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Alluri AA, Guntupalli Y, Suvarna SS, Prystupa Y, Khetan SP, Vejandla B, Babu Swathi NL. Incretin-based therapies: advancements, challenges, and future directions in type 2 diabetes management. J Basic Clin Physiol Pharmacol 2025:jbcpp-2025-0031. [PMID: 40150960 DOI: 10.1515/jbcpp-2025-0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025]
Abstract
Incretin-based medicines have considerably impacted the treatment of type 2 diabetes mellitus (T2DM), providing considerable advantages in glycemic regulation, weight control, and cardiovascular results. This narrative review examines progress in incretin medicines, encompassing glucagon-like peptide-1 (GLP-1) receptor agonists, dual-receptor, and triple-receptor agonists, while emphasizing their therapeutic advantages, obstacles, and prospective developments. The examined articles were sourced from databases including PubMed and Google Scholar, concentrating on publications predominantly from 2010 to 2024. Selective foundational papers released before this timeline were incorporated to furnish critical historical context about incretin processes and their discovery. Incretin-based medicines, despite their therapeutic efficacy, encounter hurdles including elevated treatment costs, patient compliance difficulties, and variability in response attributable to genetic and physiological variables. Moreover, there are still deficiencies in comprehending the long-term cardiovascular safety and cancer risks linked to these medicines. Emerging dual- and triple-receptor agonists demonstrate potential in overcoming the shortcomings of conventional GLP-1 receptor agonists, providing enhanced metabolic results and broader uses in intricate disease profiles. Future research must concentrate on economic obstacles, streamlined regimens, customized medicine, the integration of artificial intelligence, patient stratification, as well as the safety and efficacy of incretin-based medicines for holistic management of T2DM.
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Affiliation(s)
- Amruth A Alluri
- Internal Medicine, American University of the Caribbean School of Medicine, Cupecoy, Netherlands
| | - Yashaswi Guntupalli
- Internal Medicine, 28660 Sri Venkateswara Institute of Medical Sciences , Tirupati, Andhra Pradesh, India
| | | | | | | | - Bharath Vejandla
- Internal Medicine, All American Institute of Medical Science, Black River, Jamaica
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Beavers KM, Cortes TM, Foy CM, Dinkla L, Reyes San Martin F, Ard JD, Serra MC, Beavers DP. GLP1Ra-based therapies and DXA-acquired musculoskeletal health outcomes: a focused meta-analysis of placebo-controlled trials. Obesity (Silver Spring) 2025; 33:225-237. [PMID: 39710882 PMCID: PMC11774015 DOI: 10.1002/oby.24172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/13/2024] [Accepted: 09/16/2024] [Indexed: 12/24/2024]
Abstract
OBJECTIVE The objective of this study was to evaluate the effect of glucagon-like peptide-1 receptor agonist (GLP1Ra)-based therapies on change in dual-energy x-ray absorptiometry (DXA)-acquired lean mass (LM) or bone mineral density (BMD). METHODS PubMed and Web of Science were searched from database inception through January 29, 2024, for randomized, placebo-controlled trials reporting on change in DXA-acquired LM or BMD measures associated with 12+ weeks of GLP1Ra-based treatment. Of 2618 articles, 9 trials met prespecified search criteria, with 7 reporting on change in total body LM and 2 reporting on change in BMD. For LM outcomes, a hierarchical Bayesian model was used to estimate treatment mean differences. BMD outcomes were described narratively. RESULTS LM was reported in a total of 659 participants (GLP1Ra-based therapies: n = 419; placebo: n = 240), with follow-up times ranging from mean (SD) 12 to 72 (33.5) weeks. At baseline, participants were aged mean (SD) 41.7 (7.6) years, and 75% were female, with BMI values ranging from 30 to 43 kg/m2. Compared with placebo, GLP1Ra-based treatment was associated with significantly reduced total body weight (-6.9 kg; 95% credible interval [CI]: -10.7 to -3.0). GLP1Ra-based treatment was also associated with significantly reduced LM (-1.9 kg; 95% CI: -3.5 to -0.2). CONCLUSIONS Approximately 30% of body weight lost with GLP1Ra-based therapy is LM. More data are needed assessing BMD outcomes.
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Affiliation(s)
- Kristen M. Beavers
- Department of Internal MedicineWake Forest School of MedicineWinston‐SalemNorth CarolinaUSA
- Department of Health and Exercise ScienceWake Forest UniversityWinston‐SalemNorth CarolinaUSA
| | - Tiffany M. Cortes
- Division of Endocrinology, Department of MedicineUT Health San AntonioSan AntonioTexasUSA
- Sam and Ann Barshop Institute for Longevity and Aging StudiesUT Health San AntonioSan AntonioTexasUSA
- San Antonio Geriatric Research Education and Clinical Center (GRECC)South Texas Veterans Health Care SystemSan AntonioTexasUSA
| | - Colleen M. Foy
- Zachary Smith Reynolds LibraryWake Forest UniversityWinston‐SalemNorth CarolinaUSA
| | - Lauren Dinkla
- Department of Health and Exercise ScienceWake Forest UniversityWinston‐SalemNorth CarolinaUSA
| | | | - Jamy D. Ard
- Department of Epidemiology and PreventionWake Forest School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Monica C. Serra
- Sam and Ann Barshop Institute for Longevity and Aging StudiesUT Health San AntonioSan AntonioTexasUSA
- San Antonio Geriatric Research Education and Clinical Center (GRECC)South Texas Veterans Health Care SystemSan AntonioTexasUSA
- Division of Geriatrics, Gerontology & Palliative MedicineUT Health San AntonioSan AntonioTexasUSA
| | - Daniel P. Beavers
- Department of Statistical SciencesWake Forest UniversityWinston‐SalemNorth CarolinaUSA
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Bin Dayel AF, Alrasheed NM, Alonazi AS, Alamin MA, Al-Mutairi NM, Alateeq RA. Renoprotective effect of liraglutide on diabetic nephropathy by modulation of Krüppel-like transcription factor 5 expression in rats. J Pharm Pharmacol 2024; 76:1563-1571. [PMID: 39403839 DOI: 10.1093/jpp/rgae127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 09/17/2024] [Indexed: 03/22/2025]
Abstract
OBJECTIVES Diabetic nephropathy (DN) is a serious consequence of diabetes that can develop through the lysophosphatidic acid axis. The purpose of this study was to determine whether the antidiabetic drug liraglutide can slow the development of diabetic kidney damage by altering the lysophosphatidic acid axis via KLF5. METHODS Wistar albino rats were divided into nondiabetic and diabetic rats (resulting from an intraperitoneal streptozotocin dose of 30 mg/kg and a high-fat diet). These rats were further divided into four groups: nondiabetic control, liraglutide-treated nondiabetic, diabetic control, and liraglutide-treated diabetic. The nondiabetic and diabetic control groups received normal saline for 42 days, while the liraglutide-treated nondiabetic and diabetic groups received normal saline for 21 days, followed by a subcutaneous dose of liraglutide (200 μg/kg/day) for 21 days. Subsequently, serum levels of DN biomarkers were evaluated, and kidney tissues were histologically examined. The protein expression of PCNA, autotaxin, and KLF5 was detected. KEY FINDINGS Liraglutide treatment in diabetic rats decreased DN biomarkers, histological abnormalities in kidney tissues, and the protein expression of PCNA, autotaxin, and KLF5. CONCLUSION Liraglutide can slow the progression of DN by modulating KLF5-related lysophosphatidic acid axis. Thus, liraglutide may be an effective treatment for preventing or mitigating diabetes-related kidney damage.
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Affiliation(s)
- Anfal F Bin Dayel
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Nouf M Alrasheed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Asma S Alonazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Maha A Alamin
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Nawal M Al-Mutairi
- PharmD Program, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Raghad A Alateeq
- PharmD Program, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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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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Yurtcu E, Keyif B, Yilmaz G, Erkilinc S, Akkaya H, Ozgu-Erdinc AS. The role of incretins in gestational diabetes: a case-control study on the impact of obesity. Diabetol Metab Syndr 2024; 16:248. [PMID: 39420427 PMCID: PMC11487933 DOI: 10.1186/s13098-024-01483-w] [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: 06/07/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND This study aimed to evaluate the role of serum Glucagon-Like Peptide-1 (GLP-1), Glucagon-Like Peptide-2 (GLP-2), and Glucose-Dependent Insulinotropic Polypeptide (GIP) levels in relation to obesity and gestational diabetes mellitus (GDM) in pregnancy. METHODS A case-control study was conducted, including 96 pregnant women with singleton pregnancies who underwent the Oral Glucose Tolerance Test (OGTT) for GDM diagnosis during the 24th-28th weeks of gestation. Blood samples were collected for measuring GLP-1, GLP-2, GIP, and fasting glucose. Statistical analyses included receiver operating characteristic (ROC) curves and correlation analysis. RESULTS Among the 96 women, no significant difference in age was observed between the groups, but Body Mass Index (BMI) was significantly higher in GDM-O (Gestational Diabetes Mellitus-Obese) and non-GDM-O groups (p < 0.001). GLP-1 had an area under the curve (AUC) of 0.666 (95% CI: 0.553-0.778, p = 0.005) for diagnosing GDM. The optimal GLP-1 cutoff was 815.86 ng/mL, with 65% sensitivity and 77% specificity. A significant correlation was found between GLP-2 and GIP (r = 0.289, p = 0.004), but no significant correlations were observed between GLP-1 and other peptides or gestational age (p > 0.05). CONCLUSIONS Impaired secretion of GLP-1, GLP-2, and GIP likely contributes to the pathogenesis of GDM. GLP-1 may serve as a potential biomarker for diagnosing GDM.
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Affiliation(s)
- Engin Yurtcu
- Department of Gynecology and Obstetrics, Faculty of Medicine, Duzce University, Merkez/Düzce, 81620, Turkey.
| | - Betul Keyif
- Department of Gynecology and Obstetrics, Faculty of Medicine, Duzce University, Merkez/Düzce, 81620, Turkey
- Department of Gynecology and Obstetrics, Ankara Bilkent City Hospital, Ankara, Turkey
- Department of Gynecology and Obstetrics, Faculty of Medicine, Izmir Demokrasi University, İzmir, Turkey
| | - Gamze Yilmaz
- Department of Gynecology and Obstetrics, Faculty of Medicine, Duzce University, Merkez/Düzce, 81620, Turkey
- Department of Gynecology and Obstetrics, Ankara Bilkent City Hospital, Ankara, Turkey
- Department of Gynecology and Obstetrics, Faculty of Medicine, Izmir Demokrasi University, İzmir, Turkey
| | - Selcuk Erkilinc
- Department of Gynecology and Obstetrics, Faculty of Medicine, Duzce University, Merkez/Düzce, 81620, Turkey
- Department of Gynecology and Obstetrics, Ankara Bilkent City Hospital, Ankara, Turkey
- Department of Gynecology and Obstetrics, Faculty of Medicine, Izmir Demokrasi University, İzmir, Turkey
| | - Hatice Akkaya
- Department of Obstetrics and Gynecology, University of Health Sciences, Ankara Bilkent City Hospital, Ankara, Turkey
| | - A Seval Ozgu-Erdinc
- Department of Obstetrics and Gynecology, University of Health Sciences, Ankara Bilkent City Hospital, Ankara, Turkey
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Jee W, Cho HS, Kim SW, Bae H, Chung WS, Cho JH, Kim H, Song MY, Jang HJ. Lycium chinense Mill Induces Anti-Obesity and Anti-Diabetic Effects In Vitro and In Vivo. Int J Mol Sci 2024; 25:8572. [PMID: 39201257 PMCID: PMC11354703 DOI: 10.3390/ijms25168572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/31/2024] [Accepted: 08/04/2024] [Indexed: 09/02/2024] Open
Abstract
This study investigated the effects of Lycium chinense Mill (LCM) extract on obesity and diabetes, using both in vitro and high-fat diet (HFD)-induced obesity mouse models. We found that LCM notably enhanced glucagon-like peptide-1 (GLP-1) secretion in NCI-h716 cells from 411.4 ± 10.75 pg/mL to 411.4 ± 10.75 pg/mL compared to NT (78.0 ± 0.67 pg/mL) without causing cytotoxicity, implying the involvement of Protein Kinase A C (PKA C) and AMP-activated protein kinase (AMPK) in its action mechanism. LCM also decreased lipid droplets and lowered the expression of adipogenic and lipogenic indicators, such as Fatty Acid Synthase (FAS), Fatty Acid-Binding Protein 4 (FABP4), and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), indicating the suppression of adipocyte differentiation and lipid accumulation. LCM administration to HFD mice resulted in significant weight loss (41.5 ± 3.3 g) compared to the HFD group (45.1 ± 1.8 g). In addition, improved glucose tolerance and serum lipid profiles demonstrated the ability to counteract obesity-related metabolic issues. Additionally, LCM exhibited hepatoprotective properties by reducing hepatic lipid accumulation and diminishing white adipose tissue mass and adipocyte size, thereby demonstrating its effectiveness against hepatic steatosis and adipocyte hypertrophy. These findings show that LCM can be efficiently used as a natural material to treat obesity and diabetes, providing a new approach for remedial and therapeutic purposes.
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Affiliation(s)
- Wona Jee
- College of Korean Medicine, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (W.J.); (S.W.K.); (H.B.)
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hong-Seok Cho
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seok Woo Kim
- College of Korean Medicine, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (W.J.); (S.W.K.); (H.B.)
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hanbit Bae
- College of Korean Medicine, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (W.J.); (S.W.K.); (H.B.)
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Won-Seok Chung
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae-Heung Cho
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyungsuk Kim
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Mi-Yeon Song
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyeung-Jin Jang
- College of Korean Medicine, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (W.J.); (S.W.K.); (H.B.)
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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Albaghlany RM, Shahsavani MB, Hoshino M, Moosavi-Movahedi AA, Ghasemi Y, Yousefi R. Optimizing expression, purification, structural and functional assessments of a novel dimeric incretin (GLP-1cpGLP-1). Biochimie 2024; 223:133-146. [PMID: 37931794 DOI: 10.1016/j.biochi.2023.10.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/08/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces postprandial glycemic excursions by enhancing insulin secretion. In this study, a new dimeric GLP-1 analogue (GLP-1cpGLP-1) was designed by inserting human insulin C-peptide (CP) in the middle of a dimer of [Gly8] GLP-1 (7-36). Then, the dimeric incretin (GLP-1cpGLP-1) was ligated to human αB-crystallin (αB-Cry) to create a hybrid protein, abbreviated as αB-GLP-1cpGLP-1. The constructed gene was well expressed in the bacterial host system. After specific chemical release from the hybrid protein, the dimeric incretin was purified by size exclusion chromatography (SEC). Finally, the RP-HPLC analysis indicated a purity of >99 % for the dimeric incretin. The secondary structure assessments by various spectroscopic methods, and in silico analysis suggested that the dimeric incretin has α-helical rich structure. The dynamic light scattering (DLS) analysis indicates that our dimeric incretin forms large oligomeric structures. This incretin analogue significantly reduced blood glucose levels in both healthy and diabetic mice while effectively triggering insulin release. The size exclusion HPLC also indicates the interaction of the new incretin analogue with human serum albumin, the main carrier protein in the bloodstream. Consistent with the results obtained from the biological activity assessments, this significant interaction indicates its potential as a viable therapeutic agent with a long-lasting effect. The results of our research represent a significant breakthrough in the successful design of an active incretin dimer capable of effectively controlling blood sugar levels and inducing insulin secretion in the realm of diabetes treatment.
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Affiliation(s)
- Rawayh Muslim Albaghlany
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
| | - Mohammad Bagher Shahsavani
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
| | - Masaru Hoshino
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | | | - Younes Ghasemi
- Department of Pharmaceutical Biotechnology and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, 71345, Iran
| | - Reza Yousefi
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran; Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran.
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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: 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: 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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Skov-Jeppesen K, Christiansen CB, Hansen LS, Windeløv JA, Hedbäck N, Gasbjerg LS, Hindsø M, Svane MS, Madsbad S, Holst JJ, Rosenkilde MM, Hartmann B. Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes. J Clin Endocrinol Metab 2024; 109:1773-1780. [PMID: 38217866 PMCID: PMC11180509 DOI: 10.1210/clinem/dgae022] [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: 05/09/2023] [Revised: 12/11/2023] [Accepted: 01/09/2024] [Indexed: 01/15/2024]
Abstract
CONTEXT Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. OBJECTIVE The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. METHODS We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. RESULTS GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. CONCLUSION Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.
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Affiliation(s)
- Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Charlotte B Christiansen
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Laura S Hansen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Johanne A Windeløv
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Nora Hedbäck
- Department of Endocrinology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Lærke S Gasbjerg
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Morten Hindsø
- Department of Endocrinology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Maria S Svane
- Department of Endocrinology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
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11
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Riemma MA, Mele E, Donniacuo M, Telesca M, Bellocchio G, Castaldo G, Rossi F, De Angelis A, Cappetta D, Urbanek K, Berrino L. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, anti-diabetic drugs in heart failure and cognitive impairment: potential mechanisms of the protective effects. Front Pharmacol 2024; 15:1422740. [PMID: 38948473 PMCID: PMC11212466 DOI: 10.3389/fphar.2024.1422740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 05/21/2024] [Indexed: 07/02/2024] Open
Abstract
Heart failure and cognitive impairment emerge as public health problems that need to be addressed due to the aging global population. The conditions that often coexist are strongly related to advancing age and multimorbidity. Epidemiological evidence indicates that cardiovascular disease and neurodegenerative processes shares similar aspects, in term of prevalence, age distribution, and mortality. Type 2 diabetes increasingly represents a risk factor associated not only to cardiometabolic pathologies but also to neurological conditions. The pathophysiological features of type 2 diabetes and its metabolic complications (hyperglycemia, hyperinsulinemia, and insulin resistance) play a crucial role in the development and progression of both heart failure and cognitive dysfunction. This connection has opened to a potential new strategy, in which new classes of anti-diabetic medications, such as glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, are able to reduce the overall risk of cardiovascular events and neuronal damage, showing additional protective effects beyond glycemic control. The pleiotropic effects of GLP-1R agonists and SGLT2 inhibitors have been extensively investigated. They exert direct and indirect cardioprotective and neuroprotective actions, by reducing inflammation, oxidative stress, ions overload, and restoring insulin signaling. Nonetheless, the specificity of pathways and their contribution has not been fully elucidated, and this underlines the urgency for more comprehensive research.
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Affiliation(s)
- Maria Antonietta Riemma
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Elena Mele
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Maria Donniacuo
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Marialucia Telesca
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Gabriella Bellocchio
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Giuseppe Castaldo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy
- CEINGE-Advanced Biotechnologies, Naples, Italy
| | - Francesco Rossi
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Donato Cappetta
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Konrad Urbanek
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy
- CEINGE-Advanced Biotechnologies, Naples, Italy
| | - Liberato Berrino
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
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12
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Di Giuseppe G, Soldovieri L, Ciccarelli G, Ferraro PM, Quero G, Cinti F, Capece U, Moffa S, Nista EC, Gasbarrini A, Mari A, Alfieri S, Tondolo V, Pontecorvi A, Holst JJ, Giaccari A, Mezza T. Reduced incretin effect precedes diabetes development following duodenopancreatectomy in individuals without diabetes. J Clin Invest 2024; 134:e175133. [PMID: 38470487 PMCID: PMC11014652 DOI: 10.1172/jci175133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2024] Open
Affiliation(s)
- Gianfranco Di Giuseppe
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura Soldovieri
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gea Ciccarelli
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Giuseppe Quero
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Digestive Surgery Unit and
| | - Francesca Cinti
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Umberto Capece
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Simona Moffa
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Enrico Celestino Nista
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Pancreas Unit, CEMAD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Pancreas Unit, CEMAD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Research Council of Italy, Padua, Italy
| | - Sergio Alfieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Digestive Surgery Unit and
| | - Vincenzo Tondolo
- Digestive Surgery Unit, Ospedale Isola Tiberina — Gemelli Isola, Rome, Italy
| | - Alfredo Pontecorvi
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Jens Juul Holst
- Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Andrea Giaccari
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Teresa Mezza
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Pancreas Unit, CEMAD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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13
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Park JH, Jee W, Park SM, Park YR, Kim SW, Bae H, Chung WS, Cho JH, Kim H, Song MY, Jang HJ. Timosaponin A3 Induces Anti-Obesity and Anti-Diabetic Effects In Vitro and In Vivo. Int J Mol Sci 2024; 25:2914. [PMID: 38474161 DOI: 10.3390/ijms25052914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Obesity is a serious global health challenge, closely associated with numerous chronic conditions including type 2 diabetes. Anemarrhena asphodeloides Bunge (AA) known as Jimo has been used to address conditions associated with pathogenic heat such as wasting-thirst in Korean Medicine. Timosaponin A3 (TA3), a natural compound extracted from AA, has demonstrated potential therapeutic effects in various disease models. However, its effects on diabetes and obesity remain largely unexplored. We investigated the anti-obesity and anti-diabetic properties of TA3 using in vitro and in vivo models. TA3 treatment in NCI-H716 cells stimulated the secretion of glucagon-like peptide 1 (GLP-1) through the activation of phosphorylation of protein kinase A catalytic subunit (PKAc) and 5'-AMP-activated protein kinase (AMPK). In 3T3-L1 adipocytes, TA3 effectively inhibited lipid accumulation by regulating adipogenesis and lipogenesis. In a high-fat diet (HFD)-induced mice model, TA3 administration significantly reduced body weight gain and food intake. Furthermore, TA3 improved glucose tolerance, lipid profiles, and mitigated hepatic steatosis in HFD-fed mice. Histological analysis revealed that TA3 reduced the size of white adipocytes and inhibited adipose tissue generation. Notably, TA3 downregulated the expression of lipogenic factor, including fatty-acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP1c), emphasizing its potential as an anti-obesity agent. These findings revealed that TA3 may be efficiently used as a natural compound for tackling obesity, diabetes, and associated metabolic disorders, providing a novel approach for therapeutic intervention.
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Affiliation(s)
- Ji-Hyuk Park
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Wona Jee
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - So-Mi Park
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Ye-Rin Park
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Seok Woo Kim
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Hanbit Bae
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Won-Suk Chung
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae-Heung Cho
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyungsuk Kim
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Mi-Yeon Song
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyeung-Jin Jang
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
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14
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Fernandes MF, Aristizabal-Henao JJ, Marvyn PM, M'Hiri I, Wiens MA, Hoang M, Sebastian M, Nachbar R, St-Pierre P, Diaguarachchige De Silva K, Wood GA, Joseph JW, Doucette CA, Marette A, Stark KD, Duncan RE. Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity. Mol Metab 2024; 81:101887. [PMID: 38280449 PMCID: PMC10850971 DOI: 10.1016/j.molmet.2024.101887] [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: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 01/29/2024] Open
Abstract
OBJECTIVE Lipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. METHODS Male and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10-12 and 16-18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. RESULTS All groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. CONCLUSIONS TAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.
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Affiliation(s)
- Maria F Fernandes
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | | | - Phillip M Marvyn
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | - Iman M'Hiri
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | - Meghan A Wiens
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | - Monica Hoang
- School of Pharmacy, University of Waterloo, Ontario, Canada
| | - Manuel Sebastian
- Max Rady College of Medicine, University of Manitoba, Manitoba, Canada
| | - Renato Nachbar
- Québec Heart and Lung Institute, Department of Medicine, Laval University, Québec, Canada
| | - Philippe St-Pierre
- Québec Heart and Lung Institute, Department of Medicine, Laval University, Québec, Canada
| | | | - Geoffrey A Wood
- Ontario Veterinary College, University of Guelph, Ontario, Canada
| | - Jamie W Joseph
- School of Pharmacy, University of Waterloo, Ontario, Canada
| | | | - André Marette
- Québec Heart and Lung Institute, Department of Medicine, Laval University, Québec, Canada
| | - Ken D Stark
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | - Robin E Duncan
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada.
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15
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Ashcroft SP, Stocks B, Egan B, Zierath JR. Exercise induces tissue-specific adaptations to enhance cardiometabolic health. Cell Metab 2024; 36:278-300. [PMID: 38183980 DOI: 10.1016/j.cmet.2023.12.008] [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: 07/06/2023] [Revised: 10/06/2023] [Accepted: 12/05/2023] [Indexed: 01/08/2024]
Abstract
The risk associated with multiple cancers, cardiovascular disease, diabetes, and all-cause mortality is decreased in individuals who meet the current recommendations for physical activity. Therefore, regular exercise remains a cornerstone in the prevention and treatment of non-communicable diseases. An acute bout of exercise results in the coordinated interaction between multiple tissues to meet the increased energy demand of exercise. Over time, the associated metabolic stress of each individual exercise bout provides the basis for long-term adaptations across tissues, including the cardiovascular system, skeletal muscle, adipose tissue, liver, pancreas, gut, and brain. Therefore, regular exercise is associated with a plethora of benefits throughout the whole body, including improved cardiorespiratory fitness, physical function, and glycemic control. Overall, we summarize the exercise-induced adaptations that occur within multiple tissues and how they converge to ultimately improve cardiometabolic health.
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Affiliation(s)
- Stephen P Ashcroft
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ben Stocks
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Brendan Egan
- School of Health and Human Performance, Dublin City University, Dublin, Ireland
| | - Juleen R Zierath
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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16
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Subramanian V, Bagger JI, Harihar V, Holst JJ, Knop FK, Villsbøll T. An extended minimal model of OGTT: estimation of α- and β-cell dysfunction, insulin resistance, and the incretin effect. Am J Physiol Endocrinol Metab 2024; 326:E182-E205. [PMID: 38088864 PMCID: PMC11193523 DOI: 10.1152/ajpendo.00278.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/27/2023] [Accepted: 12/07/2023] [Indexed: 12/20/2023]
Abstract
Loss of insulin sensitivity, α- and β-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here, we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from eight individuals with T2D and eight weight-matched controls (CS) without diabetes to obtain parameters related to insulin sensitivity, β- and α-cell function. The parameters, i.e., measures of insulin sensitivity, a1, suppression of glucagon secretion, k1, magnitude of glucagon secretion, γ2, and incretin-dependent insulin secretion, γ3, were found to be different between CS and T2D with P values < 0.002, <0.017, <0.009, <0.004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman rank test correlation coefficient of 0.67 (P < 0.012). The average incretin effect was found to be different between CS and T2D (P < 0.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.NEW & NOTEWORTHY A new extended model of oral glucose tolerance test (OGTT) has been developed that includes glucagon dynamics and incretin contribution to insulin secretion. The model allows the estimation of parameters related to α- and β-cell dysfunction, insulin sensitivity, and incretin action. A new function describing the influx of glucose from the gut has been introduced. A new rubric for estimating the incretin effect directly from the OGTT experiment has been developed. The effect of glucose dose was also investigated.
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Affiliation(s)
- Vijaya Subramanian
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States
| | - Jonatan I Bagger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Vinayak Harihar
- Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, United States
- Biophysics Graduate Group, University of California, Berkeley, California, United States
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Villsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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17
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Foghsgaard S, Vedtofte L, Andersen ES, Bahne E, Andreasen C, Sørensen AL, Forman JL, Mathiesen ER, Svare JA, Clausen TD, Damm P, Holst JJ, Knop FK, Vilsbøll T. Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial. Diabetes Obes Metab 2024; 26:201-214. [PMID: 37846555 DOI: 10.1111/dom.15306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/18/2023] [Accepted: 09/18/2023] [Indexed: 10/18/2023]
Abstract
AIM We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.
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Affiliation(s)
- Signe Foghsgaard
- Clinical Research, Steno Diabetes Center Copenhagen, University of Copenhagen, Herlev, Denmark
- Department of Gynaecology and Obstetrics, Herlev Hospital, University of Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Louise Vedtofte
- Clinical Research, Steno Diabetes Center Copenhagen, University of Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Emilie S Andersen
- Clinical Research, Steno Diabetes Center Copenhagen, University of Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Emilie Bahne
- Clinical Research, Steno Diabetes Center Copenhagen, University of Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Camilla Andreasen
- Clinical Research, Steno Diabetes Center Copenhagen, University of Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Anne L Sørensen
- Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Julie L Forman
- Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Elisabeth R Mathiesen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Pregnant Women with Diabetes, Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens A Svare
- Department of Gynaecology and Obstetrics, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Tine D Clausen
- Center for Pregnant Women with Diabetes, Department of Obstetrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Peter Damm
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Pregnant Women with Diabetes, Department of Obstetrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Clinical Research, Steno Diabetes Center Copenhagen, University of Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Clinical Research, Steno Diabetes Center Copenhagen, University of Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Engin A. Endothelial Dysfunction in Obesity and Therapeutic Targets. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:489-538. [PMID: 39287863 DOI: 10.1007/978-3-031-63657-8_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter β, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Barakat G, Assi G, Khalil H, El Khatib S. A Comprehensive Review on GLP-1 Signaling Pathways in the Management of Diabetes Mellitus - Focus on the Potential Role of GLP-1 Receptors Agonists and Selenium among Various Organ Systems. Curr Diabetes Rev 2024; 21:e160424228945. [PMID: 38629376 DOI: 10.2174/0115733998287178240403055901] [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: 10/13/2023] [Revised: 02/20/2024] [Accepted: 03/10/2024] [Indexed: 10/30/2024]
Abstract
Diabetes Mellitus develops when the body becomes unable to fuel its cells with glucose, which results in the accumulation of sugar excess in the bloodstream. Because it has diverse pathophysiological impacts on the body, diabetes mellitus represents a significant issue of concern in an attempt to find suitable treatment modalities and medications for afflicted diabetic patients. Glucagon-like peptide 1 (GLP-1) plays a pivotal role in the incretin effect, emerging as a prospective treatment for diabetes mellitus and a promising means of regenerating pancreatic cells, whether directly or through its receptor agonists. It has been shown that GLP-1 efficiently increases insulin production, lowers blood sugar levels in patients with type 2 diabetes mellitus, and decreases appetite, craving, and hunger, therefore amplifying the sensation of fullness and satiety. Moreover, since they are all dependent on GLP-1 effect, intricate signaling pathways share some similarities during specific phases, although the pathways continue to exhibit significant divergence engendered by specific reactions and effects in each organ, which encompasses the rationale behind observed differences. This triggers an expanding range of GLP-1 R agonists, creating new unforeseen research and therapeutic application prospects. This review aims to explain the incretin effect, discuss how GLP-1 regulates blood glucose levels, and how it affects different body organs, as well as how it transmits signals, before introducing selenium's role in the incretin impact.
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Affiliation(s)
- Ghinwa Barakat
- Department of Biological and Chemical Sciences, School of Arts and Sciences, Lebanese International University, Beirut, Lebanon
| | - Ghaith Assi
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon
| | - Hussein Khalil
- Department of Biological and Chemical Sciences, School of Arts and Sciences, Lebanese International University, Beirut, Lebanon
| | - Sami El Khatib
- Department of Biomedical Sciences, School of Arts and Sciences, Lebanese International University, Bekaa, Lebanon
- Center for Applied Mathematics and Bioinformatics (CAMB), Gulf University for Science and Technology (GUST), Mubarak Al-Abdullah, Kuwait
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20
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Meling S, Tjora E, Eichele H, Nedergaard RB, Knop FK, Ejskjaer N, Carlsen S, Njølstad PR, Brock C, Søfteland E. Rectal sensitivity correlated with gastrointestinal-mediated glucose disposal, but not the incretin effect. Endocrinol Diabetes Metab 2024; 7:e463. [PMID: 38059537 PMCID: PMC10782140 DOI: 10.1002/edm2.463] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/08/2023] [Accepted: 11/19/2023] [Indexed: 12/08/2023] Open
Abstract
OBJECTIVE The mechanisms behind the diminished incretin effect in type 2 diabetes are uncertain, but impaired vagal transmission has been suggested. We aimed to investigate the association between the incretin effect and autonomic neuropathy, and the degree of dysglycaemia and duration of diabetes. DESIGN AND METHODS For a cross-sectional study, we included participants with either longstanding type 2 diabetes, recent onset, untreated diabetes and controls without diabetes matched for age, sex and body mass index. Autonomic nerve function was assessed with cardiovascular reflex tests, heart rate variability and sudomotor function. Visceral afferent nerves in the gut were tested performing rapid rectal balloon distention. An oral glucose tolerance test and an intravenous isoglycaemic glucose infusion were performed to calculate the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). RESULTS Sixty-five participants were recruited. Participants with diabetes had rectal hyposensitivity for earliest sensation (3.7 ± 1.1 kPa in longstanding, 4.0 ± 1.3 in early), compared to controls (3.0 ± 0.9 kPa), p = .005. Rectal hyposensitivity for earliest sensation was not associated with the incretin effect (rho = -0.204, p = .106), but an association was found with GIGD (rho -0.341, p = .005). Incretin effect and GIGD were correlated with all glucose values, HbA1c and duration of diabetes. CONCLUSIONS Rectal hyposensitivity was uncovered in both longstanding and early type 2 diabetes, and was not associated with the incretin effect, but with GIGD, implying a potential link between visceral neuropathy and gastrointestinal handling of glucose. Both the incretin effect and GIGD were associated with the degree of dysglycaemia and the duration of diabetes. PREVIOUSLY PUBLISHED Some of the data have previously been published and presented as a poster on the American Diabetes Association 83rd Scientific Sessions: Meling et al; 1658-P: Rectal Hyposensitivity, a Potential Marker of Enteric Autonomic Nerve Dysfunction, Is Significantly Associated with Gastrointestinally Mediated Glucose Disposal in Persons with Type 2 Diabetes. Diabetes 20 June 2023; 72 (Supplement_1): 1658-P. https://doi.org/10.2337/db23-1658-P.
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Affiliation(s)
- Sondre Meling
- Department of MedicineStavanger University HospitalStavangerNorway
- Department of Clinical ScienceUniversity of BergenBergenNorway
| | - Erling Tjora
- Department of Clinical ScienceUniversity of BergenBergenNorway
- Children and Youth ClinicHaukeland University HospitalBergenNorway
| | - Heike Eichele
- Department of Biological and Medical Psychology, Faculty of PsychologyUniversity of BergenBergenNorway
- Regional resource Centre for Autism, ADHD and Tourette Syndrome Western Norway, Division of PsychiatryHaukeland University HospitalBergenNorway
| | - Rasmus B. Nedergaard
- Mech‐Sense, Department of Gastroenterology and HepatologyAalborg University HospitalAalborgDenmark
| | - Filip K. Knop
- Center for Clinical Metabolic ResearchCopenhagen University Hospital—Herlev and GentofteCopenhagenDenmark
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Steno Diabetes Center CopenhagenGentofteDenmark
- Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
| | - Niels Ejskjaer
- Department of Clinical Medicine, Faculty of MedicineAalborg University HospitalAalborgDenmark
- Steno Diabetes Center North DenmarkAalborg University HospitalAalborgDenmark
- Department of EndocrinologyAalborg University HospitalAalborgDenmark
| | - Siri Carlsen
- Department of MedicineStavanger University HospitalStavangerNorway
| | - Pål R. Njølstad
- Department of Clinical ScienceUniversity of BergenBergenNorway
- Children and Youth ClinicHaukeland University HospitalBergenNorway
- Mohn Center for Diabetes Precision Medicine, Department of Clinical ScienceUniversity of BergenBergenNorway
| | - Christina Brock
- Mech‐Sense, Department of Gastroenterology and HepatologyAalborg University HospitalAalborgDenmark
- Department of Clinical Medicine, Faculty of MedicineAalborg University HospitalAalborgDenmark
- Steno Diabetes Center North DenmarkAalborg University HospitalAalborgDenmark
| | - Eirik Søfteland
- Department of Clinical ScienceUniversity of BergenBergenNorway
- Department of MedicineHaukeland University HospitalBergenNorway
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21
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Bahari H, Ashtary-Larky D, Goudarzi K, Mirmohammadali SN, Asbaghi O, Hosseini Kolbadi KS, Naderian M, Hosseini A. The effects of pomegranate consumption on glycemic indices in adults: A systematic review and meta-analysis. Diabetes Metab Syndr 2024; 18:102940. [PMID: 38194826 DOI: 10.1016/j.dsx.2024.102940] [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: 05/27/2023] [Revised: 09/16/2023] [Accepted: 01/01/2024] [Indexed: 01/11/2024]
Abstract
BACKGROUND AND AIM Epidemiologic studies have shown that type 2 diabetes (T2D) is more prevalent worldwide; therefore, improving glycemic indices to prevent or control T2D is vital. Randomized controlled trials (RCTs) on the effects of pomegranate consumption on glycemic indices have shown inconsistent results. Therefore, we aim to evaluate the impact of pomegranate consumption on fasting blood glucose (FBG), fasting insulin, hemoglobin A1c (HbA1c), and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) in adults. METHODS A systematic literature search was performed using electronic databases, including PubMed, Web of Science, and Scopus, up to May 2023 to identify eligible RCTs evaluating the effect of pomegranate consumption on glycemic indices. Heterogeneity tests of the included trials were performed using the I2 statistic. Random effects models were assessed based on the heterogeneity tests, and pooled data were determined as the weighted mean difference with a 95 % confidence interval. RESULTS Of 1999 records, 32 eligible RCTs were included in the current study. Our meta-analysis of the pooled findings showed that pomegranate consumption significantly reduced FBG (WMD: -2.22 mg/dL; 95 % CI: -3.95 to -0.50; p = 0.012), fasting insulin (WMD: -1.06 μU/ml; 95%CI: -1.79 to -0.33; p = 0.004), HbA1c (WMD: -0.22 %; 95% CI: -0.43 to -0.01; p = 0.037), and HOMA-IR (WMD: -0.30; 95%CI: -0.61 to -0.00; p = 0.046). CONCLUSION Overall, the results demonstrated that pomegranate consumption benefits glycemic indices in adults. However, further research with long-term interventions is required. PROSPERO REGISTRATION CODE CRD42023422780.
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Affiliation(s)
- Hossein Bahari
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Damoon Ashtary-Larky
- Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Kian Goudarzi
- Faculty of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran.
| | | | - Omid Asbaghi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | | | - Moslem Naderian
- Department of Pharmacognosy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Ali Hosseini
- Department of Pharmacognosy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Wang QY, Zhang W, Zhao Y, Chen HL, Liu Q, Wang ZH, Zeng LT, Li J, Chen SJ, Wei L, Iwakuma T, Cai JP. Colonic L-cell impairment in aged subjects with type 2 diabetes leads to diminished GLP-1 production. Diabetes Metab Syndr 2023; 17:102907. [PMID: 37980723 DOI: 10.1016/j.dsx.2023.102907] [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: 08/09/2023] [Revised: 10/27/2023] [Accepted: 11/08/2023] [Indexed: 11/21/2023]
Abstract
AIMS Glucagon-like peptide 1 (GLP-1) is produced by the L subtype of enteroendocrine cells (EECs). Patients with type 2 diabetes (T2D) exhibit reduced incretin effect, but the pathophysiology and functional change of the L-cells remain unclear. Deciphering the mechanisms of the biological changes in L-cells under T2D conditions may assist in the research of gut-based strategies for T2D therapy. METHODS We investigated the fasting serum GLP-1 levels and the distribution of colonic L-cells in young and aged participants with and without T2D. Additionally, we established an aged male T2D Wistar rat model subjected to a long-term high-fat and high-fructose (HFHF) diet. Histological investigations and single-cell RNA sequencing (scRNA-seq) analyses were performed to explore the mechanisms underlying functional changes in the colonic EECs. RESULTS We observed a decline in circulating GLP-1 levels and a reduced number of colonic L-cells in elderly patients with T2D. The mechanisms underlying impaired L-cell formation and disturbed GLP-1 production were revealed using aged T2D rats induced by a long-term HFHF diet. The scRNA-seq results showed that the transcription factors that regulate L-cell commitment, such as Foxa1, were downregulated, and the expression of genes that participate in encoding GLP-1, GLP-1 posttranslational processing, hormone secretion, and nutrient sensing was disturbed. CONCLUSIONS Taken together, the reduced L-cell lineage commitment and disturbed L-cell functions might be the major cause of the reduced GLP-1 production in aged populations with T2D. Our study provides new insights for identifying novel targets in colonic L-cells for improving endogenous GLP-1 production.
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Affiliation(s)
- Qing-Yu Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Wei Zhang
- Department of Pathology, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yue Zhao
- Clinical Laboratory, The Second Hospital of Shanxi Medical University, Taiyuan, 030000, China
| | - Hui-Lian Chen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Qian Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zi-Hui Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Lv-Tao Zeng
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jin Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Si-Jie Chen
- MOE Key Lab of Bioinformatics, Bioinformatics Division of BNRIST and Department of Automation, Tsinghua University, Beijing, 100084, China
| | - Lei Wei
- MOE Key Lab of Bioinformatics, Bioinformatics Division of BNRIST and Department of Automation, Tsinghua University, Beijing, 100084, China
| | - Tomoo Iwakuma
- Children's Mercy Research Institute, Kansas City, MO, 64108, USA
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
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Bany Bakar R, Reimann F, Gribble FM. The intestine as an endocrine organ and the role of gut hormones in metabolic regulation. Nat Rev Gastroenterol Hepatol 2023; 20:784-796. [PMID: 37626258 DOI: 10.1038/s41575-023-00830-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2023] [Indexed: 08/27/2023]
Abstract
Gut hormones orchestrate pivotal physiological processes in multiple metabolically active tissues, including the pancreas, liver, adipose tissue, gut and central nervous system, making them attractive therapeutic targets in the treatment of obesity and type 2 diabetes mellitus. Most gut hormones are derived from enteroendocrine cells, but bioactive peptides that are derived from other intestinal epithelial cell types have also been implicated in metabolic regulation and can be considered gut hormones. A deeper understanding of the complex inter-organ crosstalk mediated by the intestinal endocrine system is a prerequisite for designing more effective drugs that are based on or target gut hormones and their receptors, and extending their therapeutic potential beyond obesity and diabetes mellitus. In this Review, we present an overview of gut hormones that are involved in the regulation of metabolism and discuss their action in the gastrointestinal system and beyond.
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Affiliation(s)
- Rula Bany Bakar
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Frank Reimann
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Fiona M Gribble
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
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24
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Zhang J, Zheng Y, Martens L, Pfeiffer AFH. The Regulation and Secretion of Glucagon in Response to Nutrient Composition: Unraveling Their Intricate Mechanisms. Nutrients 2023; 15:3913. [PMID: 37764697 PMCID: PMC10536047 DOI: 10.3390/nu15183913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/31/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Glucagon was initially regarded as a hyperglycemic substance; however, recent research has revealed its broader role in metabolism, encompassing effects on glucose, amino acids (AAs), and lipid metabolism. Notably, the interplay of glucagon with nutrient intake, particularly of AAs, and non-nutrient components is central to its secretion. Fasting and postprandial hyperglucagonemia have long been linked to the development and progression of type 2 diabetes (T2DM). However, recent studies have brought to light the positive impact of glucagon agonists on lipid metabolism and energy homeostasis. This review explores the multifaceted actions of glucagon, focusing on its regulation, signaling pathways, and effects on glucose, AAs, and lipid metabolism. The interplay between glucagon and other hormones, including insulin and incretins, is examined to provide a mechanistic understanding of its functions. Notably, the liver-α-cell axis, which involves glucagon and amino acids, emerges as a critical aspect of metabolic regulation. The dysregulation of glucagon secretion and its impact on conditions such as T2DM are discussed. The review highlights the potential therapeutic applications of targeting the glucagon pathway in the treatment of metabolic disorders.
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Affiliation(s)
- Jiudan Zhang
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310053, China;
- Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (L.M.); (A.F.H.P.)
| | - Yang Zheng
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310053, China;
| | - Lisa Martens
- Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (L.M.); (A.F.H.P.)
- Nutritional Science, University of Potsdam, 14469 Potsdam, Germany
| | - Andreas F. H. Pfeiffer
- Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (L.M.); (A.F.H.P.)
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Sheth S, Patel A, Foreman M, Mumtaz M, Reddy A, Sharaf R, Sheth S, Lucke-Wold B. The protective role of GLP-1 in neuro-ophthalmology. EXPLORATION OF DRUG SCIENCE 2023; 1:221-238. [PMID: 37711214 PMCID: PMC10501042 DOI: 10.37349/eds.2023.00015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/22/2023] [Indexed: 09/16/2023]
Abstract
Despite recent advancements in the field of neuro-ophthalmology, the rising rates of neurological and ophthalmological conditions, mismatches between supply and demand of clinicians, and an aging population underscore the urgent need to explore new therapeutic approaches within the field. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), traditionally used in the treatment of type 2 diabetes, are becoming increasingly appreciated for their diverse applications. Recently, GLP-1RAs have been approved for the treatment of obesity and recognized for their cardioprotective effects. Emerging evidence indicates some GLP-1RAs can cross the blood-brain barrier and may have neuroprotective effects. Therefore, this article aims to review the literature on the neurologic and neuro-ophthalmic role of glucagon-like peptide 1 (GLP-1). This article describes GLP-1 peptide characteristics and the mechanisms mediating its known role in increasing insulin, decreasing glucagon, delaying gastric emptying, and promoting satiety. This article identifies the sources and targets of GLP-1 in the brain and review the mechanisms which mediate its neuroprotective effects, as well as implications for Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, the preclinical works which unravel the effects of GLP-1 in ocular dynamics and the preclinical literature regarding GLP-1RA use in the management of several neuro-ophthalmic conditions, including diabetic retinopathy (DR), glaucoma, and idiopathic intracranial hypertension (IIH) are discussed.
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Affiliation(s)
- Sohum Sheth
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Aashay Patel
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Marco Foreman
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Mohammed Mumtaz
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Akshay Reddy
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Ramy Sharaf
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Siddharth Sheth
- College of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA
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Al-Sabah S, Jamal MH, Al-Khaledi G, Dsouza C, AlOtaibi F, Al-Ali W, Cherian P, Al-Khairi I, Ali H, Abu-Farha M, Abubaker J, Al-Mulla F. Increased Glucagon Immunoreactivity in a Rat Model of Diet-induced Obesity following Sleeve Gastrectomy. Med Princ Pract 2023; 32:000533746. [PMID: 37634505 PMCID: PMC10659591 DOI: 10.1159/000533746] [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: 02/15/2023] [Accepted: 08/22/2023] [Indexed: 08/29/2023] Open
Abstract
OBJECTIVE Bariatric surgery is currently the most effective treatment for obesity, and procedures such as Roux-en Y gastric bypass and sleeve gastrectomy (SG) also result in rapid improvements in insulin sensitivity and glucose tolerance. In addition, these procedures cause changes in the secretion of various gut-derived hormones. The role these hormones play in the mechanism of the beneficial effects of bariatric surgery is still debated, but nonetheless, their importance provides inspiration for novel obesity-targeted pharmacotherapies. METHODS Male Sprague Dawley rats were fed either regular chow or a cafeteria diet to induce obesity. A sub-group of the obese animals then underwent either sham surgery or SG. RESULTS Following a 4-week recovery period, SG rats weighed significantly less than obese or sham-operated rats. Improvements in glucose tolerance and insulin sensitivity also occurred in the SG group, but these were not always statistically significant. We measured the intracellular lipid content of liver samples and found that obese rats showed signs of non-alcoholic fatty liver disease, which were significantly ameliorated by SG. There were significantly higher glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to a standard mixed meal in the SG group, as well as paradoxically higher glucagon secretion. CONCLUSION These data highlight the need for more specific anti-glucagon antibodies to characterize the changes in proglucagon-derived peptide concentrations that occur following SG. Further studies are required to determine whether these peptides contribute to the therapeutic effects of SG.
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Affiliation(s)
- Suleiman Al-Sabah
- Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Mohammad H. Jamal
- Department of Surgery, College of Medicine, Kuwait University, Kuwait City, Kuwait
- Department of Organ Transplant, College of Medicine, Kuwait City, Kuwait
| | - Ghanim Al-Khaledi
- Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Carol Dsouza
- Department of Surgery, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Fatemah AlOtaibi
- Department of Surgery, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Waleed Al-Ali
- Department of Pathology, College of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Preethi Cherian
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Irina Al-Khairi
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Hamad Ali
- Department of Medical Laboratory Sciences, College of Allied Health Sciences, Kuwait University, Kuwait City, Kuwait
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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Serbis A, Giapros V, Tsamis K, Balomenou F, Galli-Tsinopoulou A, Siomou E. Beta Cell Dysfunction in Youth- and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients. Nutrients 2023; 15:2217. [PMID: 37432389 PMCID: PMC10180650 DOI: 10.3390/nu15092217] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 07/12/2023] Open
Abstract
Traditionally a disease of adults, type 2 diabetes (T2D) has been increasingly diagnosed in youth, particularly among adolescents and young adults of minority ethnic groups. Especially, during the recent COVID-19 pandemic, obesity and prediabetes have surged not only in minority ethnic groups but also in the general population, further raising T2D risk. Regarding its pathogenesis, a gradually increasing insulin resistance due to central adiposity combined with a progressively defective β-cell function are the main culprits. Especially in youth-onset T2D, a rapid β-cell activity decline has been observed, leading to higher treatment failure rates, and early complications. In addition, it is well established that both the quantity and quality of food ingested by individuals play a key role in T2D pathogenesis. A chronic imbalance between caloric intake and expenditure together with impaired micronutrient intake can lead to obesity and insulin resistance on one hand, and β-cell failure and defective insulin production on the other. This review summarizes our evolving understanding of the pathophysiological mechanisms involved in defective insulin secretion by the pancreatic islets in youth- and adult-onset T2D and, further, of the role various micronutrients play in these pathomechanisms. This knowledge is essential if we are to curtail the serious long-term complications of T2D both in pediatric and adult populations.
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Affiliation(s)
- Anastasios Serbis
- Department of Pediatrics, School of Medicine, University of Ioannina, St. Niarhcos Avenue, 45500 Ioannina, Greece;
| | - Vasileios Giapros
- Neonatal Intensive Care Unit, School of Medicine, University of Ioannina, St. Νiarhcos Avenue, 45500 Ioannina, Greece (F.B.)
| | - Konstantinos Tsamis
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, St. Niarhcos Avenue, 45500 Ioannina, Greece
| | - Foteini Balomenou
- Neonatal Intensive Care Unit, School of Medicine, University of Ioannina, St. Νiarhcos Avenue, 45500 Ioannina, Greece (F.B.)
| | - Assimina Galli-Tsinopoulou
- Second Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, Stilponos Kyriakidi 1, 54636 Thessaloniki, Greece;
| | - Ekaterini Siomou
- Department of Pediatrics, School of Medicine, University of Ioannina, St. Niarhcos Avenue, 45500 Ioannina, Greece;
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Sanches JM, Zhao LN, Salehi A, Wollheim CB, Kaldis P. Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk. FEBS J 2023; 290:620-648. [PMID: 34847289 DOI: 10.1111/febs.16306] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 10/14/2021] [Accepted: 11/29/2021] [Indexed: 02/06/2023]
Abstract
Diabetes is a complex and multifactorial disease that affects millions of people worldwide, reducing the quality of life significantly, and results in grave consequences for our health care system. In type 2 diabetes (T2D), the lack of β-cell compensatory mechanisms overcoming peripherally developed insulin resistance is a paramount factor leading to disturbed blood glucose levels and lipid metabolism. Impaired β-cell functions and insulin resistance have been studied extensively resulting in a good understanding of these pathways but much less is known about interorgan crosstalk, which we define as signaling between tissues by secreted factors. Besides hormones and organokines, dysregulated blood glucose and long-lasting hyperglycemia in T2D is associated with changes in metabolism with metabolites from different tissues contributing to the development of this disease. Recent data suggest that metabolites, such as lipids including free fatty acids and amino acids, play important roles in the interorgan crosstalk during the development of T2D. In general, metabolic remodeling affects physiological homeostasis and impacts the development of T2D. Hence, we highlight the importance of metabolic interorgan crosstalk in this review to gain enhanced knowledge of the pathophysiology of T2D, which may lead to new therapeutic approaches to treat this disease.
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Affiliation(s)
| | - Li Na Zhao
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Albert Salehi
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Claes B Wollheim
- Department of Clinical Sciences, Lund University, Malmö, Sweden.,Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Philipp Kaldis
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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Jørgensen NT, Erichsen TM, Jørgensen MB, Idorn T, Feldt-Rasmussen B, Holst JJ, Feldt-Rasmussen U, Klose M. Glucose metabolism, gut-brain hormones, and acromegaly treatment: an explorative single centre descriptive analysis. Pituitary 2023; 26:152-163. [PMID: 36609655 DOI: 10.1007/s11102-022-01297-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/30/2022] [Indexed: 01/09/2023]
Abstract
PURPOSE Active acromegaly is associated with impaired glucose metabolism, which improves upon treatment. Treatment options include surgery, medical therapy with somatostatin analogues (SSA) and Pegvisomant (PEG), and irradiation. The objective of the study was to describe the differential effect of various treatment regimens on the secretion of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) in patients with acromegaly. METHODS 23 surgically treated, non-diabetic patients with acromegaly and 12 healthy controls underwent an oral glucose tolerance test (OGTT) and subsequently isoglycaemic intravenous glucose infusion on a separate day. Baseline hormone concentrations, time-to-peak and area under the curve (AUC) on the OGTT-day and incretin effect were compared according to treatment regimens. RESULTS The patients treated with SSA (N = 15) had impaired GIP-response (AUC, P = 0.001), and numerical impairment of all other hormone responses (P > 0.3). Patients co-treated with PEG (SSA + PEG, N = 4) had increased secretion of insulin and glucagon compared to patients only treated with SSA (SSA ÷ PEG, N = 11) (insulinAUC mean ± SEM, SSA + PEG 49 ± 8.3 nmol/l*min vs SSA ÷ PEG 25 ± 3.4, P = 0.007; glucagonAUC, SSA + PEG 823 ± 194 pmol/l*min vs SSA ÷ PEG 332 ± 69, P = 0.009). GIP secretion remained significantly impaired, whereas GLP-1 secretion was numerically increased with PEG (SSA + PEG 3088 ± 366 pmol/l*min vs SSA ÷ PEG 2401 ± 239, P = 0.3). No difference was found in patients treated with/without radiotherapy nor substituted or not with hydrocortisone. CONCLUSION SSA impaired the insulin, glucagon, and incretin hormone secretions. Co-treatment with PEG seemed to counteract the somatostatinergic inhibition of the glucagon and insulin response to OGTT. We speculate that PEG may exert its action through GH-receptors on pancreatic δ-cells. Clinical trial registration NCT02005978.
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Affiliation(s)
- Nanna Thurmann Jørgensen
- Department of Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Trine Møller Erichsen
- Department of Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Morten Buus Jørgensen
- Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Thomas Idorn
- Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Bo Feldt-Rasmussen
- Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, and NNF Centre for Basic Metabolic Research Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ulla Feldt-Rasmussen
- Department of Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marianne Klose
- Department of Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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Kashtanova ЕV, Polonskaya YV, Shramko VS, Shcherbakova LV, Stakhneva ЕМ, Sadovski EV, Spiridonov AN, Ragino YI. Associations of adipokines and metabolic hormones with low-density lipoprotein hypercholesterolemia in men and women under 45 years of age. KARDIOLOGIIA 2022; 62:63-70. [DOI: 10.18087/cardio.2022.11.n2239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 08/26/2022] [Indexed: 12/23/2022]
Abstract
Aim To study the adipokine profile in young people with hypercholesterolemia and low-density lipoproteins (LDL) and to evaluate the relationship between concentrations of LDL cholesterol (LDL-C) and metabolic hormones in men and women younger than 45 years. Material and methods This study included 304 subjects (group 1, 56 men with LDL-C concentration <2.1 mmol/l; group 2, 87 men with LDL-C concentration ≥4.2 mmol/l; group 3, 90 women with LDL-C concentration <2.1 mmol/l; and group 4, 71 women with LDL-C concentration ≥4.2 mmol/l). Serum concentrations of total cholesterol (C), triglycerides (TG), high-density lipoprotein C, and glucose were measured by an enzymatic assay with ThermoFisher Scientific kits and a KonelabPrime 30i biochemical analyzer. LDL-C was calculated using the Friedewald’s formula. Concentrations of amylin, C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 (GLP-1), glucagon, interleukin 6, insulin, leptin, monocyte chemotactic protein 1 (MCP-1), pancreatic polypeptide (PP), peptide YY (PYY), tumor necrosis factor alpha (TNF-α), adiponectin, adipsin, lipocalin-2, plasminogen activator inhibitor 1 (PAI-1), and resistin were measured by multiplex analysis (Human Metabolic Hormone V3 and Human Adipokine Panel 1 panels).Results The groups differed in traditional cardiometabolic risk factors. In the male and female patient groups with LDL-C ≥4.2 mmol/l, the prevalence of impaired fasting glucose, incidence of insulin resistance, TG, and TC were higher than in subjects with LDL-C <2.1 mmol/l. The odds for the presence of LDL hypercholesterolemia (LDL-C ≥4.2 mmol/l) were significantly associated with increased concentrations of C-peptide and lipocalin-2 in men and with increased concentrations of lipocalin-2 and decreased concentrations of GLP-1 in women (р<0.05).Conclusion Increased concentrations of LDL-C in young people were associated with changes in the adipokine profile and with the presence of metabolic syndrome components. These results were confirmed by changes in blood concentrations of metabolic markers that characterize disorders of metabolic processes.
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Affiliation(s)
- Е. V. Kashtanova
- Research Institute of Therapy and Preventive Medicine, Affiliation of the Federal Research Center Institute of Cytology and Genetics
| | - Yа. V. Polonskaya
- Research Institute of Therapy and Preventive Medicine, Affiliation of the Federal Research Center Institute of Cytology and Genetics
| | - V. S. Shramko
- Research Institute of Therapy and Preventive Medicine, Affiliation of the Federal Research Center Institute of Cytology and Genetics
| | - L. V. Shcherbakova
- Research Institute of Therapy and Preventive Medicine, Affiliation of the Federal Research Center Institute of Cytology and Genetics
| | - Е. М. Stakhneva
- Research Institute of Therapy and Preventive Medicine, Affiliation of the Federal Research Center Institute of Cytology and Genetics
| | - E. V. Sadovski
- Research Institute of Therapy and Preventive Medicine, Affiliation of the Federal Research Center Institute of Cytology and Genetics
| | - A. N. Spiridonov
- Research Institute of Therapy and Preventive Medicine, Affiliation of the Federal Research Center Institute of Cytology and Genetics
| | - Yu. I. Ragino
- Research Institute of Therapy and Preventive Medicine, Affiliation of the Federal Research Center Institute of Cytology and Genetics
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Ferrari F, Moretti A, Villa RF. Incretin-based drugs as potential therapy for neurodegenerative diseases: current status and perspectives. Pharmacol Ther 2022; 239:108277. [DOI: 10.1016/j.pharmthera.2022.108277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 10/14/2022]
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Al‐Zaid B, Chacko S, Ezeamuzie CI, Bünemann M, Krasel C, Karimian T, Lanzerstorfer P, Al‐Sabah S. Differential effects of glucose-dependent insulinotropic polypeptide receptor/glucagon-like peptide-1 receptor heteromerization on cell signaling when expressed in HEK-293 cells. Pharmacol Res Perspect 2022; 10:e01013. [PMID: 36177761 PMCID: PMC9523454 DOI: 10.1002/prp2.1013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 09/12/2022] [Indexed: 12/15/2022] Open
Abstract
The incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important regulators of many aspects of metabolism including insulin secretion. Their receptors (GIPR and GLP-1R) are closely related members of the secretin class of G-protein-coupled receptors. As both receptors are expressed on pancreatic β-cells there is at least the hypothetical possibility that they may form heteromers. In the present study, we investigated GIPR/GLP-1R heteromerization and the impact of GIPR on GLP-1R-mediated signaling and vice versa in HEK-293 cells. Real-time fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) saturation experiments confirm that GLP-1R and GIPR form heteromers. Stimulation with 1 μM GLP-1 caused an increase in both FRET and BRET ratio, whereas stimulation with 1 μM GIP caused a decrease. The only other ligand tested to cause a significant change in BRET signal was the GLP-1 metabolite, GLP-1 (9-36). GIPR expression had no significant effect on mini-Gs recruitment to GLP-1R but significantly inhibited GLP-1 stimulated mini-Gq and arrestin recruitment. In contrast, the presence of GLP-1R improved GIP stimulated mini-Gs and mini-Gq recruitment to GIPR. These data support the hypothesis that GIPR and GLP-1R form heteromers with differential consequences on cell signaling.
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Affiliation(s)
- Bashaier Al‐Zaid
- Department of Pharmacology and Toxicology, Faculty of MedicineKuwait UniversityKuwait CityKuwait
| | - Siby Chacko
- Department of Pharmacology and Toxicology, Faculty of MedicineKuwait UniversityKuwait CityKuwait
| | | | - Moritz Bünemann
- School of Pharmacy, Institute for Pharmacology and ToxicologyThe Philipps University of MarburgMarburgGermany
| | - Cornelius Krasel
- School of Pharmacy, Institute for Pharmacology and ToxicologyThe Philipps University of MarburgMarburgGermany
| | - Tina Karimian
- University of Applied Sciences Upper Austria, School of EngineeringWelsAustria
| | - Peter Lanzerstorfer
- University of Applied Sciences Upper Austria, School of EngineeringWelsAustria
| | - Suleiman Al‐Sabah
- Department of Pharmacology and Toxicology, Faculty of MedicineKuwait UniversityKuwait CityKuwait
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Åkerström T, Stolpe MN, Widmer R, Dejgaard TF, Højberg JM, Møller K, Hansen JS, Trinh B, Holst JJ, Thomsen C, Pedersen BK, Ellingsgaard H. Endurance Training Improves GLP-1 Sensitivity and Glucose Tolerance in Overweight Women. J Endocr Soc 2022; 6:bvac111. [PMID: 35935071 PMCID: PMC9351379 DOI: 10.1210/jendso/bvac111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Indexed: 11/19/2022] Open
Abstract
Context and objective Obesity and inactivity are risk factors for developing impaired glucose tolerance characterized by insulin resistance and reduced beta-cell function. The stimulatory effect of glucagon-like peptide 1 (GLP-1) on insulin secretion is also impaired in obese, inactive individuals. The aim of this study was to investigate whether endurance training influences beta-cell sensitivity to GLP-1. Participants and intervention Twenty-four female participants, age 46 ± 2 years, body mass index 32.4 ± 0.9 kg/m2, and maximal oxygen consumption 24.7 ± 0.8 mL/kg/min participated in a 10-week exercise training study. Methods Beta-cell sensitivity to GLP-1 was assessed in a subset of participants (n = 6) during a 120-minute hyperglycemic glucose clamp (8.5 mM) including a 1-hour GLP-1 (7-36 amide) infusion (0.4 pmol/kg/min). Changes in glucose tolerance, body composition, and cardiorespiratory fitness were assessed by oral glucose tolerance tests (OGTTs), dual-energy X-ray absorptiometry scans, magnetic resonance scans, and maximal oxygen consumption (VO2max) tests, respectively. Results The c-peptide response to infusion of GLP-1 increased 28 ± 3% (P < 0.05) toward the end of the hyperglycemic clamp. The insulin response remained unchanged. Training improved glucose tolerance and reduced GLP-1, insulin, and glucagon levels during the OGTTs. Training increased VO2max (from 24.7 ± 0.8 to 27.0 ± 0.7 mL/kg/min; P < 0.05) and reduced visceral fat volume (from 4176 ± 265 to 3888 ± 266 cm3; P < 0.01). Conclusion Along with improved glycemic control, endurance training improved beta-cell sensitivity to GLP-1 in overweight women. The study was deemed not to constitute a clinical trial and was not registered as such.
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Affiliation(s)
- Thorbjörn Åkerström
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
- Diabetes Pharmacology 1, Novo Nordisk A/S , Maaløv , Denmark
| | - Malene N Stolpe
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen , DK 2200 Copenhagen , Denmark
| | - Renate Widmer
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Thomas F Dejgaard
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Jens M Højberg
- Department of Cardiothoracic Anesthesiology and Intensive Care, Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Kirsten Møller
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
- Intensive Care Unit 4131, Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Jakob S Hansen
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
- Novo Nordisk A/S , Søborg , Denmark
| | - Beckey Trinh
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Jens J Holst
- Department of Biomedical Sciences and the NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , DK 2200 Copenhagen , Denmark
| | - Carsten Thomsen
- Department of Radiology, Rigshospitalet, University of Copenhagen , DK 2100 Copenhagen , Denmark
| | - Bente K Pedersen
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Helga Ellingsgaard
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
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Fujimura Y, Watanabe M, Morikawa-Ichinose T, Fujino K, Yamamoto M, Nishioka S, Inoue C, Ogawa F, Yonekura M, Nakasone A, Kumazoe M, Tachibana H. Metabolic Profiling for Evaluating the Dipeptidyl Peptidase-IV Inhibitory Potency of Diverse Green Tea Cultivars and Determining Bioactivity-Related Ingredients and Combinations. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:6455-6466. [PMID: 35543229 DOI: 10.1021/acs.jafc.2c01693] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
There are numerous cultivars of tea (Camellia sinensis L.), but the differences in their anti-hyperglycemic-related effects are largely unknown. The inhibition of the dipeptidyl peptidase (DPP)-IV enzyme plays an essential role in controlling hyperglycemia in diabetes by blocking the degradation of incretin hormones, which is necessary for insulin secretion. In this study, we examined the DPP-IV inhibitory activity of leaf extracts from diverse Japanese green tea cultivars. The inhibitory rates differed among tea extracts. Metabolic profiling (MP), using liquid chromatography-mass spectrometry, of all cultivars revealed compositional differences among cultivars according to their DPP-IV inhibitory capacity. Epigallocatechin-3-O-(3-O-methyl)gallate, kaempferol-3-O-rutinoside, myricetin-3-O-glucoside/galactoside, and theogallin were newly identified as DPP-IV inhibitors. The bioactivity of a tea extract was potentiated by adding these ingredients in combination. Our results show that MP is a useful approach for evaluating the DPP-IV inhibitory potency of green tea and for determining bioactivity-related ingredients and combinations.
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Affiliation(s)
- Yoshinori Fujimura
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Mototsugu Watanabe
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Tomomi Morikawa-Ichinose
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Konatsu Fujino
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Mao Yamamoto
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Seita Nishioka
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Chihiro Inoue
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Fumiyo Ogawa
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Madoka Yonekura
- Agriculture and Biotechnology Business Division, Toyota Motor Corporation, Toyota-shi, Aichi 471-8571, Japan
| | - Akari Nakasone
- Agriculture and Biotechnology Business Division, Toyota Motor Corporation, Toyota-shi, Aichi 471-8571, Japan
| | - Motofumi Kumazoe
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
| | - Hirofumi Tachibana
- Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
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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] [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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Fernandes MF, Tomczewski MV, Duncan RE. Glucagon-like Peptide-1 Secretion Is Inhibited by Lysophosphatidic Acid. Int J Mol Sci 2022; 23:ijms23084163. [PMID: 35456981 PMCID: PMC9025735 DOI: 10.3390/ijms23084163] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 12/27/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) potentiates glucose-stimulated insulin secretion (GSIS). While dozens of compounds stimulate GLP-1 secretion, few inhibit. Reduced GLP-1 secretion and impaired GSIS occur in chronic inflammation. Lysophosphatidic acids (LPAs) are bioactive phospholipids elevated in inflammation. The aim of this study was to test whether LPA inhibits GLP-1 secretion in vitro and in vivo. GLUTag L-cells were treated with various LPA species, with or without LPA receptor (LPAR) antagonists, and media GLP-1 levels, cellular cyclic AMP and calcium ion concentrations, and DPP4 activity levels were analyzed. Mice were injected with LPA, with or without LPAR antagonists, and serum GLP-1 and DPP4 activity were measured. GLUTag GLP-1 secretion was decreased ~70–90% by various LPAs. GLUTag expression of Lpar1, 2, and 3 was orders of magnitude higher than Lpar4, 5, and 6, implicating the former group in this effect. In agreement, inhibition of GLP-1 secretion was reversed by the LPAR1/3 antagonist Ki16425, the LPAR1 antagonists AM095 and AM966, or the LPAR2 antagonist LPA2-antagonist 1. We hypothesized involvement of Gαi-mediated LPAR activity, and found that intracellular cyclic AMP and calcium ion concentrations were decreased by LPA, but restored by Ki16425. Mouse LPA injection caused an ~50% fall in circulating GLP-1, although only LPAR1 or LPAR1/3 antagonists, but not LPAR2 antagonism, prevented this. GLUTag L-cell and mouse serum DPP4 activity was unchanged by LPA or LPAR antagonists. LPA therefore impairs GLP-1 secretion in vitro and in vivo through Gαi-coupled LPAR1/3 signaling, providing a new mechanism linking inflammation with impaired GSIS.
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Increased of fasting active glucagon-like peptide-1 is associated with insulin resistance in patients with hypertriglyceridemia. Int J Diabetes Dev Ctries 2022. [DOI: 10.1007/s13410-021-00971-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Olivera-Nappa Á, Contreras S, Tevy MF, Medina-Ortiz D, Leschot A, Vigil P, Conca C. Patient-Wise Methodology to Assess Glycemic Health Status: Applications to Quantify the Efficacy and Physiological Targets of Polyphenols on Glycemic Control. Front Nutr 2022; 9:831696. [PMID: 35252308 PMCID: PMC8892255 DOI: 10.3389/fnut.2022.831696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/25/2022] [Indexed: 11/13/2022] Open
Abstract
A growing body of evidence indicates that dietary polyphenols could be used as an early intervention to treat glucose-insulin (G-I) dysregulation. However, studies report heterogeneous information, and the targets of the intervention remain largely elusive. In this work, we provide a general methodology to quantify the effects of any given polyphenol-rich food or formulae over glycemic regulation in a patient-wise manner using an Oral Glucose Tolerance Test (OGTT). We use a mathematical model to represent individual OGTT curves as the coordinated action of subsystems, each one described by a parameter with physiological interpretation. Using the parameter values calculated for a cohort of 1198 individuals, we propose a statistical model to calculate the risk of dysglycemia and the coordination among subsystems for each subject, thus providing a continuous and individual health assessment. This method allows identifying individuals at high risk of dysglycemia—which would have been missed with traditional binary diagnostic methods—enabling early nutritional intervention with a polyphenol-supplemented diet where it is most effective and desirable. Besides, the proposed methodology assesses the effectiveness of interventions over time when applied to the OGTT curves of a treated individual. We illustrate the use of this method in a case study to assess the dose-dependent effects of Delphinol® on reducing dysglycemia risk and improving the coordination between subsystems. Finally, this strategy enables, on the one hand, the use of low-cost, non-invasive methods in population-scale nutritional studies. On the other hand, it will help practitioners assess the effectiveness of an intervention based on individual vulnerabilities and adapt the treatment to manage dysglycemia and avoid its progression into disease.
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Affiliation(s)
- Álvaro Olivera-Nappa
- Centre for Biotechnology and Bioengineering (CeBiB), University of Chile, Santiago, Chile
- Department of Chemical Engineering, Biotechnology and Materials, University of Chile, Santiago, Chile
- *Correspondence: Álvaro Olivera-Nappa
| | - Sebastian Contreras
- Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany
- Sebastian Contreras
| | - María Florencia Tevy
- Laboratory of Cell Biology, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile
| | - David Medina-Ortiz
- Centre for Biotechnology and Bioengineering (CeBiB), University of Chile, Santiago, Chile
- Department of Chemical Engineering, Biotechnology and Materials, University of Chile, Santiago, Chile
| | | | - Pilar Vigil
- Reproductive Health Research Institute, Santiago, Chile
| | - Carlos Conca
- Centre for Biotechnology and Bioengineering (CeBiB), University of Chile, Santiago, Chile
- Center for Mathematical Modelling (CMM), University of Chile, Santiago, Chile
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Review of Novel Potential Insulin Resistance Biomarkers in PCOS Patients—The Debate Is Still Open. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19042099. [PMID: 35206286 PMCID: PMC8871992 DOI: 10.3390/ijerph19042099] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/27/2022] [Accepted: 02/09/2022] [Indexed: 12/12/2022]
Abstract
Research on proteins and peptides that play roles in metabolic regulation, which may be considered potential insulin resistance markers in some medical conditions, such as diabetes mellitus, obesity and polycystic ovarian syndrome (PCOS), has recently gained in interest. PCOS is a common endocrine disorder associated with hyperandrogenemia and failure of ovulation, which is often accompanied by metabolic abnormalities, including obesity, dyslipidemia, hyperinsulinemia, and insulin resistance. In this review, we focus on less commonly known peptides/proteins and investigate their role as potential biomarkers for insulin resistance in females affected by PCOS. We summarize studies comparing the serum fasting concentration of particular agents in PCOS individuals and healthy controls. Based on our analysis, we propose that, in the majority of studies, the levels of nesfastin-1, myonectin, omentin, neudesin were decreased in PCOS patients, while the levels of the other considered agents (e.g., preptin, gremlin-1, neuregulin-4, xenopsin-related peptide, xenin-25, and galectin-3) were increased. However, there also exist studies presenting contrary results; in particular, most data existing for lipocalin-2 are inconsistent. Therefore, further research is required to confirm those hypotheses, as well as to elucidate the involvement of these factors in PCOS-related metabolic complications.
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Lindquist P, Gasbjerg LS, Mokrosinski J, Holst JJ, Hauser AS, Rosenkilde MM. The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection. Front Endocrinol (Lausanne) 2022; 13:891586. [PMID: 35846282 PMCID: PMC9277503 DOI: 10.3389/fendo.2022.891586] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 03/08/2022] [Accepted: 05/04/2022] [Indexed: 11/16/2022] Open
Abstract
The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading to physiological changes can be identified in large-scale sequencing, no systematic investigation of GIP missense variants has been performed. Here, we identified 168 naturally occurring missense variants in the human GIP genes from three independent cohorts comprising ~720,000 individuals. We examined amino acid changing variants scattered across the pre-pro-GIP peptide using in silico effect predictions, which revealed that the sequence of the fully processed GIP hormone is more protected against mutations than the rest of the precursor protein. Thus, we observed a highly species-orthologous and population-specific conservation of the GIP peptide sequence, suggestive of evolutionary constraints to preserve the GIP peptide sequence. Elucidating the mutational landscape of GIP variants and how they affect the structural and functional architecture of GIP can aid future biological characterization and clinical translation.
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Affiliation(s)
- Peter Lindquist
- Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lærke Smidt Gasbjerg
- Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jacek Mokrosinski
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, United States
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alexander Sebastian Hauser
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Alexander Sebastian Hauser, ; Mette Marie Rosenkilde,
| | - Mette Marie Rosenkilde
- Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Alexander Sebastian Hauser, ; Mette Marie Rosenkilde,
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Mohsen M, Elberry AA, Mohamed Rabea A, Abdelrahim MEA, Hussein RRS. Recent therapeutic targets in diabetic nephropathy. Int J Clin Pract 2021; 75:e14650. [PMID: 34310818 DOI: 10.1111/ijcp.14650] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/18/2021] [Accepted: 07/15/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The prevalence of diabetes mellitus has been increased dramatically which in turn leads to complications including cardiovascular diseases, diabetic kidney disease, and substantially end-stage renal disease. METHODS We reviewed articles discussing the pathophysiology of diabetic nephropathy with new agents that may be useful in the management of the disease. We used PubMed, Scopus, Google Scholar and the Open-access searching engines. RESULTS The recent recommendations primarily depend on glycaemic and blood pressure control and the use of standard renin-angiotensin system blockade. Currently, the use of agents with nephroprotective effects beyond the hyperglycaemic lowering effect has been evidenced clinically. CONCLUSIONS In his review, the pathophysiology, clinical manifestations, and lines of treatment of diabetic nephropathy are discussed. In addition, a focus on the clinical role and nephroprotective effects of the emerging therapeutic class, dipeptidyl peptidase IV (DPP-4) inhibitors, is addressed in detail.
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Affiliation(s)
- Marwa Mohsen
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed A Elberry
- Clinical Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Alaa Mohamed Rabea
- Internal Medicine and Nephrology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed E A Abdelrahim
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Raghda R S Hussein
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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A Pilot Double-Blind Placebo-Controlled Randomized Clinical Trial to Investigate the Effects of Early Enteral Nutrients in Sepsis. Crit Care Explor 2021; 3:e550. [PMID: 34651137 PMCID: PMC8505333 DOI: 10.1097/cce.0000000000000550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Supplemental Digital Content is available in the text. Preclinical studies from our laboratory demonstrated therapeutic effects of enteral dextrose administration in the acute phase of sepsis, mediated by the intestine-derived incretin hormone glucose-dependent insulinotropic peptide. The current study investigated the effects of an early enteral dextrose infusion on systemic inflammation and glucose metabolism in critically ill septic patients.
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Bhar S, Bose T, Dutta A, Mande SS. A perspective on the benefits of consumption of parboiled rice over brown rice for glycaemic control. Eur J Nutr 2021; 61:615-624. [PMID: 34613432 DOI: 10.1007/s00394-021-02694-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 09/28/2021] [Indexed: 12/25/2022]
Abstract
PURPOSE Rice is a staple food for over 3.5 billion people worldwide. The nutritional content of rice varies with different post-harvest processing techniques. Major varieties include brown rice (BR), white rice (WR) and parboiled rice (PBR). While consumption of BR is advocated due to its higher nutritional content compared to other varieties, some studies have indicated lower post-prandial blood glucose (PPBG) levels when PBR is consumed. This apparent benefit of PBR consumption is not well publicised and no commentaries on underlying mechanisms are available in literature. METHODS In this review, we looked into differential nutrient content of PBR, as compared to BR and WR, and tried to understand how their consumption could be associated with glycaemic control. Various roles played by these nutrients in mechanisms of insulin secretion, insulin resistance, nutrient absorption and T2DM-associated inflammation were reviewed from literature-based evidence. RESULTS We report differential nutritional factors in PBR, with respect to BR (and WR), such as higher calcium and selenium content, lower phytic acids, and enriched vitamin B6 which might aid PBR's ability to provide better glycaemic control than BR. CONCLUSION Our interpretation of reviewed literature leads us to suggest the possible benefits of PBR consumption in glycaemic control and its inclusion as the preferred rice variant in diets of T2DM patients and at-risk individuals.
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Affiliation(s)
- Subhrajit Bhar
- TCS Research, Tata Consultancy Services Ltd, 54-B Hadapsar Industrial Estate, Pune, 411 013, India
| | - Tungadri Bose
- TCS Research, Tata Consultancy Services Ltd, 54-B Hadapsar Industrial Estate, Pune, 411 013, India
| | - Anirban Dutta
- TCS Research, Tata Consultancy Services Ltd, 54-B Hadapsar Industrial Estate, Pune, 411 013, India.
| | - Sharmila S Mande
- TCS Research, Tata Consultancy Services Ltd, 54-B Hadapsar Industrial Estate, Pune, 411 013, India.
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In Vitro and In Vivo Effects of Palmaria palmata Derived Peptides on Glucose Metabolism. Int J Pept Res Ther 2021. [DOI: 10.1007/s10989-021-10199-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
AbstractThree synthetic peptides, ILAP, LLAP and MAGVDHI, derived from a Palmaria palmata protein hydrolysate were assessed for their antidiabetic potential in vitro and in vivo. In addition to inhibiting dipeptidyl peptidase-IV in a cell-based in situ assay all three peptides significantly increased the half-life of the incretin hormone glucagon-like peptide-1 (GLP-1). ILAP and LLAP mediated a significant increase (p < 0.001) in insulin secretion from BRIN-BD11 cells compared to the glucose control, while MAGVDHI had no insulinotropic activity at an eqimolar concentration (10–6 M). A significant increase in the concentration of cyclic adenosine monophosphate production in BRIN-BD11 cells mediated by ILAP (p < 0.001) and LLAP (p < 0.01) compared to the basal control, would indicate that insulin secretion may be mediated by membrane based activation. Furthermore, ILAP and LLAP acted as glucose-dependent insulinotropic polypeptide (GIP) secretagogues, stimulating a significant increase (p < 0.01) in the concentration of GIP released from enteroendocrine STC-1 cells compared to the glucose control. When tested in vivo in healthy male NIH Swiss mice, ILAP and LLAP, mediated a significant increase (p < 0.01) in plasma insulin and decrease (p < 0.05) in blood glucose, respectively, compared to the control. MAGVDHI mediated a significant (p < 0.001) sustained reduction in food intake in food deprived trained mice. These results demonstrate that the Palmaria palmata peptides studied herein have prospective antidiabetic activity and have the potential to act as agents that can be used alone or in combination with drugs, to aid in the prevention and management of Type 2 diabetes mellitus.
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Grøndahl MFG, Johannesen J, Kristensen K, Knop FK. Treatment of type 2 diabetes in children: what are the specific considerations? Expert Opin Pharmacother 2021; 22:2127-2141. [PMID: 34420454 DOI: 10.1080/14656566.2021.1954160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: The number of individuals under 18 years of age with type 2 diabetes is increasing at an alarming rate worldwide. These patients are often characterized by obesity and they often experience a more rapid disease progression than adults with type 2 diabetes. Thus, focus on prevention and management of complications and comorbidities is imperative. With emphasis on weight loss and optimal glycemic control, treatment includes lifestyle changes and pharmacotherapy, which in this patient group is limited to metformin, liraglutide and insulin. In selected cases, bariatric surgery is indicated.Areas covered: This perspective article provides an overview of the literature covering pathophysiology, diagnosis, characteristics and treatment of pediatric type 2 diabetes, and outlines the gaps in our knowledge where further research is needed. The paper draws on both mechanistic studies, large scale intervention trials, epidemiological studies and international consensus statements.Expert opinion: Type 2 diabetes in pediatric patients is an increasing health care problem, and the current treatment strategies do not successfully meet the many challenges and obstacles in this patient group. Treatments must be early, intensive, multifaceted and durable. Also, prevention of obesity and type 2 diabetes in at-risk children should be addressed and prioritized on all levels.
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Affiliation(s)
- Magnus F G Grøndahl
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper Johannesen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Pediatrics, Copenhagen University Hospital, Herlev and Gentofte, Denmark
| | - Kurt Kristensen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Steno Diabetes Center Aarhus - Children and Adolescence, Aarhus University, Aarhus, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Steno Diabetes Center Copenhagen, Gentofte, Denmark.,Novo Nordisk Foundation for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Rao M, Zumbro EL, Broughton KS, LeMieux MJ. RETRACTED: Whey protein preload enhances the active GLP-1 response and reduces circulating glucose in women with polycystic ovarian syndrome. Nutr Res 2021; 92:84-98. [PMID: 34284269 DOI: 10.1016/j.nutres.2021.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 05/17/2021] [Accepted: 06/15/2021] [Indexed: 02/08/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. The article is a duplicate of a paper that has already been published in Nutrients: (Nutrients 2021, 13(7), 2451. https://doi.org/10.3390/nu13072451. Redundant publications overweigh the relative importance of published findings and distort the academic record of the authors. One of the conditions of submission of a paper for publication is therefore that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.
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Affiliation(s)
- Manisha Rao
- School of Health Promotion and Kinesiology, Texas Woman's University, Denton, TX, USA
| | - Emily L Zumbro
- School of Health Promotion and Kinesiology, Texas Woman's University, Denton, TX, USA
| | | | - Monique J LeMieux
- Nutrition and Food Sciences Department, Texas Woman's University, Denton, TX, USA.
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Holst JJ, Gasbjerg LS, Rosenkilde MM. The Role of Incretins on Insulin Function and Glucose Homeostasis. Endocrinology 2021; 162:6199910. [PMID: 33782700 PMCID: PMC8168943 DOI: 10.1210/endocr/bqab065] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Indexed: 12/14/2022]
Abstract
The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.
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Affiliation(s)
- Jens Juul Holst
- Department of Biomedical Sciences and the NovoNordisk Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Copenhagen N, DK-2200 Denmark
- Correspondence: Jens Juul Holst, MD, University of Copenhagen, Department of Biomedical Sciences, The Panum Institute, 3 Blegdamsvej, Copenhagen, DK-2200 Denmark.
| | - Lærke Smidt Gasbjerg
- Department of Biomedical Sciences and the NovoNordisk Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Copenhagen N, DK-2200 Denmark
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences and the NovoNordisk Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Copenhagen N, DK-2200 Denmark
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Hira T, Trakooncharoenvit A, Taguchi H, Hara H. Improvement of Glucose Tolerance by Food Factors Having Glucagon-Like Peptide-1 Releasing Activity. Int J Mol Sci 2021; 22:6623. [PMID: 34205659 PMCID: PMC8235588 DOI: 10.3390/ijms22126623] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 12/14/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes.
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Affiliation(s)
- Tohru Hira
- Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan
- Graduate School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan;
- School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan;
| | | | - Hayate Taguchi
- School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan;
| | - Hiroshi Hara
- Department of Food Science and Human Nutrition, Fuji Women’s University, Ishikari-shi 061-320, Japan;
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Guo X, Lv J, Xi R. The specification and function of enteroendocrine cells in Drosophila and mammals: a comparative review. FEBS J 2021; 289:4773-4796. [PMID: 34115929 DOI: 10.1111/febs.16067] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/26/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022]
Abstract
Enteroendocrine cells (EECs) in both invertebrates and vertebrates derive from intestinal stem cells (ISCs) and are scattered along the digestive tract, where they function in sensing various environmental stimuli and subsequently secrete neurotransmitters or neuropeptides to regulate diverse biological and physiological processes. To fulfill these functions, EECs are specified into multiple subtypes that occupy specific gut regions. With advances in single-cell technology, organoid culture experimental systems, and CRISPR/Cas9-mediated genomic editing, rapid progress has been made toward characterization of EEC subtypes in mammals. Additionally, studies of genetic model organisms-especially Drosophila melanogaster-have also provided insights about the molecular processes underlying EEC specification from ISCs and about the establishment of diverse EEC subtypes. In this review, we compare the regulation of EEC specification and function in mammals and Drosophila, with a focus on EEC subtype characterization, on how internal and external regulators mediate EEC subtype specification, and on how EEC-mediated intra- and interorgan communications affect gastrointestinal physiology and pathology.
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Affiliation(s)
- Xingting Guo
- National Institute of Biological Sciences, Beijing, China
| | - Jiaying Lv
- National Institute of Biological Sciences, Beijing, China.,School of Life Sciences, Tsinghua University, Beijing, China
| | - Rongwen Xi
- National Institute of Biological Sciences, Beijing, China.,Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
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