and those with normal glucose tolerance (NGT) was -27.3% (CI -36.5% to -18.1%; P < .001; I2 = 86.6%) and was affected by age (P < .005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (P < .05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (P < .0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI 9.2-13.2%; P < .0001; I2 = 28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose. CONCLUSION The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in subjects with T2D only, the OGTT dose is a significant covariate.
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Affiliation(s)
| | - Annamaria Guolo
- Department of Statistical Sciences, University of Padua, Padua, Italy
| | - Elza Muscelli
- Department of Internal Medicine, School of Medical Sciences, State University of Campinas, Campinas, Brazil
| | | | - Andrea Mari
- C.N.R. Institute of Neuroscience, Padua, Italy
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Hu Y, Zhang P, Ding B, Cao X, Zhong Y, Lee KO, Ma JH. Response of blood glucose and GLP-1 to different food temperature in normal subject and patients with type 2 diabetes. Nutr Diabetes 2022; 12:28. [PMID: 35624116 PMCID: PMC9142530 DOI: 10.1038/s41387-022-00208-0] [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: 11/09/2021] [Revised: 05/05/2022] [Accepted: 05/23/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Eating behavior is a major factor in type 2 diabetes. We investigated the different responses of glucose-regulating hormones to cold and hot glucose solutions in normal subjects and patients with type 2 diabetes. METHODS In this crossover, self-controlled study, normal subjects (N = 19) and patients with type 2 diabetes (N = 22) were recruited and randomly assigned to a hot (50 °C) or a cold (8 °C) oral glucose-tolerance test (OGTT). The subsequent day, they were switched to the OGTT at the other temperature. Blood glucose, insulin, GIP, glucagon-like peptide-1 (GLP-1), and cortisol were measured at 0, 5, 10, 30, 60, and 120 min during each OGTT. After the hot OGTT, all subjects ingested hot (>42 °C) food and water for that day, and ingested food and water at room temperature (≤24 °C) for the day after cold OGTT. All participants had continuous glucose monitoring (CGM) throughout the study. RESULTS Compared to cold OGTT, blood glucose was significantly higher with hot OGTT in both groups (both P < 0.05). However, insulin and GLP-1 levels were significantly higher in hot OGTT in normal subjects only (both P < 0.05). The GIP and cortisol responses did not differ with temperature in both groups. CGM showed that normal subjects had significantly higher 24-h mean glucose (MBG) (6.11 ± 0.13 vs. 5.84 ± 0.11 mmol/L, P = 0.021), and standard deviation of MBG with hot meals (0.59 ± 0.06 vs. 0.48 ± 0.05 mmol/L, P = 0.043), T2DM patients had higher MBG only (8.46 ± 0.38 vs. 8.88 ± 0.39 mmol/L, P = 0.022). CONCLUSIONS Food temperature is an important factor in glucose absorption and GLP-1 response. These food temperatures elicited differences are lost in type 2 diabetes.
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Affiliation(s)
- Yun Hu
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Peng Zhang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Bo Ding
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xin Cao
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yi Zhong
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Kok-Onn Lee
- Department of Endocrinology, National university hospital of Singapore, Singapore, Singapore
| | - Jian-Hua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
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Sakornyutthadej N, Mahachoklertwattana P, Chanprasertyothin S, Pongratanakul S, Khlairit P, Poomthavorn P. Beta cell function, incretin hormones, and incretin effect in obese children and adolescents with prediabetes. Pediatr Diabetes 2022; 23:203-211. [PMID: 34913553 DOI: 10.1111/pedi.13303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/04/2021] [Accepted: 12/12/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Defects of incretin hormones and incretin effect may be underlying mechanisms of abnormal glucose metabolism in youth. OBJECTIVE To assess incretin hormone dynamics during an oral glucose tolerance test (OGTT) and incretin effect in obese children with prediabetes in comparison with those with normal glucose tolerance (NGT). METHODS Overweight and obese children were enrolled and classified according to OGTT results as NGT and prediabetes. Insulin sensitivity, insulin secretion, incretin hormone concentrations during OGTT; and incretin effect derived from OGTT and intravenous glucose tolerance test were determined and compared between NGT and prediabetes groups. RESULTS Sixty-three patients (43 NGT and 20 prediabetes) were enrolled. Their median (interquartile range) age was 12.5 (11.1, 13.8) years. Peak glucagon-like peptide-1 (GLP-1) was demonstrated at 30 min during OGTT and was higher in the prediabetes group (49.2 [35.6, 63.6] versus 36.5 [27.6, 44.2] pmol/L, p = 0.009). However, incremental areas under the curves (iAUCs) of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were not different between the two groups. There was no difference in incretin effect between NGT and prediabetes (NGT: 66.5% [60.2%, 77.5%] vs. prediabetes: 70.0% [61.5%, 75.0%], p = 0.645). Incretin effect had positive correlations with iAUCs of both GLP-1 and GIP (GLP-1: r = 0.40, p = 0.004 and GIP: r = 0.37, p = 0.009). CONCLUSIONS Comparing between obese children with prediabetes and NGT, there were no differences in overall incretin hormone changes during OGTT and incretin effect. Incretin effect was positively correlated with iAUCs of GLP-1 and GIP.
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Affiliation(s)
- Natee Sakornyutthadej
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pat Mahachoklertwattana
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Sarunyu Pongratanakul
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Patcharin Khlairit
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Preamrudee Poomthavorn
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Kawaguchi Y, Miyamoto S, Hajika Y, Ashida N, Masumoto K, Sawa J, Hamazaki K, Kumeda Y. Comparisons of efficacy and safety in insulin glargine and lixisenatide plus glulisine combination therapy with multiple daily injection therapy in Japanese patients with type 2 diabetes. J Diabetes Investig 2022; 13:505-514. [PMID: 34551215 PMCID: PMC8902399 DOI: 10.1111/jdi.13677] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 09/08/2021] [Accepted: 09/18/2021] [Indexed: 11/27/2022] Open
Abstract
AIMS/INTRODUCTION Multiple daily injection therapy for early glycemic control in patients with type 2 diabetes mellitus is associated with hypoglycemia and weight gain. This study aimed to compare the efficacy (time in range of glucose level 70-180 mg/dL), safety (time below range level 1 of glucose <70 mg/dL), glycemic variability changes, therapeutic indices, body mass index and titration periods between multiple daily injection and insulin glargine U100 and lixisenatide (iGlarLixi) combination (iGlarLixi + insulin glulisine; injected once daily [evenings]) therapies using intermittent continuous glucose monitoring. MATERIALS AND METHODS A total of 40 hospitalized patients with type 2 diabetes were randomly assigned to the iGlarLixi + insulin glulisine group or the multiple daily injection group. An intermittent continuous glucose monitoring system was attached, and each injection was adjusted to achieve the target glucose level according to the respective titration algorithm. Times in and below the range were analyzed using data collected on days 11-13 of the intermittent continuous glucose monitoring. RESULTS The time in range did not significantly differ between the groups. However, the time below range level 1 was lower in the iGlarLixi + insulin glulisine group (P = 0.047). The changes in glycemic variability, therapeutic indices and body mass index were not significantly different between the groups, although the titration period was significantly shorter in the iGlarLixi + insulin glulisine group (P = 0.033). CONCLUSIONS iGlarLixi + insulin glulisine combination therapy is safe and equally efficacious as multiple daily injection therapy for glycemic control, while avoiding hypoglycemia risk and reducing the number of injections are required.
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Affiliation(s)
- Yuji Kawaguchi
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Shoko Miyamoto
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Yuriko Hajika
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Narumi Ashida
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Koji Masumoto
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Jun Sawa
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Kenji Hamazaki
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
| | - Yasuro Kumeda
- Department of Internal MedicineMinami Osaka HospitalOsakaJapan
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Jonik S, Marchel M, Grabowski M, Opolski G, Mazurek T. Gastrointestinal Incretins-Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) beyond Pleiotropic Physiological Effects Are Involved in Pathophysiology of Atherosclerosis and Coronary Artery Disease-State of the Art. BIOLOGY 2022; 11:biology11020288. [PMID: 35205155 PMCID: PMC8869592 DOI: 10.3390/biology11020288] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 02/06/2023]
Abstract
Simple Summary The presented manuscript contains the most current and extensive summary of the role of the most predominant gastrointestinal hormones—GIP and GLP-1 in the pathophysiology of atherosclerosis and coronary artery disease both in animals and humans. We have described GIP and GLP-1 as (1) expressed in many human tissues, (2) emphasized relationship between GIP and GLP-1 and inflammation, (3) highlighted importance of GIP and GLP-1-dependent pathways in atherosclerosis and coronary artery disease and (4) proved that GIP and GLP-1 could be used as markers of incidence, clinical course and recurrence of coronary artery disease, and related to extent and severity of atherosclerosis and myocardial ischemia. Our initial review may state a cornerstone for the future, however, there are still many unknowns and understatements on this topic. Due to the widespread growing interest for the potential use of incretins in cardiovascular diseases, we think that further research in this direction is desirable. For the future, we would like to recognize GIP and GLP-1 as widely implemented into clinical practice as new biomarkers of atherosclerosis and coronary artery disease. Abstract Coronary artery disease (CAD), which is the manifestation of atherosclerosis in coronary arteries, is the most common single cause of death and is responsible for disabilities of millions of people worldwide. Despite numerous dedicated clinical studies and an enormous effort to develop diagnostic and therapeutic methods, coronary atherosclerosis remains one of the most serious medical problems of the modern world. Hence, new markers are still being sought to identify and manage CAD optimally. Trying to face this problem, we have raised the question of the most predominant gastrointestinal hormones; glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), mainly involved in carbohydrates disorders, could be also used as new markers of incidence, clinical course, and recurrence of CAD and are related to extent and severity of atherosclerosis and myocardial ischemia. We describe GIP and GLP-1 as expressed in many animal and human tissues, known to be connected to inflammation and related to enormous noncardiac and cardiovascular (CV) diseases. In animals, GIP and GLP-1 improve endothelial function and lead to reduced atherosclerotic plaque macrophage infiltration and stabilize atherosclerotic lesions by directly blocking monocyte migration. Moreover, in humans, GIPR activation induces the pro-atherosclerotic factors ET-1 (endothelin-1) and OPN (osteopontin) but also has anti-atherosclerotic effects through secretion of NO (nitric oxide). Furthermore, four large clinical trials showed a significant reduction in composite of CV death, MI, and stroke in long-term follow-up using GLP-1 analogs for DM 2 patients: liraglutide in LEADER, semaglutide in SUSTAIN-6, dulaglutide in REWIND and albiglutide in HARMONY. However, very little is known about GIP metabolism in the acute phase of myocardial ischemia or for stable patients with CAD, which constitutes a direction for future research. This review aims to comprehensively discuss the impact of GIP and GLP-1 on atherosclerosis and CAD and its potential therapeutic implications.
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Effects of Sambiloto (Andrographis paniculata) on GLP-1 and DPP-4 Concentrations between Normal and Prediabetic Subjects: A Crossover Study. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1535703. [PMID: 35075363 PMCID: PMC8783715 DOI: 10.1155/2022/1535703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/04/2021] [Accepted: 12/29/2021] [Indexed: 11/18/2022]
Abstract
Background. The extract of Andrographis paniculata (Burm. F.) Wall. Ex. Nees. (sambiloto) (穿心蓮 chuān xīn lián) has been reported to have an antidiabetic effect on mice models and has been used traditionally in the community. The exact mechanism of sambiloto extract in decreasing plasma glucose is unclear, so we investigated the role of sambiloto extract in the incretin pathway in healthy and prediabetic subjects. Methods. This study was a randomized, placebo-controlled, crossover, double-blind trial. It included 38 people who were healthy and 35 people who had prediabetes. All subjects were randomly assigned to receive either the intervention sambiloto extract or a placebo. All subjects were randomly assigned to receive the first intervention for 14 days. There was a washout period between subsequent interventions. The primary outcome was glucagon-like peptide 1 (GLP-1) concentration, and secondary outcomes were fasting insulin, 2-hour postprandial insulin, homeostasis model assessment of insulin resistance (HOMA-IR), fasting blood glucose, 2-hour postprandial blood glucose, dipeptidyl peptidase-4 (DPP-4), and glycated albumin before and after the intervention. Result. After the intervention, GLP-1 concentration significantly increased in prediabetes by 19.6% compared to the placebo (
). There were no significant differences in the changes of fasting insulin, 2-hour postprandial insulin, HOMA-IR, fasting blood glucose, 2-hour postprandial blood glucose, DPP-4, and glycated albumin levels after the intervention. Sambiloto extract did not inhibit the DPP-4 enzyme in healthy and prediabetic subjects. Conclusion. Sambiloto extract increased GLP-1 concentration without inhibiting the DPP-4 enzyme in prediabetic subjects. This trial is registered with ClinicalTrials.gov (ID: NCT03455049), registered on 6 March 2018—retrospectively registered (https://clinicaltrials.gov/ct2/show/NCT03455049).
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22
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In Vitro and In Vivo Antidiabetic Potential of Monoterpenoids: An Update. MOLECULES (BASEL, SWITZERLAND) 2021; 27:molecules27010182. [PMID: 35011414 PMCID: PMC8746715 DOI: 10.3390/molecules27010182] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/20/2021] [Accepted: 12/25/2021] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM) is a chronic metabolic condition characterized by persistent hyperglycemia due to insufficient insulin levels or insulin resistance. Despite the availability of several oral and injectable hypoglycemic agents, their use is associated with a wide range of side effects. Monoterpenes are compounds extracted from different plants including herbs, vegetables, and fruits and they contribute to their aroma and flavor. Based on their chemical structure, monoterpenes are classified into acyclic, monocyclic, and bicyclic monoterpenes. They have been found to exhibit numerous biological and medicinal effects such as antipruritic, antioxidant, anti-inflammatory, and analgesic activities. Therefore, monoterpenes emerged as promising molecules that can be used therapeutically to treat a vast range of diseases. Additionally, monoterpenes were found to modulate enzymes and proteins that contribute to insulin resistance and other pathological events caused by DM. In this review, we highlight the different mechanisms by which monoterpenes can be used in the pharmacological intervention of DM via the alteration of certain enzymes, proteins, and pathways involved in the pathophysiology of DM. Based on the fact that monoterpenes have multiple mechanisms of action on different targets in in vitro and in vivo studies, they can be considered as lead compounds for developing effective hypoglycemic agents. Incorporating these compounds in clinical trials is needed to investigate their actions in diabetic patients in order to confirm their ability in controlling hyperglycemia.
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Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab 2021; 23 Suppl 3:5-29. [PMID: 34310013 DOI: 10.1111/dom.14496] [Citation(s) in RCA: 191] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 11/27/2022]
Abstract
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.
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Affiliation(s)
- Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Daniel R Quast
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Jakob Wefers
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Andreas F H Pfeiffer
- Charité - Universitätsmedizin Berlin, Klinik für Endokrinologie, Stoffwechsel- und Ernährungsmedizin, Berlin, Germany
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Reed J, Bain S, Kanamarlapudi V. A Review of Current Trends with Type 2 Diabetes Epidemiology, Aetiology, Pathogenesis, Treatments and Future Perspectives. Diabetes Metab Syndr Obes 2021; 14:3567-3602. [PMID: 34413662 PMCID: PMC8369920 DOI: 10.2147/dmso.s319895] [Citation(s) in RCA: 178] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes (T2D), which has currently become a global pandemic, is a metabolic disease largely characterised by impaired insulin secretion and action. Significant progress has been made in understanding T2D aetiology and pathogenesis, which is discussed in this review. Extrapancreatic pathology is also summarised, which demonstrates the highly multifactorial nature of T2D. Glucagon-like peptide (GLP)-1 is an incretin hormone responsible for augmenting insulin secretion from pancreatic beta-cells during the postprandial period. Given that native GLP-1 has a very short half-life, GLP-1 mimetics with a much longer half-life have been developed, which are currently an effective treatment option for T2D by enhancing insulin secretion in patients. Interestingly, there is continual emerging evidence that these therapies alleviate some of the post-diagnosis complications of T2D. Additionally, these therapies have been shown to induce weight loss in patients, suggesting they could be an alternative to bariatric surgery, a procedure associated with numerous complications. Current GLP-1-based therapies all act as orthosteric agonists for the GLP-1 receptor (GLP-1R). Interestingly, it has emerged that GLP-1R also has allosteric binding sites and agonists have been developed for these sites to test their therapeutic potential. Recent studies have also demonstrated the potential of bi- and tri-agonists, which target multiple hormonal receptors including GLP-1R, to more effectively treat T2D. Improved understanding of T2D aetiology/pathogenesis, coupled with the further elucidation of both GLP-1 activity/targets and GLP-1R mechanisms of activation via different agonists, will likely provide better insight into the therapeutic potential of GLP-1-based therapies to treat T2D.
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Affiliation(s)
- Josh Reed
- Institute of Life Science 1, Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - Stephen Bain
- Institute of Life Science 1, Medical School, Swansea University, Swansea, SA2 8PP, UK
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25
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Preventing Diabetes and Atherosclerosis in the Cardiometabolic Syndrome. Curr Atheroscler Rep 2021; 23:16. [PMID: 33686460 DOI: 10.1007/s11883-021-00913-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/11/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Cardiometabolic syndrome is characterized by abdominal adiposity, insulin resistance, hypertension, and dyslipidemia. There is a growing burden of cardiometabolic disease in many parts of the world. This review highlights the critical preventive and therapeutic measures that need to be implemented to reduce the impact of cardiometabolic syndrome on cardiovascular health. RECENT FINDINGS Recent cardiovascular outcome trials demonstrated that newer glucose-lowering medications reduce cardiovascular and renal events in patients with type 2 diabetes mellitus (T2DM). These medications should be considered in patients with T2DM and atherosclerotic cardiovascular disease (ASCVD). These novel drugs may also play a role in primary prevention of cardiovascular disease (CVD) and renal disease in high-risk patients without T2DM. To manage dyslipidemia associated with cardiometabolic syndrome, in addition to lifestyle interventions and statin therapy, ezetimibe, and proprotein convertase subtilisin/Kexin type 9 (PCSK9), inhibitors can be used to reduce the risk of major adverse cardiovascular outcomes (MACE) especially in patients with T2DM and coronary artery disease (CAD). The residual risk of MACE in such a high-risk population can be further mitigated by treatment with an omega-3 fatty acid such as icosapent ethyl. Lifestyle modifications and the use of proven pharmacological therapies are essential for the prevention and progression of diabetes and ASCVD in those with the cardiometabolic syndrome.
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26
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Cho KY, Nomoto H, Nakamura A, Kawata S, Sugawara H, Takeuchi J, Nagai S, Omori K, Tsuchida K, Miya A, Shigesawa I, Tsuchida K, Yanagiya S, Kameda H, Yokoyama H, Taneda S, Kurihara Y, Aoki S, Nishimoto N, Atsumi T, Miyoshi H. Improved time in range and postprandial hyperglycemia with canagliflozin in combination with teneligliptin: Secondary analyses of the CALMER study. J Diabetes Investig 2021; 12:1417-1424. [PMID: 33421309 PMCID: PMC8354497 DOI: 10.1111/jdi.13498] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/19/2020] [Accepted: 01/01/2021] [Indexed: 01/15/2023] Open
Abstract
Aims/Introduction We recently reported the beneficial effect of the combination of sodium–glucose cotransporter 2 inhibitor and dipeptidyl peptidase‐4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. Materials and Methods The CALMER study was a multicenter, open‐label, prospective, randomized, parallel‐group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. Results All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2–82.7%, P < 0.001). The extent of the reduction in time above target range was significantly larger in the COMB group compared with the SWITCH group (−14.8% vs −7.5%, P < 0.01). Area under the curve values for glucose at 120 min after all meal tolerance tests were significantly decreased in the COMB group compared with the SWITCH group (P < 0.05). Conclusions Sodium–glucose cotransporter 2 inhibitor combined with dipeptidyl peptidase‐4 inhibitor improved the quality of glycemic variability and reduced postprandial hyperglycemia compared with each monotherapy.
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Affiliation(s)
- Kyu Yong Cho
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan
| | - Hiroshi Nomoto
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akinobu Nakamura
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shinichiro Kawata
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hajime Sugawara
- Third Department of Internal Medicine, Hokkaido PWFAC Obihiro-Kosei General Hospital, Obihiro, Japan
| | - Jun Takeuchi
- Sapporo Diabetes and Thyroid Clinic, Sapporo, Japan
| | - So Nagai
- Division of Diabetes and Endocrinology, Department of Medicine, Sapporo Medical Center, NTT East Corporation, Sapporo, Japan
| | - Kazuno Omori
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kazuhisa Tsuchida
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Aika Miya
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Ikumi Shigesawa
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Division of Diabetes and Endocrinology, Department of Medicine, Sapporo Medical Center, NTT East Corporation, Sapporo, Japan
| | | | - Shingo Yanagiya
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiraku Kameda
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroki Yokoyama
- Department of Internal Medicine, Jiyugaoka Medical Clinic, Obihiro, Japan
| | - Shinji Taneda
- Diabetes Center, Manda Memorial Hospital, Sapporo, Japan
| | | | | | - Naoki Nishimoto
- Biostatistics Section, Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hideaki Miyoshi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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27
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Kshirsagar V, Thingore C, Juvekar A. Insulin resistance: a connecting link between Alzheimer's disease and metabolic disorder. Metab Brain Dis 2021; 36:67-83. [PMID: 32986168 DOI: 10.1007/s11011-020-00622-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/22/2020] [Indexed: 12/11/2022]
Abstract
Recent evidence suggests that Alzheimer's disease (AD) is closely linked with insulin resistance, as seen in type 2 diabetes mellitus (T2DM). Insulin signaling is impaired in AD brains due to insulin resistance, ultimately resulting in the formation of neurofibrillary tangles (NFTs). AD and T2DM are connected at molecular, clinical, and epidemiological levels making it imperative to understand the contribution of T2DM, and other metabolic disorders, to AD pathogenesis. In this review, we have discussed various modalities involved in the pathogenesis of these two diseases and explained the contributing parameters. Insulin is vital for maintaining glucose homeostasis and it plays an important role in regulating inflammation. Here, we have discussed the roles of various contributing factors like miRNA, leptin hormone, neuroinflammation, metabolic dysfunction, and gangliosides in insulin impairment both in AD and T2DM. Understanding these mechanisms will be a big step forward for making molecular therapies that may help maintain or prevent both AD and T2DM, thus reducing the burden of both these diseases.
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Affiliation(s)
- Viplav Kshirsagar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Near Khalsa college, Matunga, Mumbai, Maharashtra, 400019, India
| | - Chetan Thingore
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Near Khalsa college, Matunga, Mumbai, Maharashtra, 400019, India
| | - Archana Juvekar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Near Khalsa college, Matunga, Mumbai, Maharashtra, 400019, India.
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28
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Broome DT, Pantalone KM, Kashyap SR, Philipson LH. Approach to the Patient with MODY-Monogenic Diabetes. J Clin Endocrinol Metab 2021; 106:237-250. [PMID: 33034350 PMCID: PMC7765647 DOI: 10.1210/clinem/dgaa710] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 10/02/2020] [Indexed: 12/14/2022]
Abstract
UNLABELLED Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants). LEARNING OBJECTIVES Upon completion of this educational activity, participants should be able to. TARGET AUDIENCE This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.
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Affiliation(s)
- David T Broome
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
- Correspondence and Reprint Requests: David T. Broome, MD, Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, 9500 Euclid Avenue, Mail code: F-20, Cleveland, OH 44195, USA. E-mail:
| | - Kevin M Pantalone
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Sangeeta R Kashyap
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Louis H Philipson
- Kovler Diabetes Center, Departments of Medicine and Pediatrics, University of Chicago, Chicago, Illinois
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29
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Liu Q, Garg P, Hasdemir B, Wang L, Tuscano E, Sever E, Keane E, Hernandez AGL, Yuan TZ, Kwan E, Lai J, Szot G, Paruthiyil S, Axelrod F, K. Sato A. Functional GLP-1R antibodies identified from a synthetic GPCR-focused library demonstrate potent blood glucose control. MAbs 2021; 13:1893425. [PMID: 33706686 PMCID: PMC7971233 DOI: 10.1080/19420862.2021.1893425] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 02/04/2021] [Accepted: 02/17/2021] [Indexed: 11/15/2022] Open
Abstract
G protein-coupled receptors (GPCRs) are a group of seven-transmembrane receptor proteins that have proven to be successful drug targets. Antibodies are becoming an increasingly promising modality to target these receptors due to their unique properties, such as exquisite specificity, long half-life, and fewer side effects, and their improved pharmacokinetic and pharmacodynamic profiles compared to peptides and small molecules, which results from their more favorable biodistribution. To date, there are only two US Food and Drug Administration-approved GPCR antibody drugs, namely erenumab and mogamulizumab, and this highlights the challenges encountered in identifying functional antibodies against GPCRs. Utilizing Twist's precision DNA writing technologies, we have created a GPCR-focused phage display library with 1 × 1010 diversity. Specifically, we mined endogenous GPCR binding ligand and peptide sequences and incorporated these binding motifs into the heavy chain complementarity-determining region 3 in a synthetic antibody library. Glucagon-like peptide-1 receptor (GLP-1 R) is a class B GPCR that acts as the receptor for the incretin GLP-1, which is released to regulate insulin levels in response to food intake. GLP-1 R agonists have been widely used to increase insulin secretion to lower blood glucose levels for the treatment of type 1 and type 2 diabetes, whereas GLP-1 R antagonists have applications in the treatment of severe hypoglycemia associated with bariatric surgery and hyperinsulinomic hypoglycemia. Here we present the discovery and creation of both antagonistic and agonistic GLP-1 R antibodies by panning this GPCR-focused phage display library on a GLP-1 R-overexpressing Chinese hamster ovary cell line and demonstrate their in vitro and in vivo functional activity.
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Affiliation(s)
- Qiang Liu
- Twist Biopharma, South San Francisco, CA, USA
| | - Pankaj Garg
- Twist Biopharma, South San Francisco, CA, USA
- Alamar Biosciences, Fremont, CA, USA
| | - Burcu Hasdemir
- Twist Biopharma, South San Francisco, CA, USA
- Catalyst Biosciences, South San Francisco, CA, USA
| | - Linya Wang
- Twist Biopharma, South San Francisco, CA, USA
| | | | - Emily Sever
- Twist Biopharma, South San Francisco, CA, USA
| | - Erica Keane
- Twist Biopharma, South San Francisco, CA, USA
| | | | - Tom Z. Yuan
- Twist Biopharma, South San Francisco, CA, USA
| | - Eric Kwan
- Twist Biopharma, South San Francisco, CA, USA
| | - Joyce Lai
- Twist Biopharma, South San Francisco, CA, USA
| | - Greg Szot
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
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30
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Vitale M, Haxhi J, Cirrito T, Pugliese G. Renal protection with glucagon-like peptide-1 receptor agonists. Curr Opin Pharmacol 2020; 54:91-101. [PMID: 33027748 DOI: 10.1016/j.coph.2020.08.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/31/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023]
Abstract
There is an unmet need for renoprotective drugs for more pronounced reduction of albuminuria beyond that provided by renin-angiotensin system (RAS) blockers and for effective slowdown of eGFR decline independent of albuminuria. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have proven effective in reducing prespecified secondary composite kidney outcomes in cardiovascular outcome trials. However, GLP-1 RAs showed a prevailing anti-albuminuric effect, additional to that of RAS blockers, and a non-significant risk reduction in worsening of kidney function, at variance with sodium-glucose cotransporter 2 inhibitors. Mechanisms underlying renal protection with GLP-1 RAs are porly understood. Though treatment with GLP-1 RAs resulted in better glycaemic, blood pressure and body weight control versus placebo, correction for on-trial changes in these parameters did not significantly affect results. Anti-inflammatory/anti-oxidant effects via intracellular signalling through protein kinase A, natriuretic effect via inhibition of sodium-hydrogen exchanger 3 and reduction of hyperfiltration have been proposed as direct renoprotective effects.
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Affiliation(s)
- Martina Vitale
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Jonida Haxhi
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Tiziana Cirrito
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
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31
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Gabe MBN, van der Velden WJC, Gadgaard S, Smit FX, Hartmann B, Bräuner‐Osborne H, Rosenkilde MM. Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system. Basic Clin Pharmacol Toxicol 2020; 126 Suppl 6:122-132. [PMID: 31299132 PMCID: PMC7317972 DOI: 10.1111/bcpt.13289] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 07/03/2019] [Indexed: 12/21/2022]
Abstract
In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP-1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP-1-based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose. Here, we present an in-depth molecular pharmacological phenotyping of GIPR-[E354Q]. In silico modelling suggested similar interaction of the endogenous agonist GIP(1-42) to [E354Q] as to GIPR wt. This was supported by homologous competition binding in COS-7 cells revealing GIPR wt-like affinities of GIP(1-42) with Kd values of ~2 nmol/L and wt-like agonist association rates (Kon ). In contrast, the dissociation rates (Koff ) were slower, resulting in 25% higher agonist residence time for GIPR-[E354Q]. Moreover, in Gαs signalling (cAMP production) GIP(1-42) was ~2-fold more potent and more efficacious on GIPR-[E354Q] compared to wt with 17.5% higher basal activity. No difference from GIPR wt was found in the recruitment of β-arrestin 2, whereas the agonist-induced internalization rate was 2.1- to 2.3-fold faster for [E354Q]. Together with the previously described impaired recycling of [E354Q], our findings with enhanced signalling and internalization rate possibly explained by an altered ligand-binding kinetics will lead to receptor desensitization and down-regulation. This could explain the long-term functional impairment of the GIP system in bone metabolism and blood sugar maintenance for [E354Q] carriers and may shed light on the desensitization of the insulinotropic action of GIP in patients with T2DM.
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Affiliation(s)
- Maria Buur Nordskov Gabe
- Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Wijnand J. C. van der Velden
- Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Sarina Gadgaard
- Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Florent Xavier Smit
- Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
| | - Hans Bräuner‐Osborne
- Department of Drug Design and Pharmacology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
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Aroda VR, Capehorn MS, Chaykin L, Frias JP, Lausvig NL, Macura S, Lüdemann J, Madsbad S, Rosenstock J, Tabak O, Tadayon S, Bain SC. Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous once-weekly semaglutide: A patient-level, pooled analysis of the SUSTAIN 1-5 trials. Diabetes Obes Metab 2020; 22:303-314. [PMID: 31608552 PMCID: PMC7065219 DOI: 10.1111/dom.13896] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/01/2019] [Accepted: 10/08/2019] [Indexed: 01/09/2023]
Abstract
AIM To evaluate the impact of relevant patient-level characteristics on the efficacy and safety of subcutaneous, once-weekly semaglutide in subjects with type 2 diabetes. MATERIALS AND METHODS Exploratory post hoc analyses of pooled SUSTAIN 1-5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glucose-confirmed symptomatic hypoglycaemia at week 30 with semaglutide (0.5/1.0 mg) across clinically relevant patient subgroups: baseline HbA1c (≤7.5%, >7.5%-8.0%, >8.0%-8.5%, >8.5%-9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta-cell function. RESULTS Mean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (-0.9%, -1.2%,-1.5%, -1.7% and -2.3% [effect of subgroup within treatment: P = 0.247] for semaglutide 0.5 mg, and -1.1%, -1.4%, -1.9%, -2.1% and -2.7% [P = 0.045] for semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%-7.3% and 6.1%-6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (-4.4, -3.9, -3.9, -3.3 and -2.9 kg [P = 0.004], and -6.4, -5.9, -5.2, -4.5 and -4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta-cell function subgroups. Adverse events with semaglutide were consistent with the glucagon-like peptide-1 receptor agonist class, with gastrointestinal events the most common. CONCLUSIONS Semaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics.
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Affiliation(s)
| | | | | | | | | | | | - Jörg Lüdemann
- Diabetes‐Falkensee, Diabetes‐Centre and Centre for Clinical StudiesFalkenseeGermany
| | | | | | - Omur Tabak
- Istanbul Kanuni Sultan Suleyman Education and Research HospitalIstanbulTurkey
| | | | - Stephen C. Bain
- Diabetes Research Unit Cymru, Swansea University Medical SchoolSwanseaUK
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Khan R, Tomas A, Rutter GA. Effects on pancreatic Beta and other Islet cells of the glucose-dependent insulinotropic polypeptide. Peptides 2020; 125:170201. [PMID: 31751656 DOI: 10.1016/j.peptides.2019.170201] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/11/2019] [Accepted: 11/11/2019] [Indexed: 12/13/2022]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin that, in common with glucagon-like peptide-1 (GLP-1), has both insulin releasing and extra-pancreatic glucoregulatory actions. GIP is released in response to glucose or fat absorption and acts on the GIP receptor (GIPR) to potentiate insulin release from pancreatic beta cells. GIP has also been shown to promote beta cell survival and stimulate the release of GLP-1 from islet alpha cells. There is now evidence to suggest that low levels of GIP are secreted from alpha cells and may act in a paracrine manner to prime neighboring beta cells for insulin release. In addition, GIP acts on adipocytes to stimulate fat storage and can exert anorexigenic effects via actions in the hypothalamus. Contrary to GLP-1, the development of effective GIP-based T2D treatments has been hindered by poor bioavailability and attenuation of beta cell responses to GIP in some patients with sub-optimally controlled T2D. Recently, longer-acting GIP agonists that exhibit enzymatic stability, as well as dual GLP-1/GIP agonists which provide simultaneous improvement in glucose and weight control have been generated and successfully tested in animal T2D models. This, together with reports on GIP antagonists that may protect against obesity, has revived the interest on the GIP/GIPR axis as a potential anti-diabetic pathway. In this review, we summarize the known aspects of the effects of GIP on beta and other islet cells and discuss the most recent developments on GIP-based therapeutic agents for the improvement of beta cell function in T2D patients.
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Affiliation(s)
- Rabeet Khan
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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Nauck MA. The rollercoaster history of using physiological and pharmacological properties of incretin hormones to develop diabetes medications with a convincing benefit-risk relationship. Metabolism 2020; 103:154031. [PMID: 31785258 DOI: 10.1016/j.metabol.2019.154031] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 11/15/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital (Ruhr-University Bochum), Gudrunstr. 56, 44791 Bochum, Germany.
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35
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Frost F, Jones GH, Dyce P, Jackson V, Nazareth D, Walshaw MJ. Loss of incretin effect contributes to postprandial hyperglycaemia in cystic fibrosis-related diabetes. Diabet Med 2019; 36:1367-1374. [PMID: 31466128 DOI: 10.1111/dme.14121] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/27/2019] [Indexed: 12/23/2022]
Abstract
AIM To investigate the incretin axis in people with cystic fibrosis. METHODS Adults with cystic fibrosis-related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C-peptide, total and active glucagon-like peptide-1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min. RESULTS Five adults with cystic fibrosis-related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis-related diabetes group (cystic fibrosis-related diabetes vs control group: -6% vs 28%; p=0.03). No hyposecretion of glucagon-like peptide-1 or gastric inhibitory polypeptide was observed; conversely, 60-min incremental area under the curve for total glucagon-like peptide-1 was significantly higher in the cystic fibrosis-related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03] CONCLUSIONS: The incretin effect was lost in cystic fibrosis-related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis-related diabetes.
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Affiliation(s)
- F Frost
- Adult CF Centre, Liverpool Heart and Chest NHS Foundation Trust, Liverpool, UK
- Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
| | - G H Jones
- Adult CF Centre, Liverpool Heart and Chest NHS Foundation Trust, Liverpool, UK
- Royal Liverpool and Broadgreen University NHS Foundation Trust, Liverpool, UK
| | - P Dyce
- Cystic Fibrosis Related Diabetes Service, Liverpool Heart and Chest NHS Foundation Trust, Liverpool, UK
| | - V Jackson
- Cystic Fibrosis Related Diabetes Service, Liverpool Heart and Chest NHS Foundation Trust, Liverpool, UK
| | - D Nazareth
- Adult CF Centre, Liverpool Heart and Chest NHS Foundation Trust, Liverpool, UK
- Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
| | - M J Walshaw
- Adult CF Centre, Liverpool Heart and Chest NHS Foundation Trust, Liverpool, UK
- Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
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Hidayat K, Du X, Shi BM. Milk in the prevention and management of type 2 diabetes: The potential role of milk proteins. Diabetes Metab Res Rev 2019; 35:e3187. [PMID: 31111646 DOI: 10.1002/dmrr.3187] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 03/31/2019] [Accepted: 05/07/2019] [Indexed: 12/17/2022]
Abstract
Globally, diabetes mellitus is not only considered a leading cause of mortality and morbidities but has also created a substantial economic burden. There is growing evidence that foods and their components can be implemented in the prevention and management of type 2 diabetes mellitus (T2DM). Increased dairy consumption has been linked to a lower risk of T2DM. The protective role of dairy foods in the development of T2DM is thought to be largely attributable to dairy nutrients, one of them being dairy protein. There is considerable evidence that milk proteins increase the postprandial insulin response and lower the postprandial blood glucose response in both healthy subjects and patients with T2DM. The exact mechanisms by which milk proteins lower postprandial glucose levels are yet to established; however, the amino acids and bioactive peptides derived from milk proteins are thought to modify a physiological milieu, which includes delayed gastric emptying and the enhancement of incretin and insulin responses, consequently leading to lower postprandial glucose levels. The present review will focus on providing a clear presentation of the potential implementation of milk proteins as a dietary supplement in the prevention and management of T2DM by summarizing the relevant supporting evidence for this particular topic.
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Affiliation(s)
- Khemayanto Hidayat
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuan Du
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Bi-Min Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
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Nolen-Doerr E, Stockman MC, Rizo I. Mechanism of Glucagon-Like Peptide 1 Improvements in Type 2 Diabetes Mellitus and Obesity. Curr Obes Rep 2019; 8:284-291. [PMID: 31124035 DOI: 10.1007/s13679-019-00350-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to emphasize the pivotal role of glucagon-like peptide 1 (GLP-1) in tackling the parallel epidemics of obesity and type 2 diabetes (T2DM). RECENT FINDINGS GLP-1-based therapies and in particular GLP-1 receptor agonists (GLP-1 RA) have proven to be effective in lowering blood glucose and decreasing weight. GLP-1 RA not only mitigate these significant medical burdens but also result in weight loss and weight loss independent factors that decrease cardiovascular disease (CVD) and microvascular complications of T2DM, such as diabetic nephropathy. GLP-1-based therapies are critical for a patient-centered approach in choosing appropriate pharmacotherapy for T2DM and obesity while also taking into consideration comorbidities, such as cardiovascular and chronic kidney diseases.
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Affiliation(s)
- Eric Nolen-Doerr
- Section of Endocrinology, Diabetes, Nutrition, and Weight Management, Boston University School of Medicine and Boston Medical Center, 720 Harrison Avenue, Doctor's Office Building, Suite 8100, Boston, MA, 02118, USA.
| | - Mary-Catherine Stockman
- Section of Endocrinology, Diabetes, Nutrition, and Weight Management, Boston University School of Medicine and Boston Medical Center, 720 Harrison Avenue, Doctor's Office Building, Suite 8100, Boston, MA, 02118, USA.
| | - Ivania Rizo
- Section of Endocrinology, Diabetes, Nutrition, and Weight Management, Boston University School of Medicine and Boston Medical Center, 720 Harrison Avenue, Doctor's Office Building, Suite 8100, Boston, MA, 02118, USA.
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Dogruel H, Balci MK. Development of therapeutic options on type 2 diabetes in years: Glucagon-like peptide-1 receptor agonist’s role intreatment; from the past to future. World J Diabetes 2019; 10:446-453. [PMID: 31523380 PMCID: PMC6715574 DOI: 10.4239/wjd.v10.i8.446] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/13/2019] [Accepted: 07/27/2019] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease characterized by hypergly-cemia. Type 2 diabetes (T2DM) accounting for 90% of cases globally. The worldwide prevalence of DM is rising dramatically over the last decades, from 30 million cases in 1985 to 382 million cases in 2013. It’s estimated that 451 million people had diabetes in 2017. As the pathophysiology was understood over the years, treatment options for diabetes increased. Incretin-based therapy is one of them. Glucagon-like peptide-1 receptor agonist (GLP-1 RA) not only significantly lower glucose level with minimal risk of hypoglycemia but also, they have an important advantage in themanagement of cardiovascular risk and obesity. Thus, we will review here GLP-1 RAsrole in the treatment of diabetes.
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Affiliation(s)
- Hakan Dogruel
- Department of Internal Medicine, Antalya Ataturk State Hospital, Antalya 07040, Turkey
| | - Mustafa Kemal Balci
- Akdeniz University Faculty of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, Antalya 07070, Turkey
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Yoo S, Yang EJ, Koh G. Factors Related to Blood Intact Incretin Levels in Patients with Type 2 Diabetes Mellitus. Diabetes Metab J 2019; 43:495-503. [PMID: 30877705 PMCID: PMC6712231 DOI: 10.4093/dmj.2018.0105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 11/22/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND We performed this study to identify factors related to intact incretin levels in patients with type 2 diabetes mellitus (T2DM). METHODS We cross-sectionally analyzed 336 patients with T2DM. Intact glucagon-like peptide 1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 minutes after ingestion of a standard mixed meal. The differences between 30 and 0 minute iGLP-1 and iGIP levels were indicated as ΔiGLP-1 and ΔiGIP. RESULTS In simple correlation analyses, fasting iGLP-1 was positively correlated with glucose, C-peptide, creatinine, and triglyceride levels, and negatively correlated with estimated glomerular filtration rate. ΔiGLP-1 was positively correlated only with ΔC-peptide levels. Fasting iGIP showed positive correlations with glycosylated hemoglobin (HbA1c) and fasting glucose levels, and negative correlations with ΔC-peptide levels. ΔiGIP was negatively correlated with diabetes duration and HbA1c levels, and positively correlated with Δglucose and ΔC-peptide levels. In multivariate analyses adjusting for age, sex, and covariates, fasting iGLP-1 levels were significantly related to fasting glucose levels, ΔiGLP-1 levels were positively related to ΔC-peptide levels, fasting iGIP levels were related to fasting C-peptide levels, and ΔiGIP levels were positively related to ΔC-peptide and Δglucose levels. CONCLUSION Taken together, intact incretin levels are primarily related to C-peptide and glucose levels. This result suggests that glycemia and insulin secretion are the main factors associated with intact incretin levels in T2DM patients.
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Affiliation(s)
- Soyeon Yoo
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
- Department of Internal Medicine, Jeju National University Hospital, Jeju, Korea
| | - Eun Jin Yang
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
| | - Gwanpyo Koh
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
- Department of Internal Medicine, Jeju National University Hospital, Jeju, Korea.
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de la Monte SM. The Full Spectrum of Alzheimer's Disease Is Rooted in Metabolic Derangements That Drive Type 3 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1128:45-83. [PMID: 31062325 PMCID: PMC9996398 DOI: 10.1007/978-981-13-3540-2_4] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The standard practice in neuropathology is to diagnose Alzheimer's disease (AD) based on the distribution and abundance of neurofibrillary tangles and Aβ deposits. However, other significant abnormalities including neuroinflammation, gliosis, white matter degeneration, non-Aβ microvascular disease, and insulin-related metabolic dysfunction require further study to understand how they could be targeted to more effectively remediate AD. This review addresses non-Aβ and non-pTau AD-associated pathologies, highlighting their major features, roles in neurodegeneration, and etiopathic links to deficits in brain insulin and insulin-like growth factor signaling and cognitive impairment. The discussion delineates why AD with its most characteristic clinical and pathological phenotypic profiles should be regarded as a brain form of diabetes, i.e., type 3 diabetes, and entertains the hypothesis that type 3 diabetes is just one of the categories of insulin resistance diseases that can occur independently or overlap with one or more of the others, including type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease.
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Affiliation(s)
- Suzanne M de la Monte
- Departments of Neurology, Neuropathology, and Neurosurgery, Rhode Island Hospital, and the Alpert Medical School of Brown University, Providence, RI, USA.
- Department of Pathology and Laboratory Medicine, Providence VA Medical Center, Providence, RI, USA.
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Bhattamisra SK, Siang TC, Rong CY, Annan NC, Sean EHY, Xi LW, Lyn OS, Shan LH, Choudhury H, Pandey M, Gorain B. Type-3c Diabetes Mellitus, Diabetes of Exocrine Pancreas - An Update. Curr Diabetes Rev 2019; 15:382-394. [PMID: 30648511 DOI: 10.2174/1573399815666190115145702] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 11/02/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The incidence of diabetes is increasing steeply; the number of diabetics has doubled over the past three decades. Surprisingly, the knowledge of type 3c diabetes mellitus (T3cDM) is still unclear to the researchers, scientist and medical practitioners, leading towards erroneous diagnosis, which is sometimes misdiagnosed as type 1 diabetes mellitus (T1DM), or more frequently type 2 diabetes mellitus (T2DM). This review is aimed to outline recent information on the etiology, pathophysiology, diagnostic procedures, and therapeutic management of T3cDM patients. METHODS The literature related to T3cDM was thoroughly searched from the public domains and reviewed extensively to construct this article. Further, existing literature related to the other forms of diabetes is reviewed for projecting the differences among the different forms of diabetes. Detailed and updated information related to epidemiological evidence, risk factors, symptoms, diagnosis, pathogenesis and management is structured in this review. RESULTS T3cDM is often misdiagnosed as T2DM due to the insufficient knowledge differentiating between T2DM and T3cDM. The pathogenesis of T3cDM is explained which is often linked to the history of chronic pancreatitis, pancreatic cancer. Inflammation, and fibrosis in pancreatic tissue lead to damage both endocrine and exocrine functions, thus leading to insulin/glucagon insufficiency and pancreatic enzyme deficiency. CONCLUSION Future advancements should be accompanied by the establishment of a quick diagnostic tool through the understanding of potential biomarkers of the disease and newer treatments for better control of the diseased condition.
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Affiliation(s)
- Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Tiew Chin Siang
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Chieng Yi Rong
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Naveenya Chetty Annan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Esther Ho Yung Sean
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Lim Wen Xi
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ong Siu Lyn
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Liew Hui Shan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Bapi Gorain
- School of Pharmacy, Taylor's University, 1, Jalan Taylors, 47500 Subang Jaya, Selangor, Malaysia
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Horie I, Haraguchi A, Sako A, Akeshima J, Niri T, Shigeno R, Ito A, Nozaki A, Natsuda S, Akazawa S, Mori Y, Ando T, Kawakami A, Abiru N. Predictive factors of efficacy of combination therapy with basal insulin and liraglutide in type 2 diabetes when switched from longstanding basal-bolus insulin: Association between the responses of β- and α-cells to GLP-1 stimulation and the glycaemic control at 6 months after switching therapy. Diabetes Res Clin Pract 2018; 144:161-170. [PMID: 30194951 DOI: 10.1016/j.diabres.2018.08.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/10/2018] [Accepted: 08/29/2018] [Indexed: 01/15/2023]
Abstract
AIMS To evaluate the glycaemic control of combination therapy with basal insulin and liraglutide, and to explore the factors predictive of efficacy in patients with type 2 diabetes when switched from longstanding basal-bolus insulin therapy. METHODS We studied 41 patients who switched from basal-bolus insulin therapy of more than 3 years to basal insulin/liraglutide combination therapy. Glycaemic control was evaluated at 6 months after switching therapy and used to subdivide the patients into good-responders (HbA1c <7.0% or 1.0% decrease) and poor-responders (the rest of participants). To evaluate the glucose-dependent insulin/glucagon responses without/with liraglutide, a 75-g oral glucose tolerance test (OGTT) was performed twice, before (1st-OGTT) and 2-days after (2nd-OGTT) liraglutide administration. RESULTS Twenty-eight patients (68.3%) were identified as good-responders. No differences were found in baseline characteristics including insulin/glucagon responses during 1st-OGTT between the groups. 2nd-OGTT revealed that paradoxical hyperglucagonemia were significantly improved in both groups, but significant increases in insulin secretory response were observed only in good-responders. Logistic regression analyses revealed that the improvement of the insulin-response during 2nd-OGTT compared to that during 1st-OGTT is associated with the good-responder. CONCLUSIONS Enhancement of glucose-dependent insulin-response under liraglutide administration is a potential predictor of long-term glycaemic control after switching the therapies.
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Affiliation(s)
- Ichiro Horie
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.
| | - Ai Haraguchi
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Ayaka Sako
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Junya Akeshima
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Tetsuro Niri
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Riyoko Shigeno
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Ayako Ito
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Aya Nozaki
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Shoko Natsuda
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Satoru Akazawa
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Yoshitaka Mori
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Takao Ando
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Atsushi Kawakami
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
| | - Norio Abiru
- Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
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Sfairopoulos D, Liatis S, Tigas S, Liberopoulos E. Clinical pharmacology of glucagon-like peptide-1 receptor agonists. Hormones (Athens) 2018; 17:333-350. [PMID: 29949126 DOI: 10.1007/s42000-018-0038-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 05/14/2018] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an important asset in the armamentarium for the treatment of type 2 diabetes mellitus (type 2 DM). Incretin failure is a critical etiopathogenetic feature of type 2 DM, which, if reversed, results in improved glycaemic control. GLP-1 RAs are injectable peptides that resemble the structure and function of endogenous incretin GLP-1, but as they are not deactivated by the dipeptidyl peptidase-4 (DPP-4), their half-life is prolonged compared with native GLP-1. Based on their ability to activate GLP-1 receptor, GLP-1 RAs are classified as short-acting (exenatide twice-daily and lixisenatide once-daily), and long-acting (liraglutide once-daily and the once-weekly formulations of exenatide extended-release, dulaglutide, and albiglutide). Semaglutide, another long-acting, once-weekly GLP-1 RA, was recently approved by the FDA and EMA. Although all of these agents potently reduce haemoglobin A1C (HbA1c), there are unique features and fundamental differences among them related to fasting and postprandial hyperglycaemia reduction, weight loss potency, cardiovascular protection efficacy, and adverse events profile. It is imperative that current evidence be integrated and applied in the context of an individualised patient-centred approach. This should include not only glucose management but also targeting as many as possible of the pathophysiologic mechanisms responsible for type 2 DM development and progression.
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Affiliation(s)
- Dimitrios Sfairopoulos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Str, 45110, Ioannina, Greece
| | - Stavros Liatis
- First Department of Propaedeutic and Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, 10559, Athens, Greece
| | - Stelios Tigas
- Department of Endocrinology, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Evangelos Liberopoulos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Str, 45110, Ioannina, Greece.
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Nasteska D, Hodson DJ. The role of beta cell heterogeneity in islet function and insulin release. J Mol Endocrinol 2018; 61:R43-R60. [PMID: 29661799 PMCID: PMC5976077 DOI: 10.1530/jme-18-0011] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 04/16/2018] [Indexed: 12/15/2022]
Abstract
It is becoming increasingly apparent that not all insulin-secreting beta cells are equal. Subtle differences exist at the transcriptomic and protein expression levels, with repercussions for beta cell survival/proliferation, calcium signalling and insulin release. Notably, beta cell heterogeneity displays plasticity during development, metabolic stress and type 2 diabetes mellitus (T2DM). Thus, heterogeneity or lack thereof may be an important contributor to beta cell failure during T2DM in both rodents and humans. The present review will discuss the molecular and cellular features of beta cell heterogeneity at both the single-cell and islet level, explore how this influences islet function and insulin release and look into the alterations that may occur during obesity and T2DM.
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Affiliation(s)
- Daniela Nasteska
- Institute of Metabolism and Systems Research (IMSR)University of Birmingham, Edgbaston, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
- COMPARE University of Birmingham and University of Nottingham MidlandsBirmingham, UK
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR)University of Birmingham, Edgbaston, UK
- Centre for EndocrinologyDiabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
- COMPARE University of Birmingham and University of Nottingham MidlandsBirmingham, UK
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45
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Kimura T, Obata A, Shimoda M, Hirukawa H, Kanda-Kimura Y, Nogami Y, Kohara K, Nakanishi S, Mune T, Kaku K, Kaneto H. Durability of protective effect of dulaglutide on pancreatic β-cells in diabetic mice: GLP-1 receptor expression is not reduced despite long-term dulaglutide exposure. DIABETES & METABOLISM 2018. [DOI: 10.1016/j.diabet.2017.10.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Geyer MC, Rayner CK, Horowitz M, Couper JJ. Targeting postprandial glycaemia in children with diabetes: Opportunities and challenges. Diabetes Obes Metab 2018; 20:766-774. [PMID: 29072820 DOI: 10.1111/dom.13141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 10/02/2017] [Accepted: 10/21/2017] [Indexed: 02/05/2023]
Abstract
Postprandial glycaemia makes a substantial contribution to overall glycaemic control in diabetes, particularly in patients whose preprandial glycaemia is relatively well controlled and glycated haemoglobin (HbA1c) only modestly elevated. Our review addresses the determinants of postprandial glycaemia and how it may be targeted therapeutically in children with diabetes. Postprandial glycaemia is influenced by preprandial glycaemia, macronutrients and their absorption, insulin delivery and sensitivity, the action of the enteroendocrine system, and the rate of gastric emptying. Contemporary continuous glucose monitoring systems reveal patterns of post prandial glycaemia and allow management to be guided more precisely. Delays in blood glucose determination, insulin delivery and its absorption remain challenges in the rapidly evolving closed loop continuous subcutaneous insulin and glucagon delivery systems developed for children with type 1 diabetes. Augmentation of the incretin system through nutritional preloads or incretin mimetics targets postprandial glycaemia by slowing gastric emptying as well as insulinotropic and glucagonostatic effects. These treatments are of particular relevance to children with type 2 diabetes. Following the development of targeted therapies in adults, postprandial blood glucose control will now be increasingly targeted in the treatment of diabetes in children.
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Affiliation(s)
- Myfanwy C Geyer
- Discipline of Paediatrics, University of Adelaide, Adelaide, Australia
- Department of Endocrinology and Diabetes, Women's and Children's Hospital, Adelaide, Australia
| | - Christopher K Rayner
- Discipline of Medicine, University of Adelaide, Adelaide, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Michael Horowitz
- Discipline of Medicine, University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Jennifer J Couper
- Department of Endocrinology and Diabetes, Women's and Children's Hospital, Adelaide, Australia
- Robinson Research Institute, University of Adelaide, Adelaide, Australia
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47
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Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab 2018; 20 Suppl 1:5-21. [PMID: 29364588 DOI: 10.1111/dom.13129] [Citation(s) in RCA: 513] [Impact Index Per Article: 73.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 10/12/2017] [Indexed: 12/17/2022]
Abstract
Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose-dependent insulinotropic polypeptide) und GLP-1 (glucagon-like peptide-1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP-1, L cells) gut. Together, they are responsible for the incretin effect: a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP-1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP-1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP-1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin-based glucose-lowering medications (GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 or DPP-4). GLP-1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP-1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP-1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux-en-Y gastric bypass). GIP and GLP-1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP-1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high-risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well-characterized physiological effects.
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Affiliation(s)
- Michael A Nauck
- Diabetes Center Bochum-Hattingen, Medical Department I, St. Josef-Hospital, Ruhr-University, Bochum, Germany
| | - Juris J Meier
- Diabetes Center Bochum-Hattingen, Medical Department I, St. Josef-Hospital, Ruhr-University, Bochum, Germany
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48
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Adams E, Genter P, Keefe E, Sandow K, Gray V, Rotter JI, Chen YDI, Ipp E. The GLP-1 response to glucose does not mediate beta and alpha cell dysfunction in Hispanics with abnormal glucose metabolism. Diabetes Res Clin Pract 2018; 135:185-191. [PMID: 29155153 PMCID: PMC5801173 DOI: 10.1016/j.diabres.2017.11.010] [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: 07/12/2017] [Revised: 10/16/2017] [Accepted: 11/10/2017] [Indexed: 10/18/2022]
Abstract
AIMS Glucagon-like peptide-1 (GLP-1) contributes to insulin secretion after meals. Though Hispanics have increased risk for type 2 diabetes mellitus, it is unknown if impaired GLP-1 secretion contributes to this risk. We therefore studied plasma GLP-1 secretion and action in Hispanic adults. METHODS Hispanic (H; n = 31) and non-Hispanic (nH; n = 15) participants underwent an oral glucose tolerance test (OGTT). All participants were categorized by glucose tolerance into four groups: normal glucose tolerant non-Hispanic (NGT-nH; n = 15), normal glucose tolerant Hispanic (NGT-H; n = 12), impaired glucose tolerant Hispanic (IGT-H; n = 11), or newly diagnosed type 2 diabetes mellitus, Hispanic (T2D-H; n = 8). RESULTS Glucose-induced increments in plasma GLP-1 (Δ-GLP-1) were not different in NGT-H and NGT-nH (p = .38), nor amongst Hispanic subgroups with varying degrees of glucose homeostasis (p = .6). In contrast, the insulinogenic index in T2D-H group was lower than the other groups (p = .016). Subjects with abnormal glucose homeostasis (AGH), i.e., T2D-H plus IGT-H, had a diminished glucagon suppression index compared to patients with normal glucose homeostasis (NGT-H plus NGT-nH) (p = .035). CONCLUSIONS GLP-1 responses to glucose were similar in Hispanic and Non-Hispanic NGT. Despite similar glucose-induced Δ-GLP-1, insulin and glucagon responses were abnormal in T2D-H and AGH, respectively. Thus, impaired GLP-1 secretion is unlikely to play a role in islet dysfunction in T2D. Although GLP-1 therapeutics enhance insulin secretion and glucagon suppression, it is likely due to pharmacological amplification of the GLP-1 pathways rather than treatment of hormonal deficiency.
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Affiliation(s)
- Elizabeth Adams
- California State University, Long Beach, CA, United States; Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, United States
| | - Pauline Genter
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, United States.
| | - Emma Keefe
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, United States
| | - Kevin Sandow
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, United States
| | - Virginia Gray
- California State University, Long Beach, CA, United States
| | - Jerome I Rotter
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, United States
| | - Yii-Der Ida Chen
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, United States
| | - Eli Ipp
- Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, United States
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49
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Hiyoshi T, Fujiwara M, Yao Z. Postprandial hyperglycemia and postprandial hypertriglyceridemia in type 2 diabetes. J Biomed Res 2017; 33:1. [PMID: 29089472 PMCID: PMC6352876 DOI: 10.7555/jbr.31.20160164] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 03/23/2017] [Indexed: 12/18/2022] Open
Abstract
Postprandial glucose level is an independent risk factor for cardiovascular disease that exerts effects greater than glucose levels at fasting state, whereas increase in serum triglyceride level, under both fasting and postprandial conditions, contributes to the development of arteriosclerosis. Insulin resistance is a prevailing cause of abnormalities in postabsorptive excursion of blood glucose and postprandial lipid profile. Excess fat deposition renders a vicious cycle of hyperglycemia and hypertriglyceridemia in the postprandial state, and both of which are contributors to atherosclerotic change of vessels especially in patients with type 2 diabetes mellitus. Several therapeutic approaches for ameliorating each of these abnormalities have been attempted, including various antidiabetic agents or new compounds targeting lipid metabolism.
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Affiliation(s)
- Toru Hiyoshi
- . Division of Diabetes and Endocrinology, Department of Internal Medicine, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Mutsunori Fujiwara
- . Division of Diabetes and Endocrinology, Department of Internal Medicine, Japanese Red Cross Medical Center, Tokyo, Japan
- . Department of Laboratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Zemin Yao
- . Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada
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Nakatani Y, Maeda M, Matsumura M, Shimizu R, Banba N, Aso Y, Yasu T, Harasawa H. Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. DIABETES & METABOLISM 2017. [PMID: 28648835 DOI: 10.1016/j.diabet.2017.05.009] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
AIM This study evaluated the effects of a glucagon-like peptide-1 receptor agonist on gastrointestinal (GI) tract motility and residue rates by examining GI transit time and lumen using capsule endoscopy. MATERIAL AND METHODS GI motility and lumen were assessed by capsule endoscopy before and after liraglutide administration in 14 patients with type 2 diabetes mellitus (T2DM). RESULTS Gastric transit time in the group with diabetic neuropathy (DN) was 1:12:36±1:04:30h before liraglutide administration and 0:48:40±0:32:52h after administration (nonsignificant difference, P=0.19). Gastric transit time in the non-DN group was 1:01:30±0:52:59h before administration and 2:33:29±1:37:24h after administration (significant increase, P=0.03). Duodenal and small intestine transit time in the DN group was 4:10:34±0:25:54h before and 6:38:42±3:52:42h after administration (not significant, P=0.09) and, in the non-DN group, 3:51:03±0:53:47h before and 6:45:31±2:41:36h after administration (significant increase, P=0.03). The GI residue rate in the DN group was 32.1±24% before administration and 90.0±9.1% after administration (significant increase, P<0.001), and increased in all patients; in the non-DN group, it was 32.1±35.3% before and 78.3±23.9% after administration (significant increase, P<0.001), and also increased in all patients. CONCLUSION Liraglutide causes delayed gastric emptying and inhibits duodenal and small intestine motility. However, these GI movement-inhibiting effects may be decreased or absent in patients with DN-associated dysautonomia.
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Affiliation(s)
- Y Nakatani
- Department of Diabetes and Endocrinology, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan.
| | - M Maeda
- Department of Gastroenterology, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
| | - M Matsumura
- Department of Endocrinology and Metabolism, Dokkyo Medical University, 880, Kitakobayashi Shimotsugagun Mibumachi, 321-0293 Tochigi, Japan
| | - R Shimizu
- Department of Cardiovascular Medicine, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
| | - N Banba
- Department of Diabetes and Endocrinology, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
| | - Y Aso
- Department of Endocrinology and Metabolism, Dokkyo Medical University, 880, Kitakobayashi Shimotsugagun Mibumachi, 321-0293 Tochigi, Japan
| | - T Yasu
- Department of Cardiovascular Medicine, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
| | - H Harasawa
- Department of Pulmonary Medicine, Dokkyo Medical University Nikko Medical Center, 632, Takatoku Nikkoshi, 321-2593 Tochigi, Japan
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