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Lv C, Han S, Sha Z, Liu M, Dong S, Zhang C, Li Z, Zhang K, Lu S, Xu Z, Bie L, Jiang R. Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice. CNS Neurosci Ther 2023; 29:3876-3888. [PMID: 37353947 PMCID: PMC10651945 DOI: 10.1111/cns.14308] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/21/2023] [Accepted: 05/30/2023] [Indexed: 06/25/2023] Open
Abstract
AIM We aimed to assess the effects of cerebral glucagon-like peptide-1 receptor (GLP-1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI). METHODS Immunofluorescence was employed to evaluate glymphatic system function. The blood-brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests. RESULTS Cerebral GLP-1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN-020 abolished the protective effect of the GLP-1R agonist against cognitive impairment. CONCLUSION Cerebral GLP-1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.
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Affiliation(s)
- Chuanxiang Lv
- Department of NeurosurgeryThe First Hospital of Jilin UniversityChangchunChina
| | - Shuai Han
- Department of NeurosurgeryThe First Hospital of Jilin UniversityChangchunChina
| | - Zhuang Sha
- Department of NeurosurgeryTianjin Medical University General HospitalTianjinChina
- Tianjin Neurological Institute, Key Laboratory of Post‐Neuroinjury Neuro‐repair and Regeneration in Central Nervous SystemTianjin Medical University General Hospital, Ministry of EducationTianjinChina
| | - Mingqi Liu
- Department of NeurosurgeryTianjin Medical University General HospitalTianjinChina
- Tianjin Neurological Institute, Key Laboratory of Post‐Neuroinjury Neuro‐repair and Regeneration in Central Nervous SystemTianjin Medical University General Hospital, Ministry of EducationTianjinChina
| | - Shiying Dong
- Department of NeurosurgeryTianjin Medical University General HospitalTianjinChina
- Tianjin Neurological Institute, Key Laboratory of Post‐Neuroinjury Neuro‐repair and Regeneration in Central Nervous SystemTianjin Medical University General Hospital, Ministry of EducationTianjinChina
| | - Chunyun Zhang
- Department of NeurosurgeryThe First Hospital of Jilin UniversityChangchunChina
| | - Zean Li
- Department of NeurosurgeryThe First Hospital of Jilin UniversityChangchunChina
| | - Kang Zhang
- Department of NeurosurgeryThe First Hospital of Jilin UniversityChangchunChina
| | - Shouyong Lu
- Department of NeurosurgeryThe First Hospital of Jilin UniversityChangchunChina
| | - Zhiyang Xu
- Department of NeurosurgeryThe First Hospital of Jilin UniversityChangchunChina
| | - Li Bie
- Department of NeurosurgeryThe First Hospital of Jilin UniversityChangchunChina
| | - Rongcai Jiang
- Department of NeurosurgeryTianjin Medical University General HospitalTianjinChina
- Tianjin Neurological Institute, Key Laboratory of Post‐Neuroinjury Neuro‐repair and Regeneration in Central Nervous SystemTianjin Medical University General Hospital, Ministry of EducationTianjinChina
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Sabari SS, Balasubramani K, Iyer M, Sureshbabu HW, Venkatesan D, Gopalakrishnan AV, Narayanaswamy A, Senthil Kumar N, Vellingiri B. Type 2 Diabetes (T2DM) and Parkinson's Disease (PD): a Mechanistic Approach. Mol Neurobiol 2023:10.1007/s12035-023-03359-y. [PMID: 37118323 PMCID: PMC10144908 DOI: 10.1007/s12035-023-03359-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/19/2023] [Indexed: 04/30/2023]
Abstract
Growing evidence suggest that there is a connection between Parkinson's disease (PD) and insulin dysregulation in the brain, whilst the connection between PD and type 2 diabetes mellitus (T2DM) is still up for debate. Insulin is widely recognised to play a crucial role in neuronal survival and brain function; any changes in insulin metabolism and signalling in the central nervous system (CNS) can lead to the development of various brain disorders. There is accumulating evidence linking T2DM to PD and other neurodegenerative diseases. In fact, they have a lot in common patho-physiologically, including insulin dysregulation, oxidative stress resulting in mitochondrial dysfunction, microglial activation, and inflammation. As a result, initial research should focus on the role of insulin and its molecular mechanism in order to develop therapeutic outcomes. In this current review, we will look into the link between T2DM and PD, the function of insulin in the brain, and studies related to impact of insulin in causing T2DM and PD. Further, we have also highlighted the role of various insulin signalling pathway in both T2DM and PD. We have also suggested that T2DM-targeting pharmacological strategies as potential therapeutic approach for individuals with cognitive impairment, and we have demonstrated the effectiveness of T2DM-prescribed drugs through current PD treatment trials. In conclusion, this investigation would fill a research gap in T2DM-associated Parkinson's disease (PD) with a potential therapy option.
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Affiliation(s)
- S Sri Sabari
- Department of Zoology, School of Basic Sciences, Stem Cell and Regenerative Medicine/Translational Research, Central University of Punjab (CUPB), Bathinda, 151401, Punjab, India
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Kiruthika Balasubramani
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Mahalaxmi Iyer
- Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to Be University), Coimbatore, 641021, Tamil Nadu, India
| | - Harysh Winster Sureshbabu
- Department of Zoology, School of Basic Sciences, Stem Cell and Regenerative Medicine/Translational Research, Central University of Punjab (CUPB), Bathinda, 151401, Punjab, India
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Dhivya Venkatesan
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, 632 014, India
| | - Arul Narayanaswamy
- Department of Zoology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
| | - Nachimuthu Senthil Kumar
- Department of Biotechnology, Mizoram University (A Central University), Aizawl, 796004, Mizoram, India
| | - Balachandar Vellingiri
- Department of Zoology, School of Basic Sciences, Stem Cell and Regenerative Medicine/Translational Research, Central University of Punjab (CUPB), Bathinda, 151401, Punjab, India.
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India.
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La Valle A, d'Annunzio G, Campanello C, Tantari G, Pistorio A, Napoli F, Patti G, Crocco M, Bassi M, Minuto N, Piccolo G, Maghnie M. Are glucose and insulin levels at all time points during OGTT a reliable marker of diabetes mellitus risk in pediatric obesity? J Endocrinol Invest 2023:10.1007/s40618-023-02030-6. [PMID: 36763246 DOI: 10.1007/s40618-023-02030-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 02/01/2023] [Indexed: 02/11/2023]
Abstract
PURPOSE Childhood overweight and obesity associated with insulin resistance and metabolic syndrome represent the new global pandemic and the main causative factors for dysglycemia, prediabetes, and Type 2 Diabetes Mellitus (T2DM). Predictors, such as HOMA-IR, HOMA-β%, and QUICKI lack specific reference values in children. OGTT is a gold standard for glycometabolic assessment. Recently, a glycemic level higher than 155 mg/dl at + 60' after glucose ingestion has been defined as a risk factor for T2DM in obese adolescents. We aim to analyze and correlate fasting insulin-resistance markers with OGTT results in overweight/obese children and adolescents. METHODS We retrospectively evaluated glucose and insulin values during a 2-h OGTT every 30 min in 236 overweight/obese patients. Glucose values and insulin sum during OGTT were compared to glycometabolic indexes and different cut-off values for insulin sum. RESULTS A 1-h glucose > 155 mg/dl and insulin sum > 535 microU/ml at all times during OGTT are the best predictors of diabetes risk in obese youths. A1-h glucose > 155 mg/dl is significantly associated with HbA1c > 5.7%, while no association was observed between HbA1c > 5.7% and glucose levels at baseline and 2 h. The ability of the standardized HOMA-IR to predict the prediabetes status is clearly lower than the total insulin sum at OGTT. CONCLUSION Our study demonstrates that also 1-h post-OGTT glucose, together with HbA1c, is an effective diabetes predictor.
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Affiliation(s)
- A La Valle
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - G d'Annunzio
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - C Campanello
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - G Tantari
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - A Pistorio
- Epidemiology and Biostatistics Department, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - F Napoli
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - G Patti
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - M Crocco
- Gastroenterology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - M Bassi
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - N Minuto
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - G Piccolo
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
- Neurooncology Unit, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147, Genoa, Italy.
| | - M Maghnie
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
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Tsai CJ, Tsao CF. Comparison of Glucose Lowering Efficacy of Human GLP-1 Agonist in Taiwan Type 2 Diabetes Patients after Switching from DPP-4 Inhibitor Use or Non-Use. J Pers Med 2022; 12:jpm12111915. [PMID: 36422091 PMCID: PMC9698961 DOI: 10.3390/jpm12111915] [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: 10/23/2022] [Revised: 11/12/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022] Open
Abstract
To determine the efficacy of glucose control in type 2 diabetes patients who switch from dipeptidyl peptidase-4 (DPP-4) inhibitors use or non-use to GLP-1 receptor agonists (GLP-1 RAs). We conducted a cohort study using data from the Chang Gung Research Database. Patients aged ≥18 years using newly initiated GLP-1 RAs between 1 January 2009, and 31 December 2016, were included. Cox proportional hazards models were used to adjust for treatment selection bias. The primary outcome was changes in the glycated hemoglobin (HbA1c) level. The HbA1c level fell substantially after initiating GLP-1 RAs in DPP-4 inhibitor users and nonusers. A mean HbA1c reduction of −0.42% was found in patients who received DPP-4 inhibitors. Those who were DPP-4 inhibitor nonusers had a reduction in HbA1c of −0.99%. The degree of reduction in HbA1c was significantly greater in patients who were DPP-4 inhibitor nonusers (p value < 0.01), compared to the DPP-4 inhibitor users. In routine care, DPP-4 inhibitor nonusers had better efficacy in glucose control than DPP-4 inhibitor users after switching to a GLP-1 agonist.
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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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Nasr NE, Sadek KM. Role and mechanism(s) of incretin-dependent therapies for treating diabetes mellitus. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:18408-18422. [PMID: 35031999 DOI: 10.1007/s11356-022-18534-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/03/2022] [Indexed: 06/14/2023]
Abstract
Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of β-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a 'chemical excitant' that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word 'incretin' to describe the phenomena. Incretins include GIP and GLP-1. The 'enteroinsular axis' is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM.
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Affiliation(s)
- Nasr E Nasr
- Department of Biochemistry, Faculty of Veterinary Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
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Hong JH, Kim DH, Lee MK. Glucolipotoxicity and GLP-1 secretion. BMJ Open Diabetes Res Care 2021; 9:9/1/e001905. [PMID: 33627316 PMCID: PMC7908300 DOI: 10.1136/bmjdrc-2020-001905] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/15/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION The concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and/or fatty acid levels. RESEARCH DESIGN AND METHODS To investigate the effects of chronic glucolipotoxicity on glucagon-like peptide-1-(7-36) amide (GLP-1) secretion, we generated glucolipotoxic conditions in human NCI-H716 enteroendocrine cells using either 5 or 25 mM glucose with or without 500 µM palmitate for 72 hours. For in vivo study, we have established a chronic nutrient infusion model in the rat. Serial blood samples were collected for 2 hours after the consumption of a mixed meal to evaluate insulin sensitivity and β-cell function. RESULTS Chronic glucolipotoxic conditions decreased GLP-1 secretion and the expressions of pCREB, pGSK3β, β-catenin, and TCF7L2 in NCI-H716 cells. Glucolipotoxicity conditions reduced glucose transporter expression, glucose uptake, and nicotinamide-adenine dinucleotide phosphate (NADPH) levels in L-cells, and increased triglyceride accumulation. In contrast, PPARα and ATP levels were reduced, which correlated well with decreased levels of SUR1 and Kir6.2, cAMP contents and expressions of pCAMK2, EPAC and PKA. We also observed an increase in reactive oxygen species production, UCP2 expression and Complex I activity. Simultaneous treatment with insulin restored the GLP-1 secretion. Glucolipotoxic conditions decreased insulin secretion in a time-dependent manner in INS-1 cells, which was recovered with exendin-4 cotreatment. Glucose and SMOFlipid infusion for 6 hours decreased GLP-1 secretion and proglucagon mRNA levels as well as impaired the glucose tolerance, insulin and C-peptide secretion in rats. CONCLUSION These results provide evidence for the first time that glucolipotoxicity could affect GLP-1 secretion through changes in glucose and lipid metabolism, gene expressions, and proglucagon biosynthesis and suggest the interrelationship between glucolipotoxicities of L-cells and β-cells which develops earlier than that of L-cells.
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Affiliation(s)
- Jung-Hee Hong
- Division of Endocrinology & Metabolism, Samsung Biomedical Research Institute, Seoul, South Korea
| | - Dae-Hee Kim
- Division of Cell Therapy, Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Moon-Kyu Lee
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Uijungbu Eulji Medical Center, Eulji University School of Medicine, Uijungbu, South Korea
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Jagannathan R, Neves JS, Dorcely B, Chung ST, Tamura K, Rhee M, Bergman M. The Oral Glucose Tolerance Test: 100 Years Later. Diabetes Metab Syndr Obes 2020; 13:3787-3805. [PMID: 33116727 PMCID: PMC7585270 DOI: 10.2147/dmso.s246062] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/24/2020] [Indexed: 12/15/2022] Open
Abstract
For over 100 years, the oral glucose tolerance test (OGTT) has been the cornerstone for detecting prediabetes and type 2 diabetes (T2DM). In recent decades, controversies have arisen identifying internationally acceptable cut points using fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and/or HbA1c for defining intermediate hyperglycemia (prediabetes). Despite this, there has been a steadfast global consensus of the 2-h PG for defining dysglycemic states during the OGTT. This article reviews the history of the OGTT and recent advances in its application, including the glucose challenge test and mathematical modeling for determining the shape of the glucose curve. Pitfalls of the FPG, 2-h PG during the OGTT, and HbA1c are considered as well. Finally, the associations between the 30-minute and 1-hour plasma glucose (1-h PG) levels derived from the OGTT and incidence of diabetes and its complications will be reviewed. The considerable evidence base supports modifying current screening and diagnostic recommendations with the use of the 1-h PG. Measurement of the 1-h PG level could increase the likelihood of identifying high-risk individuals when the pancreatic ß-cell function is substantially more intact with the added practical advantage of potentially replacing the conventional 2-h OGTT making it more acceptable in the clinical setting.
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Affiliation(s)
- Ram Jagannathan
- Division of Hospital Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - João Sérgio Neves
- Department of Surgery and Physiology, Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Endocrinology, Diabetes and Metabolism, Sa˜o Joa˜ o University Hospital Center, Porto, Portugal
| | - Brenda Dorcely
- NYU Grossman School of Medicine, Division of Endocrinology, Diabetes, Metabolism, New York, NY10016, USA
| | - Stephanie T Chung
- Diabetes, Obesity, and Endocrinology Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Kosuke Tamura
- Social Determinants of Obesity and Cardiovascular Risk Laboratory, Cardiovascular Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD20892, USA
| | - Mary Rhee
- Emory University School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Atlanta VA Health Care System, Atlanta, GA30322, USA
| | - Michael Bergman
- NYU Grossman School of Medicine, NYU Diabetes Prevention Program, Endocrinology, Diabetes, Metabolism, VA New York Harbor Healthcare System, Manhattan Campus, New York, NY10010, USA
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Papaetis GS. Liraglutide Therapy in a Prediabetic State: Rethinking the Evidence. Curr Diabetes Rev 2020; 16:699-715. [PMID: 31886752 DOI: 10.2174/1573399816666191230113446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/20/2019] [Accepted: 12/12/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Prediabetes is defined as a state of glucose metabolism between normal glucose tolerance and type 2 diabetes. Continuous β-cell failure and death are the reasons for the evolution from normal glucose tolerance to prediabetes and finally type 2 diabetes. INTRODUCTION The necessity of new therapeutic approaches in order to prevent or delay the development of type 2 diabetes is obligatory. Liraglutide, a long-acting GLP-1 receptor agonist, has 97% homology for native GLP-1. Identification of the trophic and antiapoptotic properties of liraglutide in preclinical studies, together with evidence of sustained β-cell function longevity during its administration in type 2 diabetes individuals, indicated its earliest possible administration during this disease, or even before its development, so as to postpone or delay its onset. METHODS Pubmed and Google databases have been thoroughly searched and relevant studies were selected. RESULTS This paper explores the current evidence of liraglutide administration both in humans and animal models with prediabetes. Also, it investigates the safety profile of liraglutide treatment and its future role to postpone or delay the evolution of type 2 diabetes. CONCLUSION Liralgutide remains a valuable tool in our therapeutic armamentarium for individuals who are overweight or obese and have prediabetes. Future well designed studies will give valuable information that will help clinicians to stratify individuals who will derive the most benefit from this agent, achieving targeted therapeutic strategies.
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Affiliation(s)
- Georgios S Papaetis
- Internal Medicine and Diabetes Clinic, Eleftherios Venizelos Avenue 62, Paphos, Cyprus
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Ferjan S, Jensterle M, Oblak T, Zitnik IP, Marc J, Goricar K, Dolzan V, Janez A. An impaired glucagon-like peptide-1 response is associated with prediabetes in polycystic ovary syndrome with obesity. J Int Med Res 2019; 47:4691-4700. [PMID: 31438749 PMCID: PMC6833370 DOI: 10.1177/0300060519865351] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Objective Impaired glucose homeostasis in polycystic ovary syndrome (PCOS) is associated with obesity, age, and disease phenotype. This study aimed to investigate the glucagon-like peptide-1 (GLP-1) response in patients with obesity and PCOS with normal glucose tolerance (NGT) or prediabetes. Methods Twenty-six women with obesity and PCOS were included. Thirteen women had NGT and 13 had prediabetes. Serum glucose, insulin, and GLP-1 levels were measured during an oral glucose tolerance test. Beta-cell function and insulin resistance were determined. Results Women with prediabetes had significantly lower GLP-1 levels than did those with NGT after a glucose load. GLP-1 levels <3.02 pM at 120 minutes were associated with prediabetes. Women with prediabetes had a lower oral glucose insulin sensitivity (OGIS) index and greater amount of visceral adipose tissue than did those with NGT. Plasma GLP-1 levels at 120 minutes were correlated with visceral adiposity and the OGIS index. A change in GLP-1 levels was correlated with a family history of type 2 diabetes. Conclusion The GLP-1 response is lower in patients with obesity, PCOS, and prediabetes than in those with obesity, PCOS, and NGT. Further investigation of the GLP-1 response as a potential separate risk factor for prediabetes in PCOS is required.
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Affiliation(s)
- Simona Ferjan
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, SI-1000 Ljubljana, Slovenia.,University of Ljubljana Faculty of Medicine, SI-1000 Ljubljana, Slovenia
| | - Mojca Jensterle
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, SI-1000 Ljubljana, Slovenia.,University of Ljubljana Faculty of Medicine, SI-1000 Ljubljana, Slovenia
| | - Tjasa Oblak
- University of Ljubljana Faculty of Medicine, SI-1000 Ljubljana, Slovenia
| | | | - Janja Marc
- University of Ljubljana Faculty of Pharmacy, SI-1000 Ljubljana, Slovenia
| | - Katja Goricar
- University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Pharmacogenetics Laboratory, SI-1000 Ljubljana, Slovenia
| | - Vita Dolzan
- University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Pharmacogenetics Laboratory, SI-1000 Ljubljana, Slovenia
| | - Andrej Janez
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, SI-1000 Ljubljana, Slovenia.,University of Ljubljana Faculty of Medicine, SI-1000 Ljubljana, Slovenia
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Mahat RK, Singh N, Arora M, Rathore V. Health risks and interventions in prediabetes: A review. Diabetes Metab Syndr 2019; 13:2803-2811. [PMID: 31405710 DOI: 10.1016/j.dsx.2019.07.041] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 07/23/2019] [Indexed: 01/03/2023]
Abstract
Prediabetes is a condition which appears prior to the development of diabetes in which blood glucose is abnormally high but do not reach the diagnostic threshold of type 2 diabetes mellitus. It is characterized by a cluster of metabolic abnormalities viz. dysglycemia, dyslipidemia, hypertension, physical inactivity, obesity, insulin resistance, procoagulant state, endothelial dysfunction, oxidative stress and inflammation, placing prediabetic subjects to an increased risk for diabetes and its complications. Recent studies demonstrate that complications of diabetes i.e. microvascular and macrovascular complications may manifest in some prediabetic subjects. This article reviews prediabetes-related risk factors and health issues. In addition, this article also highlights the interventions to prevent the development of diabetes in prediabetic subjects.
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Affiliation(s)
- Roshan Kumar Mahat
- Department of Biochemistry, Gajra Raja Medical College, Jiwaji University, Gwalior, Madhya Pradesh, 474009, India; Department of Biochemistry, Muzaffarnagar Medical College, Muzaffarnagar, Uttar Pradesh, 251203, India.
| | | | - Manisha Arora
- Department of Biochemistry, Muzaffarnagar Medical College, Muzaffarnagar, Uttar Pradesh, 251203, India
| | - Vedika Rathore
- Department of Biochemistry, Shyam Shah Medical College, Rewa, Madhya Pradesh, 486001, India
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12
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Hytting-Andreasen R, Balk-Møller E, Hartmann B, Pedersen J, Windeløv JA, Holst JJ, Kissow H. Endogenous glucagon-like peptide- 1 and 2 are essential for regeneration after acute intestinal injury in mice. PLoS One 2018; 13:e0198046. [PMID: 29864142 PMCID: PMC5986149 DOI: 10.1371/journal.pone.0198046] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 05/12/2018] [Indexed: 12/15/2022] Open
Abstract
Objective Mucositis is a side effect of chemotherapy seen in the digestive tract, with symptoms including pain, diarrhoea, inflammation and ulcerations. Our aim was to investigate whether endogenous glucagon-like peptide -1 and -2 (GLP-1 and GLP-2) are implicated in intestinal healing after chemotherapy-induced mucositis. Design We used a transgenic mouse model Tg(GCG.DTR)(Tg) expressing the human diphtheria toxin receptor in the proglucagon-producing cells. Injections with diphtheria toxin ablated the GLP-1 and GLP-2 producing L-cells in Tg mice with no effect in wild-type (WT) mice. Mice were injected with 5-fluorouracil or saline and received vehicle, exendin-4, teduglutide (gly2-GLP-2), or exendin-4/teduglutide in combination. The endpoints were body weight change, small intestinal weight, morphology, histological scoring of mucositis and myeloperoxidase levels. Results Ablation of L-cells led to impaired GLP-2 secretion; increased loss of body weight; lower small intestinal weight; lower crypt depth, villus height and mucosal area; and increased the mucositis severity score in mice given 5-fluorouracil. WT mice showed compensatory hyperproliferation as a sign of regeneration in the recovery phase. Co-treatment with exendin-4 and teduglutide rescued the body weight of the Tg mice and led to a hyperproliferation in the small intestine, whereas single treatment was less effective. Conclusion The ablation of L-cells leads to severe mucositis and insufficient intestinal healing, shown by severe body weight loss and lack of compensatory hyperproliferation in the recovery phase. Co-treatment with exendin-4 and teduglutide could prevent this. Because both peptides were needed, we can conclude that both GLP-1 and GLP-2 are essential for intestinal healing in mice.
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Affiliation(s)
- Rasmus Hytting-Andreasen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center of Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Emilie Balk-Møller
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center of Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center of Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jens Pedersen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center of Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Johanne Agerlin Windeløv
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center of Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center of Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- NNF Center of Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- * E-mail:
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13
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Koopman ADM, Rutters F, Rauh SP, Nijpels G, Holst JJ, Beulens JW, Alssema M, Dekker JM. Incretin responses to oral glucose and mixed meal tests and changes in fasting glucose levels during 7 years of follow-up: The Hoorn Meal Study. PLoS One 2018; 13:e0191114. [PMID: 29324870 PMCID: PMC5764355 DOI: 10.1371/journal.pone.0191114] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 12/28/2017] [Indexed: 12/25/2022] Open
Abstract
We conducted the first prospective observational study in which we examined the association between incretin responses to an oral glucose tolerance test (OGTT) and mixed meal test (MMT) at baseline and changes in fasting glucose levels 7 years later, in individuals who were non-diabetic at baseline. We used data from the Hoorn Meal Study; a population-based cohort study among 121 subjects, aged 61.0±6.7y. GIP and GLP-1 responses were determined at baseline and expressed as total and incremental area under the curve (tAUC and iAUC). The association between incretin response at baseline and changes in fasting glucose levels was assessed using linear regression. The average change in glucose over 7 years was 0.43 ± 0.5 mmol/l. For GIP, no significant associations were observed with changes in fasting glucose levels. In contrast, participants within the middle and highest tertile of GLP-1 iAUC responses to OGTT had significantly smaller increases (actually decreases) in fasting glucose levels; -0.28 (95% confidence interval: -0.54;-0.01) mmol/l and -0.39 (-0.67;-0.10) mmol/l, respectively, compared to those in the lowest tertile. The same trend was observed for tAUC GLP-1 following OGTT (highest tertile: -0.32 (0.61;-0.04) mmol/l as compared to the lowest tertile). No significant associations were observed for GLP-1 responses following MMT. In conclusion, within our non-diabetic population-based cohort, a low GLP-1 response to OGTT was associated with a steeper increase in fasting glucose levels during 7 years of follow-up. This suggests that a reduced GLP-1 response precedes glucose deterioration and may play a role in the etiology of type 2 diabetes mellitus.
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Affiliation(s)
- A. D. M. Koopman
- EMGO+ Institute for health and care research, VUmc, Amsterdam, the Netherlands
- Department of Epidemiology and Biostatistics, VUmc, Amsterdam, the Netherlands
- * E-mail:
| | - F. Rutters
- EMGO+ Institute for health and care research, VUmc, Amsterdam, the Netherlands
- Department of Epidemiology and Biostatistics, VUmc, Amsterdam, the Netherlands
| | - S. P. Rauh
- EMGO+ Institute for health and care research, VUmc, Amsterdam, the Netherlands
- Department of Epidemiology and Biostatistics, VUmc, Amsterdam, the Netherlands
| | - G. Nijpels
- EMGO+ Institute for health and care research, VUmc, Amsterdam, the Netherlands
- Department of General Practice & Elderly Care medicine, VUmc, Amsterdam, the Netherlands
| | - J. J. Holst
- NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - J. W. Beulens
- EMGO+ Institute for health and care research, VUmc, Amsterdam, the Netherlands
- Department of Epidemiology and Biostatistics, VUmc, Amsterdam, the Netherlands
- Julius Centre for Health Sciences and Primary Care, University Medical Centre, Utrecht, the Netherlands
| | - M. Alssema
- EMGO+ Institute for health and care research, VUmc, Amsterdam, the Netherlands
- Unilever Research and Development, Vlaardingen, the Netherlands
| | - J. M. Dekker
- EMGO+ Institute for health and care research, VUmc, Amsterdam, the Netherlands
- Department of Epidemiology and Biostatistics, VUmc, Amsterdam, the Netherlands
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GLP-1 response to sequential mixed meals: influence of insulin resistance. Clin Sci (Lond) 2017; 131:2901-2910. [PMID: 29097626 DOI: 10.1042/cs20171409] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 10/26/2017] [Accepted: 11/01/2017] [Indexed: 12/25/2022]
Abstract
Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.
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Exendin-4 attenuates neuronal death via GLP-1R/PI3K/Akt pathway in early brain injury after subarachnoid hemorrhage in rats. Neuropharmacology 2017; 128:142-151. [PMID: 28986282 DOI: 10.1016/j.neuropharm.2017.09.040] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/06/2017] [Accepted: 09/26/2017] [Indexed: 02/05/2023]
Abstract
Neuronal apoptosis is considered to be a crucial therapeutic target against early brain injury (EBI) after subarachnoid hemorrhage (SAH). Emerging evidence indicates that Exendin-4 (Ex-4), a glucagon-like peptide 1 receptor (GLP-1R) agonist, plays a neuroprotective role in cerebrovascular disease. This study was conducted in order to verify the neuroprotective role of EX-4 in EBI after SAH in rats. The endovascular perforation model of SAH was performed in Sprague-Dawley rats (n = 153). Ex-4 was intraperitoneally injected 1 h after SAH induction in the rats (SAH + Ex-4). To elucidate the underlying molecular mechanism, small interfering ribonucleic acid (siRNA) for GLP-1R and a specific inhibitor of PI3K, LY294002, were injected intracerebroventricularly into SAH + Ex-4 rats before induction of SAH (n = 6 per group). SAH grading evaluation, immunohistochemistry, Western blots, neurobehavioral assessment, and Fluoro-Jade C (FJC) staining experiments were performed. Expression of GLP-1R was significantly increased and mainly expressed in neurons at 24 h after SAH induction. Administration of Ex-4 significantly improved both short- and long-term neurobehavior in SAH + Ex-4 group compared to SAH + Vehicle group after SAH. Ex-4 treatment significantly increased the expression of GLP-1R, PI3K, p-Akt, Bcl-xl, and Bcl-2, while at the same time was found to decrease expression of Bax in the brain. Effects of Ex-4 were reversed by the intervention of GLP-1R siRNA and LY294002 in SAH + Ex-4+GLP-1R siRNA and SAH + Ex-4+LY294002 groups, respectively. In conclusion, the neuroprotective effect of Ex-4 in EBI after SAH was mediated by attenuation of neuronal apoptosis via GLP-1R/PI3K/Akt signaling pathway, therefore EX-4 should be further investigated as a potential therapeutic agent in stroke patients.
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Hemmingsen B, Sonne DP, Metzendorf M, Richter B, Cochrane Metabolic and Endocrine Disorders Group. Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev 2017; 5:CD012204. [PMID: 28489279 PMCID: PMC6481586 DOI: 10.1002/14651858.cd012204.pub2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. OBJECTIVES To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017. SELECTION CRITERIA We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence using the GRADE instrument. MAIN RESULTS We included seven completed RCTs; about 98 participants were randomised to a DPP-4 inhibitor as monotherapy and 1620 participants were randomised to a GLP-1 analogue as monotherapy. Two trials investigated a DPP-4 inhibitor and five trials investigated a GLP-1 analogue. A total of 924 participants with data on allocation to control groups were randomised to a comparator group; 889 participants were randomised to placebo and 33 participants to metformin monotherapy. One RCT of liraglutide contributed 85% of all participants. The duration of the intervention varied from 12 weeks to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported.All-cause and cardiovascular mortality following treatment with GLP-1 analogues were rarely reported; one trial of exenatide reported that no participant died. Another trial of liraglutide 3.0 mg showed that 2/1501 in the liraglutide group versus 2/747 in the placebo group died after 160 weeks of treatment (very low-quality evidence).The incidence of T2DM following treatment with liraglutide 3.0 mg compared to placebo after 160 weeks was 26/1472 (1.8%) participants randomised to liraglutide versus 46/738 (6.2%) participants randomised to placebo (very low-quality evidence). The trial established the risk for (diagnosis of) T2DM as HbA1c 5.7% to 6.4% (6.5% or greater), fasting plasma glucose 5.6 mmol/L or greater to 6.9 mmol/L or less (7.0 mmol/L or greater) or two-hour post-load plasma glucose 7.8 mmol/L or greater to 11.0 mmol/L (11.1 mmol/L). Altogether, 70/1472 (66%) participants regressed from intermediate hyperglycaemia to normoglycaemia compared with 268/738 (36%) participants in the placebo group. The incidence of T2DM after the 12-week off-treatment extension period (i.e. after 172 weeks) showed that five additional participants were diagnosed T2DM in the liraglutide group, compared with one participant in the placebo group. After 12-week treatment cessation, 740/1472 (50%) participants in the liraglutide group compared with 263/738 (36%) participants in the placebo group had normoglycaemia.One trial used exenatide and 2/17 participants randomised to exenatide versus 1/16 participants randomised to placebo developed T2DM (very low-quality evidence). This trial did not provide a definition of T2DM. One trial reported serious adverse events in 230/1524 (15.1%) participants in the liraglutide 3.0 mg arm versus 96/755 (12.7%) participants in the placebo arm (very low quality evidence). There were no serious adverse events in the trial using exenatide. Non-fatal myocardial infarction was reported in 1/1524 participants in the liraglutide arm and in 0/55 participants in the placebo arm at 172 weeks (very low-quality evidence). One trial reported congestive heart failure in 1/1524 participants in the liraglutide arm and in 1/755 participants in the placebo arm (very low-quality evidence). Participants receiving liraglutide compared with placebo had a small mean improvement in the physical component of the 36-item Short Form scale showing a difference of 0.87 points (95% CI 0.17 to 1.58; P = 0.02; 1 trial; 1791 participants; very low-quality evidence). No trial evaluating GLP-1-analogues reported data on stroke, microvascular complications or socioeconomic effects. AUTHORS' CONCLUSIONS There is no firm evidence that DPP-4 inhibitors or GLP-1 analogues compared mainly with placebo substantially influence the risk of T2DM and especially its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.
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Affiliation(s)
- Bianca Hemmingsen
- Herlev University HospitalDepartment of Internal MedicineHerlev Ringvej 75HerlevDenmarkDK‐2730
| | - David P Sonne
- Gentofte Hospital, University of CopenhagenCenter for Diabetes Research, Department of MedicineKildegaardsvej 28HellerupDenmarkDK‐2900
| | - Maria‐Inti Metzendorf
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupMoorenstr. 5DüsseldorfGermany40225
| | - Bernd Richter
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupMoorenstr. 5DüsseldorfGermany40225
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VEJRAZKOVA D, LISCHKOVA O, VANKOVA M, STANICKA S, VRBIKOVA J, LUKASOVA P, VCELAK J, VACINOVA G, BENDLOVA B. Distinct Response of Fat and Gastrointestinal Tissue to Glucose in Gestational Diabetes Mellitus and Polycystic Ovary Syndrome. Physiol Res 2017; 66:283-292. [DOI: 10.33549/physiolres.933366] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gestational diabetes mellitus (GDM) and polycystic ovary syndrome (PCOS) are distinct pathologies with impaired insulin sensitivity as a common feature. The aim of this study was to evaluate the response of fat tissue adipokines and gastrointestinal incretins to glucose load in patients diagnosed with one of the two disorders and to compare it with healthy controls. Oral glucose tolerance test (oGTT) was performed in 77 lean young women: 22 had positive history of GDM, 19 were PCOS patients, and 36 were healthy controls. Hormones were evaluated in fasting and in 60 min intervals during the 3 h oGTT using Bio-Plex ProHuman Diabetes 10-Plex Assay for C-peptide, ghrelin, GIP, GLP1, glucagon, insulin, leptin, total PAI1, resistin, visfatin and Bio-Plex ProHuman Diabetes Adipsin and Adiponectin Assays (Bio-Rad). Despite lean body composition, both PCOS and GDM women were more insulin resistant than controls. Significant postchallenge differences between the GDM and PCOS groups were observed in secretion of adipsin, leptin, glucagon, visfatin, ghrelin, GIP, and also GLP1 with higher levels in GDM. Conversely, PCOS was associated with the highest resistin, C-peptide, and PAI1 levels. Our data suggest that decreased insulin sensitivity observed in lean women with GDM and PCOS is associated with distinct hormonal response of fat and gastrointestinal tissue to glucose load.
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Affiliation(s)
- D. VEJRAZKOVA
- Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic
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Larsen MP, Torekov SS. Glucagon-Like Peptide 1: A Predictor of Type 2 Diabetes? J Diabetes Res 2017; 2017:7583506. [PMID: 29082261 PMCID: PMC5610892 DOI: 10.1155/2017/7583506] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 07/30/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The incretin effect is impaired in patients with type 2 diabetes. AIM To assess the relation between the incretin hormone GLP-1 and the prediabetic subtypes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and the combined IFG/IGT to investigate whether a low GLP-1 response may be a predictor of prediabetes in adults. METHOD 298 articles were found using a broad search phrase on the PubMed database and after the assessment of titles and abstracts 19 articles were included. RESULTS AND DISCUSSION Studies assessing i-IFG/IFG and i-IGT/IGT found both increased, unaltered, and reduced GLP-1 levels. Studies assessing IFG/IGT found unaltered or reduced GLP-1 levels. When assessing the five studies with the largest sample size, it clearly suggests a decreased GLP-1 response in IFG/IGT subjects. Several other factors (BMI, glucagon, age, and nonesterified fatty acids (NEFA)), including medications (metformin), may also influence the secretion of GLP-1. CONCLUSION This review suggests that the GLP-1 response is a variable in prediabetes possibly due to a varying GLP-1-secreting profile during the development and progression of type 2 diabetes or difference in the measurement technique. Longitudinal prospective studies are needed to assess whether a reduced GLP-1 response is a predictor of diabetes.
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Affiliation(s)
- Matthias Ploug Larsen
- Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Signe Sørensen Torekov
- Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen N, Denmark
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Di Girolamo FG, Mazzucco S, Situlin R, Mohorko N, Jenko-Pražnikar Z, Petelin A, Tence M, Pišot R, Navarini L, Biolo G. Roasting intensity of naturally low-caffeine Laurina coffee modulates glucose metabolism and redox balance in humans. Nutrition 2016; 32:928-36. [DOI: 10.1016/j.nut.2016.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 01/27/2016] [Accepted: 02/01/2016] [Indexed: 12/16/2022]
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Iepsen EW, Lundgren J, Holst JJ, Madsbad S, Torekov SS. Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36. Eur J Endocrinol 2016; 174:775-84. [PMID: 26976129 DOI: 10.1530/eje-15-1116] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 03/14/2016] [Indexed: 12/26/2022]
Abstract
OBJECTIVE The hormones glucagon-like peptide 1 (GLP-1), peptide YY3-36 (PYY3-36), ghrelin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon have all been implicated in the pathogenesis of obesity. However, it is unknown whether they exhibit adaptive changes with respect to postprandial secretion to a sustained weight loss. DESIGN The study was designed as a longitudinal prospective intervention study with data obtained at baseline, after 8 weeks of weight loss and 1 year after weight loss. METHODS Twenty healthy obese individuals obtained a 13% weight loss by adhering to an 8-week very low-calorie diet (800kcal/day). After weight loss, participants entered a 52-week weight maintenance protocol. Plasma levels of GLP-1, PYY3-36, ghrelin, GIP and glucagon during a 600-kcal meal were measured before weight loss, after weight loss and after 1 year of weight maintenance. Area under the curve (AUC) was calculated as total AUC (tAUC) and incremental AUC (iAUC). RESULTS Weight loss was successfully maintained for 52 weeks. iAUC for GLP-1 increased by 44% after weight loss (P<0.04) and increased to 72% at week 52 (P=0.0001). iAUC for PYY3-36 increased by 74% after weight loss (P<0.0001) and by 36% at week 52 (P=0.02). tAUC for ghrelin increased by 23% after weight loss (P<0.0001), but at week 52, the increase was reduced to 16% compared with before weight loss (P=0.005). iAUC for GIP increased by 36% after weight loss (P=0.001), but returned to before weight loss levels at week 52. Glucagon levels were unaffected by weight loss. CONCLUSIONS Meal responses of GLP-1 and PYY3-36 remained increased 1 year after weight maintenance, whereas ghrelin and GIP reverted toward before-weight loss values. Thus, an increase in appetite inhibitory mechanisms and a partly decrease in appetite-stimulating mechanisms appear to contribute to successful long-term weight loss maintenance.
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Affiliation(s)
- Eva W Iepsen
- Department of Biomedical SciencesFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark The Novo Nordisk Foundation Center for Basic Metabolic ResearchFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Julie Lundgren
- Department of Biomedical SciencesFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark The Novo Nordisk Foundation Center for Basic Metabolic ResearchFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical SciencesFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark The Novo Nordisk Foundation Center for Basic Metabolic ResearchFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of EndocrinologyHvidovre University Hospital, Hvidovre, Denmark
| | - Signe S Torekov
- Department of Biomedical SciencesFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark The Novo Nordisk Foundation Center for Basic Metabolic ResearchFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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21
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Hemmingsen B, Krogh J, Metzendorf MI, Richter B. Dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2016. [DOI: 10.1002/14651858.cd012204] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Suh S, Kim MY, Kim SK, Hur KY, Park MK, Kim DK, Cho NH, Lee MK. Glucose-Dependent Insulinotropic Peptide Level Is Associated with the Development of Type 2 Diabetes Mellitus. Endocrinol Metab (Seoul) 2016; 31:134-41. [PMID: 26676334 PMCID: PMC4803549 DOI: 10.3803/enm.2016.31.1.134] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 09/04/2015] [Accepted: 09/15/2015] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Incretin hormone levels as a predictor of type 2 diabetes mellitus have not been fully investigated. Therefore, we measured incretin hormone levels to examine the relationship between circulating incretin hormones, diabetes, and future diabetes development in this study. METHODS A nested case-control study was conducted in a Korean cohort. The study included the following two groups: the control group (n=149), the incident diabetes group (n=65). Fasting total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic peptide (GIP) levels were measured and compared between these groups. RESULTS Fasting total GIP levels were higher in the incident diabetes group than in the control group (32.64±22.68 pmol/L vs. 25.54±18.37 pmol/L, P=0.034). There was no statistically significant difference in fasting total GLP-1 levels between groups (1.14±1.43 pmol/L vs. 1.39±2.13 pmol/L, P=0.199). In multivariate analysis, fasting total GIP levels were associated with an increased risk of diabetes (odds ratio, 1.005; P=0.012) independent of other risk factors. CONCLUSION Fasting total GIP levels may be a risk factor for the development of type 2 diabetes mellitus. This association persisted even after adjusting for other metabolic parameters such as elevated fasting glucose, hemoglobin A1c, and obesity in the pre-diabetic period.
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Affiliation(s)
- Sunghwan Suh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dong-A Medical Center, Dong-A University College of Medicine, Busan, Korea
| | - Mi Yeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Kyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Kyu Yeon Hur
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mi Kyoung Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dong-A Medical Center, Dong-A University College of Medicine, Busan, Korea
| | - Duk Kyu Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dong-A Medical Center, Dong-A University College of Medicine, Busan, Korea
| | - Nam H Cho
- Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea.
| | - Moon Kyu Lee
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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23
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Abstract
Dipeptidyl-peptidase 4 (DPP4) is a glycoprotein of 110 kDa, which is ubiquitously expressed on the surface of a variety of cells. This exopeptidase selectively cleaves N-terminal dipeptides from a variety of substrates, including cytokines, growth factors, neuropeptides, and the incretin hormones. Expression of DPP4 is substantially dysregulated in a variety of disease states including inflammation, cancer, obesity, and diabetes. Since the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), are major regulators of post-prandial insulin secretion, inhibition of DPP4 by the gliptin family of drugs has gained considerable interest for the therapy of type 2 diabetic patients. In this review, we summarize the current knowledge on the DPP4–incretin axis and evaluate most recent findings on DPP4 inhibitors. Furthermore, DPP4 as a type II transmembrane protein is also known to be cleaved from the cell membrane involving different metalloproteases in a cell-type-specific manner. Circulating, soluble DPP4 has been identified as a new adipokine, which exerts both para- and endocrine effects. Recently, a novel receptor for soluble DPP4 has been identified, and data are accumulating that the adipokine-related effects of DPP4 may play an important role in the pathogenesis of cardiovascular disease. Importantly, circulating DPP4 is augmented in obese and type 2 diabetic subjects, and it may represent a molecular link between obesity and vascular dysfunction. A critical evaluation of the impact of circulating DPP4 is presented, and the potential role of DPP4 inhibition at this level is also discussed.
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Affiliation(s)
- Diana Röhrborn
- Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center , Düsseldorf , Germany
| | - Nina Wronkowitz
- Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center , Düsseldorf , Germany
| | - Juergen Eckel
- Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center , Düsseldorf , Germany
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Færch K, Torekov SS, Vistisen D, Johansen NB, Witte DR, Jonsson A, Pedersen O, Hansen T, Lauritzen T, Sandbæk A, Holst JJ, Jørgensen ME. GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study. Diabetes 2015; 64:2513-25. [PMID: 25677912 DOI: 10.2337/db14-1751] [Citation(s) in RCA: 234] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 02/04/2015] [Indexed: 12/19/2022]
Abstract
The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear. We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and β-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.
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Affiliation(s)
| | - Signe S Torekov
- NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Nanna B Johansen
- Steno Diabetes Center, Gentofte, Denmark Danish Diabetes Academy, Odense, Denmark
| | - Daniel R Witte
- Section for General Practice, Department of Public Health, Aarhus, Denmark
| | - Anna Jonsson
- NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Oluf Pedersen
- NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Torben Hansen
- NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Torsten Lauritzen
- Section for General Practice, Department of Public Health, Aarhus, Denmark
| | - Annelli Sandbæk
- Section for General Practice, Department of Public Health, Aarhus, Denmark
| | - Jens Juul Holst
- NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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25
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Godinho R, Mega C, Teixeira-de-Lemos E, Carvalho E, Teixeira F, Fernandes R, Reis F. The Place of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapeutics: A "Me Too" or "the Special One" Antidiabetic Class? J Diabetes Res 2015; 2015:806979. [PMID: 26075286 PMCID: PMC4449938 DOI: 10.1155/2015/806979] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Revised: 04/09/2015] [Accepted: 04/11/2015] [Indexed: 12/12/2022] Open
Abstract
Incretin-based therapies, the most recent therapeutic options for type 2 diabetes mellitus (T2DM) management, can modify various elements of the disease, including hypersecretion of glucagon, abnormal gastric emptying, postprandial hyperglycaemia, and, possibly, pancreatic β cell dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) increase glucagon-like peptide-1 (GLP-1) availability and correct the "incretin defect" seen in T2DM patients. Clinical studies have shown good glycaemic control with minimal risk of hypoglycaemia or any other adverse effects, despite the reports of pancreatitis, whose association remains to be proved. Recent studies have been focusing on the putative ability of DPP-4 inhibitors to preserve pancreas function, in particular due to the inhibition of apoptotic pathways and stimulation of β cell proliferation. In addition, other cytoprotective effects on other organs/tissues that are involved in serious T2DM complications, including the heart, kidney, and retina, have been increasingly reported. This review outlines the therapeutic potential of DPP-4 inhibitors for the treatment of T2DM, focusing on their main features, clinical applications, and risks, and discusses the major challenges for the future, in particular the possibility of becoming the preferred therapy for T2DM due to their ability to modify the natural history of the disease and ameliorate nephropathy, retinopathy, and cardiovascular complications.
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Affiliation(s)
- Ricardo Godinho
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
| | - Cristina Mega
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
- ESAV, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
| | - Edite Teixeira-de-Lemos
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
- ESAV, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
| | - Eugénia Carvalho
- Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, 3000-548 Coimbra, Portugal
- The Portuguese Diabetes Association (APDP), 1250-189 Lisbon, Portugal
| | - Frederico Teixeira
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
| | - Rosa Fernandes
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Flávio Reis
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, 3000-548 Coimbra, Portugal
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26
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Chang E, Kim L, Choi JM, Park SE, Rhee EJ, Lee WY, Oh KW, Park SW, Park DI, Park CY. Ezetimibe stimulates intestinal glucagon-like peptide 1 secretion via the MEK/ERK pathway rather than dipeptidyl peptidase 4 inhibition. Metabolism 2015; 64:633-41. [PMID: 25704082 DOI: 10.1016/j.metabol.2015.02.001] [Citation(s) in RCA: 20] [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] [Received: 09/15/2014] [Revised: 01/31/2015] [Accepted: 02/04/2015] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Ezetimibe is known as a Niemann-Pick C1-Like 1 (NPC1L1) inhibitor and has been used as an agent for hypercholesterolemia. In our previous study, ezetimibe administration improved glycemic control and increased glucagon like peptide-1 (GLP-1), an incretin hormone with anti-diabetic properties. However, the mechanisms by which ezetimibe stimulates GLP-1 secretion are not fully understood. Thus, the specific aim of this study was to investigate the mechanism(s) by which ezetimibe stimulates GLP-1 secretion. MATERIALS/METHODS Male KK/H1J mice were divided into following groups: AIN-93G (NC), NC with ezetimibe (10 mg/kg/day), 45% high fat (HF) diet, and HF diet with ezetimibe. To investigate the role of ezetimibe in glucose homeostasis and GLP-1 secretion, an insulin tolerance test was performed and serum and intestinal GLP-1 levels and intestinal mRNA expression involved in GLP-1 synthesis were measured after 6 weeks of ezetimibe treatment. In vivo and in vitro dipeptidyl peptidase-4 (DPP-4) inhibition assays were employed to demonstrate the association between ezetimibe-induced GLP-1 change and DPP-4. The molecular mechanism by which ezetimibe affects GLP-1 secretion was evaluated by using human enteroendocrine NCI-H716 cells. RESULTS Ezetimibe supplementation significantly ameliorated HF-increased glucose and insulin resistance in the type 2 diabetic KK/H1J mouse model. Serum and intestinal active GLP-1 levels were significantly increased by ezetimibe in HF-fed animals. However, mRNA expression of genes involved in intestinal GLP-1 synthesis was not altered. Furthermore, ezetimibe did not inhibit the activity of either in vivo or in vitro dipeptidyl peptidase-4 (DPP-4). The direct effects of ezetimibe on GLP-1 secretion and L cell secretory mechanisms were examined in human NCI-H716 intestinal cells. Ezetimibe significantly stimulated active GLP-1 secretion, which was accompanied by the activation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Ezetimibe-increased GLP-1 secretion was abrogated by inhibiting the MEK/ERK pathway with PD98059. CONCLUSION These findings suggest a possible novel biological role of ezetimibe in glycemic control to stimulate intestinal GLP-1 secretion via the MEK/ERK signaling pathway.
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Affiliation(s)
- Eugene Chang
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Republic of Korea
| | - Lisa Kim
- Diabetes Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Mook Choi
- Diabetes Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Eun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Eun-Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won-Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ki-Won Oh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung-Woo Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Cheol-Young Park
- Diabetes Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Sharma A, Paliwal G, Upadhyay N, Tiwari A. Therapeutic stimulation of GLP-1 and GIP protein with DPP-4 inhibitors for type-2 diabetes treatment. J Diabetes Metab Disord 2015; 14:15. [PMID: 26473146 PMCID: PMC4607261 DOI: 10.1186/s40200-015-0143-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 02/28/2015] [Indexed: 12/25/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibition is a new treatment for type-2 diabetes. DPP-4 inhibition increases levels of active GLP-1. GLP-1 enhances insulin secretion and diminishes glucagon secretion, in this manner reducing glucose concentrations in blood. A number of DPP-4 inhibitors are under clinical development. However, the durability and long-term safety of DPP-4 inhibition remain to be established. These synthetic DPP-4 inhibitors are showing some side effects. Herbal medicines are alternative medicine over synthetic drugs that can relieve the patients. Various research studies have been carried all over the world to evaluate the efficacy of herbs in the treatment of Type II diabetes mellitus. For a long time type II diabetes mellitus has been treated orally with herbal medicines, because plant products are frequently prescribed due to their less toxicity than conventional medicines.
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Affiliation(s)
- Alok Sharma
- School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya (State
Technological University of Madhya Pradesh), Bhopal, India
| | - Geetanjali Paliwal
- School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya (State
Technological University of Madhya Pradesh), Bhopal, India
| | - Nisha Upadhyay
- School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya (State
Technological University of Madhya Pradesh), Bhopal, India
| | - Archana Tiwari
- School of Biotechnology, Rajiv Gandhi Proudyogiki Vishwavidyalaya (State
Technological University of Madhya Pradesh), Bhopal, India
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28
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Cao Y, Cao X, Liu XM. Expression of cholecystokinin2-receptor in rat and human L cells and the stimulation of glucagon-like peptide-1 secretion by gastrin treatment. Acta Histochem 2015; 117:205-10. [PMID: 25601282 DOI: 10.1016/j.acthis.2014.12.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 11/30/2014] [Accepted: 12/18/2014] [Indexed: 12/21/2022]
Abstract
Gastrin is a gastrointestinal hormone secreted by G cells. Hypergastrinemia can improve blood glucose and glycosylated hemoglobin levels. These positive effects are primarily due to the trophic effects of gastrin on β-cells. In recent years, many receptors that regulate secretion of glucagon-like peptide 1 (GLP-1) have been identified in enteroendocrine L cell lines. This led us to hypothesize that, in addition to the trophic effects of gastrin on β-cells, L cells also express cholecystokinin2-receptor (CCK2R), which may regulate GLP-1 secretion and have synergistic effects on glucose homeostasis. Our research provides a preliminary analysis of CCK2R expression and the stimulating effect of gastrin treatment on GLP-1 secretion in a human endocrine L cell line, using RT-PCR, Western blot, immunocytochemistry, and ELISA analyses. The expression of proglucagon and prohormone convertase 3, which regulate GLP-1 biosynthesis, were also analyzed by real-time PCR. Double immunofluorescence labeling was utilized to assess the intracellular localization of CCK2R and GLP-1 in L cells harvested from rat colon tissue. Our results showed that CCK2R was expressed in both the human L cell line and the rat L cells. We also showed that treatment with gastrin, a CCK2R agonist, stimulated the secretion of GLP-1, and that this effect was likely due to increased expression of proglucagon and PCSK1 (also known as prohormone convertase 3 (PC3 gene)). These results not only provide a basis for the role gastrin may play in intestinal L cells, and may also provide the basis for the development of a method of gastrin-mediated glycemic regulation.
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Affiliation(s)
- Yang Cao
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xun Cao
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xiao-Min Liu
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China.
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Barengolts E, Manickam B, Eisenberg Y, Akbar A, Kukreja S, Ciubotaru I. EFFECT OF HIGH-DOSE VITAMIN D REPLETION ON GLYCEMIC CONTROL IN AFRICAN-AMERICAN MALES WITH PREDIABETES AND HYPOVITAMINOSIS D. Endocr Pract 2015; 21:604-12. [PMID: 25716637 DOI: 10.4158/ep14548.or] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE This double-blind, randomized, controlled trial evaluated whether 12 months of high-dose vitamin D2 supplementation improved insulin sensitivity and secretion and glycemic status. METHODS African-American males (AAM) with prediabetes (glycosylated hemoglobin [A1C] 5.7-6.4%), hypovitaminosis D (25-hydroxyvitamin D [25OHD] 5-29 ng/mL), and prevalent medical problems were supplemented with vitamin D3 (400 IU/day) and then randomized to weekly placebo or vitamin D2 (50,000 IU). The primary outcome was the change in oral glucose insulin sensitivity (OGIS, from an oral glucose tolerance test [OGTT]) after 12 months of treatment. Secondary outcomes included other glycemic indices, A1C, and incident diabetes. RESULTS Baseline characteristics were similar in vitamin D-supplemented (n = 87) and placebo (n = 86) subjects completing the trial with average concentrations 14.4 ng/mL, 362 mL × min(-1) × m(-2), and 6.1% for 25OHD, OGIS and A1C, respectively. After 12 months, the vitamin D-supplemented group had a change in serum 25OHD +35 versus +6 ng/mL for placebo, P<.001; OGIS +7.8 versus -16.0 mL × min(-1) × m(-2) for placebo, P = .026; and A1C -0.01 versus +0.01% for placebo, P = .66. Ten percent of subjects in both groups progressed to diabetes. A posthoc analysis of participants with baseline impaired fasting glucose (IFG) showed that more subjects in the vitamin D subgroup (31.6%) than placebo (8.3%) returned to normal glucose tolerance, but the difference did not reach significance (P = .13). CONCLUSION The trial does not provide evidence that 12 months of high-dose D2 repletion improves clinically relevant glycemic outcomes in subjects with prediabetes and hypovitaminosis D (NCT01375660).
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Abstract
Incretin-based therapy has clearly emerged as one of the most sought out strategy in managing type 2 diabetes, primarily because they generally do not causes hypoglycemia and possess weight-neutral or weight losing properties. Efficacy-wise too, these agents, are more or less similar to commonly used drugs metformin and sulfonylureas. Interestingly, some studies recently suggested that glycemic response to these incretin-based therapies could also differ ethnicity-wise. Subsequently, meta-analysis from these studies also suggested that Asians may have better response to these incretin-based therapies. This review will be an attempt to critically analyze those studies available in literature and to address as to why East-Asians and South-Asians may have different incretin response compared to non-Asians.
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Affiliation(s)
- Awadhesh Kumar Singh
- Consultant Endocrinologist, G.D. Diabetes Hospital, Kolkata, West Bengal, and Sun Valley Diabetes Hospital, Guwahati, Assam, India
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Abstract
Although GLP-1 (glucagon like peptide-1) based therapies (GLP-1 agonists and dipeptidyl peptidase-4 inhibitors) is currently playing a cornerstone role in the treatment of type 2 diabetes, dilemma does exist about some of its basic physiology. So far, we know that GLP-1 is secreted by the direct actions of luminal contents on the L cells in distal jejunum and proximal ileum. However, there is growing evidence now, which suggest that other mechanism via "neural" or "upper gut" signals may be playing a second fiddle and could stimulate GLP-1 secretion even before the luminal contents have reached into the proximities of L cells. Therefore, the contribution of direct and indirect mechanism to GLP-1 secretion remains elusive. Furthermore, no clear consensus exists about the pattern of GLP-1 secretion, although many believe it is monophasic. One of the most exciting issues in incretin science is GLP-1 level and GLP-1 responsiveness. It is not exactly known as to what happens to endogenous GLP-1 with progressive worsening of dysglycemia from normal glucose tolerance to impaired glucose to frank diabetes and furthermore with increasing duration of diabetes. Although, conventional wisdom suggests that there may be a decrease in endogenous GLP-1 level with the worsening of dysglycemia, literature showed discordant results. Furthermore, there is emerging evidence to suggest that GLP-1 response can vary with ethnicity. This mini review is an attempt to put a brief perspective on all these issues.
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Affiliation(s)
- Awadhesh Kumar Singh
- Senior Consultant Endocrinologist, G.D Diabetes Hospital, Kolkata, West Bengal, India
- Sun Valley Diabetes Hospital, Guwahati, Assam, India
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Papaetis GS. Incretin-based therapies in prediabetes: Current evidence and future perspectives. World J Diabetes 2014; 5:817-834. [PMID: 25512784 PMCID: PMC4265868 DOI: 10.4239/wjd.v5.i6.817] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Revised: 09/10/2014] [Accepted: 11/10/2014] [Indexed: 02/05/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.
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Ahmadieh H, Azar ST. The role of incretin-based therapies in prediabetes: a review. Prim Care Diabetes 2014; 8:286-294. [PMID: 24666932 DOI: 10.1016/j.pcd.2014.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/20/2014] [Accepted: 02/24/2014] [Indexed: 12/25/2022]
Abstract
Prediabetes, a high-risk state for future development of diabetes, is prevalent globally. Abnormalities in the incretin axis are important in the progression of B-cell failure in type 2 diabetes. Incretin based therapy was found to improve B cell mass and glycaemic control in addition to having multiple beneficial effects on the systolic and diastolic blood pressure, weight loss in addition to their other beneficial effects on the liver and cardiovascular system. In prediabetes, several well-designed preventive trials have shown that lifestyle and pharmacologic interventions such as metformin, thiazolidinediones (TZD), acarbose and, nateglinide and orlistat, are effective in reducing diabetes development. In recent small studies, incretin based therapy (DPP IV inhibitors and GLP-1 agonists) have also been extended to patients with prediabetes since it was shown to better preserve B-cell function and mass in animal studies and in clinical trials and it was also shown to help maintain good long term metabolic control. Because of the limited studies and clinical experience, their side effects and costs currently guidelines do not recommend incretin-based therapies as an option for treatment in patients with prediabetes. With future clinical trials and studies they may be recommended for patients with impaired fasting glucose or impaired glucose tolerance.
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Affiliation(s)
- Hala Ahmadieh
- Department of Internal Medicine, Division of Endocrinology and Metabolism, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, United States.
| | - Sami T Azar
- Department of Internal Medicine, Division of Endocrinology and Metabolism, American University of Beirut-Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, United States.
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Yang X, Li Y, Wang Y, Zheng X, Kong W, Meng F, Zhou Z, Liu C, Li Y, Gong M. Long-Acting GLP-1 Analogue in V-Shaped Conformation by Terminal Polylysine Modifications. Mol Pharm 2014; 11:4092-9. [PMID: 25243635 DOI: 10.1021/mp5002685] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Xue Yang
- Department of Pharmacy, Tianjin Traditional Medicine University, Tianjin, China
| | - Ying Li
- Tianjin Neurological
Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuli Wang
- Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Xuemin Zheng
- Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Weiling Kong
- Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Fancui Meng
- Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Zhixing Zhou
- Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Changxiao Liu
- Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Ying Li
- Tianjin Neurological
Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Min Gong
- Tianjin Institute of Pharmaceutical Research, Tianjin, China
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Arya VB, Rahman S, Senniappan S, Flanagan SE, Ellard S, Hussain K. HNF4A mutation: switch from hyperinsulinaemic hypoglycaemia to maturity-onset diabetes of the young, and incretin response. Diabet Med 2014; 31:e11-5. [PMID: 24299156 PMCID: PMC4305198 DOI: 10.1111/dme.12369] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 09/17/2013] [Accepted: 11/28/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatocyte nuclear factor 4α (HNF4A) is a member of the nuclear receptor family of ligand-activated transcription factors. HNF4A mutations cause hyperinsulinaemic hypoglycaemia in early life and maturity-onset diabetes of the young. Regular screening of HNF4A mutation carriers using the oral glucose tolerance test has been recommended to diagnose diabetes mellitus at an early stage. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are incretin hormones, responsible for up to 70% of the secreted insulin after a meal in healthy individuals. We describe, for the first time, gradual alteration of glucose homeostasis in a patient with HNF4A mutation after resolution of hyperinsulinaemic hypoglycaemia, on serial oral glucose tolerance testing. We also measured the incretin response to a mixed meal in our patient. CASE REPORT Our patient was born with macrosomia and developed hyperinsulinaemic hypoglycaemia in the neonatal period. Molecular genetic analysis confirmed HNF4A mutation (p.M116I, c.317G>A) as an underlying cause of hyperinsulinaemic hypoglycaemia. Serial oral glucose tolerance testing, after the resolution of hyperinsulinaemic hypoglycaemia, confirmed the diagnosis of maturity-onset diabetes of the young at the age of 10 years. Interestingly, the intravenous glucose tolerance test revealed normal glucose disappearance rate and first-phase insulin secretion. Incretin hormones showed a suboptimal rise in response to the mixed meal, potentially explaining the discrepancy between the oral glucose tolerance test and the intravenous glucose tolerance test. CONCLUSIONS Maturity-onset diabetes of the young can develop as early as the first decade of life in persons with an HNF4A mutation. Impaired incretin response might be contributory in the early stages of HNF4A maturity-onset diabetes of the young.
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Affiliation(s)
- V B Arya
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHSTrust, London
- The Institute of Child Health, University College LondonExeter, UK
| | - S Rahman
- The Institute of Child Health, University College LondonExeter, UK
| | - S Senniappan
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHSTrust, London
- The Institute of Child Health, University College LondonExeter, UK
| | - S E Flanagan
- Institute of Biomedical and Clinical Science, University of Exeter Medical SchoolExeter, UK
| | - S Ellard
- Institute of Biomedical and Clinical Science, University of Exeter Medical SchoolExeter, UK
| | - K Hussain
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHSTrust, London
- The Institute of Child Health, University College LondonExeter, UK
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Puddu A, Sanguineti R, Montecucco F, Viviani GL. Glucagon-like peptide-1 secreting cell function as well as production of inflammatory reactive oxygen species is differently regulated by glycated serum and high levels of glucose. Mediators Inflamm 2014; 2014:923120. [PMID: 24648662 PMCID: PMC3932225 DOI: 10.1155/2014/923120] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 12/18/2013] [Accepted: 12/19/2013] [Indexed: 12/02/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1), an intestinal hormone contributing to glucose homeostasis, is synthesized by proglucagon and secreted from intestinal neuroendocrine cells in response to nutrients. GLP-1 secretion is impaired in type 2 diabetes patients. Here, we aimed at investigating whether diabetic toxic products (glycated serum (GS) or high levels of glucose (HG)) may affect viability, function, and insulin sensitivity of the GLP-1 secreting cell line GLUTag. Cells were cultured for 5 days in presence or absence of different dilutions of GS or HG. GS and HG (alone or in combination) increased reactive oxygen species (ROS) production and upregulated proglucagon mRNA expression as compared to control medium. Only HG increased total production and release of active GLP-1, while GS alone abrogated secretion of active GLP-1. HG-mediated effects were associated with the increased cell content of the prohormone convertase 1/3 (PC 1/3), while GS alone downregulated this enzyme. HG upregulated Glucokinase (GK) and downregulated SYNTHAXIN-1. GS abrogated SYNTHAXIN-1 and SNAP-25. Finally, high doses of GS alone or in combination with HG reduced insulin-mediated IRS-1 phosphorylation. In conclusion, we showed that GS and HG might regulate different pathways of GLP-1 production in diabetes, directly altering the function of neuroendocrine cells secreting this hormone.
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Affiliation(s)
- Alessandra Puddu
- Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16143 Genoa, Italy
| | - Roberta Sanguineti
- Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16143 Genoa, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16143 Genoa, Italy
- Division of Cardiology, Department of Medicine, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, 64 Avenue de la Roseraie, 1211 Geneva, Switzerland
- Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland
| | - Giorgio L. Viviani
- Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16143 Genoa, Italy
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Setji T, Feinglos M. Albiglutide: clinical overview of a long-acting GLP-1 receptor agonist in the treatment of Type 2 diabetes. Expert Rev Endocrinol Metab 2013; 8:229-238. [PMID: 30780810 DOI: 10.1586/eem.13.2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Glucagon-like peptide-1 receptor agonists have become an important therapeutic option for patients with Type 2 diabetes because of their ability to lower blood glucose and help patients lose weight. There are currently three glucagon-like peptide-1 receptor agonists on the market. In the near future, albiglutide will undergo review by the US FDA for possible approval. Results from Phase I/II trials have demonstrated that albiglutide is a safe and efficacious medication for treating Type 2 diabetes. It lowers hemoglobin A1c and decreases bodyweight. It appears to have fewer gastrointestinal side effects than liraglutide. The once-weekly (or possibly longer duration) dosing of albiglutide may improve adherence. Several Phase III trials are expected to be completed in 2013. These trials will shed further light on the safety and efficacy of albiglutide.
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Affiliation(s)
- Tracy Setji
- b Duke University Medical Center, Durham, NC 27710, USA.
| | - Mark Feinglos
- a Duke University Medical Center, Durham, NC 27710, USA
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Incretin dysfunction in type 2 diabetes: Clinical impact and future perspectives. DIABETES & METABOLISM 2013; 39:195-201. [DOI: 10.1016/j.diabet.2013.03.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 03/08/2013] [Accepted: 03/11/2013] [Indexed: 01/21/2023]
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Runchey SS, Valsta LM, Schwarz Y, Wang C, Song X, Lampe JW, Neuhouser ML. Effect of low- and high-glycemic load on circulating incretins in a randomized clinical trial. Metabolism 2013; 62:188-95. [PMID: 22959497 PMCID: PMC3519963 DOI: 10.1016/j.metabol.2012.07.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 07/13/2012] [Accepted: 07/13/2012] [Indexed: 11/21/2022]
Abstract
OBJECTIVE Low-glycemic load diets lower post-prandial glucose and insulin responses; however, the effect of glycemic load on circulating incretin concentrations is unclear. We aimed to assess effects of dietary glycemic load on fasting and post-prandial glucose, insulin and incretin (i.e., glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)) concentrations and to examine for effect modification by adiposity. MATERIALS AND METHODS We conducted a single-center, randomized controlled crossover feeding trial in which a subset of participants had post-prandial testing. Participants were recruited from the local Seattle area. We enrolled 89 overweight-obese (BMI 28.0-39.9 kg/m(2)) and lean (BMI 18.5-25.0 kg/m(2)) healthy adults. Participants consumed two 28-day, weight-maintaining high- and low-glycemic load controlled diets in random order. Primary outcome measures were post-prandial circulating concentrations of glucose, insulin, GIP and GLP-1, following a test breakfast. RESULTS Of the 80 participants completing both diet interventions, 16 had incretin testing and comprise the group for analyses. Following each 28-day high- and low-glycemic load diet, mean fasting concentrations of insulin, glucose, GIP and GLP-1 were not significantly different. Mean integrated post-prandial concentrations of glucose, insulin and GIP were higher (1504±476 mg/dL/min, p<0.01; 2012±644 μU/mL/min, p<0.01 and 15517±4062 pg/mL/min, p<0.01, respectively) and GLP-1 was lower (-81.6±38.5 pmol/L/min, p<0.03) following the high-glycemic load breakfast as compared to the low-glycemic load breakfast. Body fat did not significantly modify the effect of glycemic load on metabolic outcomes. CONCLUSIONS High-glycemic load diets in weight-maintained healthy individuals lead to higher post-prandial GIP and lower post-prandial GLP-1 concentrations. Future studies evaluating dietary glycemic load manipulation of incretin effects would be helpful for establishing diabetes nutrition guidelines.
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Affiliation(s)
- Shauna S. Runchey
- Division of Endocrinology, Metabolism and Nutrition, Department of Medicine-University of Washington
| | - Liisa M. Valsta
- Finnish National Institute for Health and Welfare, Nutrition Unit and European Food Safety Authority (EFSA), Dietary and Chemical Monitoring Unit, Parma, Italy
| | | | | | | | - Johanna W. Lampe
- Fred Hutchinson Cancer Research Center
- Department of Epidemiology and Interdisciplinary Graduate Program in Nutritional Sciences-University of Washington
| | - Marian L. Neuhouser
- Fred Hutchinson Cancer Research Center
- Department of Epidemiology and Interdisciplinary Graduate Program in Nutritional Sciences-University of Washington
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Duarte AI, Candeias E, Correia SC, Santos RX, Carvalho C, Cardoso S, Plácido A, Santos MS, Oliveira CR, Moreira PI. Crosstalk between diabetes and brain: glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration. Biochim Biophys Acta Mol Basis Dis 2013; 1832:527-41. [PMID: 23314196 DOI: 10.1016/j.bbadis.2013.01.008] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Revised: 12/18/2012] [Accepted: 01/06/2013] [Indexed: 12/14/2022]
Abstract
According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.
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Affiliation(s)
- A I Duarte
- Life Sciences Department, University of Coimbra, Largo Marquês de Pombal, Coimbra, Portugal.
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Shin JA, Lee JH, Kim HS, Choi YH, Cho JH, Yoon KH. Prevention of diabetes: a strategic approach for individual patients. Diabetes Metab Res Rev 2012; 28 Suppl 2:79-84. [PMID: 23280871 DOI: 10.1002/dmrr.2357] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The 'diabetes epidemic' is an important health and socioeconomic problem worldwide. Type 2 diabetes is a chronic disease with gradual deterioration in glucose metabolism which causes multiple systemic complications. Therefore, early intervention in the prediabetic stage is a valuable approach to reduce diabetes development and related complications. Many clinical trials have suggested that lifestyle intervention, including moderate-intensity exercise and diet control, and pharmacologic intervention using metformin, α-glucosidase inhibitors, thiazolidinediones, anti-obesity drugs and incretin mimics, are effective in preventing diabetes development. However, an individualized approach with careful consideration of the patient's risk status and health economics is needed to perform a successful intervention programmes. In this review, we will summarize the known evidence on treatment- and cost-effectiveness of drug and lifestyle treatment. Additionally, we will propose a strategic approach algorithm that is applicable to clinical practice.
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Affiliation(s)
- Jeong-Ah Shin
- Department of Endocrinology & Metabolism, Seoul St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Korea
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Zhang F, Tang X, Cao H, Lü Q, Li N, Liu Y, Zhang X, Zhang Y, Cao M, Wan J, An Z, Tong N. Impaired secretion of total glucagon-like peptide-1 in people with impaired fasting glucose combined impaired glucose tolerance. Int J Med Sci 2012; 9:574-581. [PMID: 22991496 PMCID: PMC3444978 DOI: 10.7150/ijms.4128] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2012] [Accepted: 08/19/2012] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE We assessed the serum glucagon-like peptide-1 (GLP-1) levels for Chinese adults with pre-diabetes (PD) and newly-diagnosed diabetes mellitus (NDDM) during oral glucose tolerance test (OGTT). The relationships between total GLP-1 level and islet β cell function, insulin resistance (IR) and insulin sensitivity (IS) were also investigated. METHODS A 75g glucose OGTT was given to 531 subjects. Based on the results, they were divided into groups of normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), IFG combined IGT (IFG+IGT) and NDDM. Total GLP-1 levels were measured at 0- and 2-hour during OGTT. Homeostasis model assessment of β cell function (HOMA-β), HOMA of insulin resistance (HOMA-IR), Gutt and Matsuda indexes were calculated. The relationships between GLP-1 level and β cell function, IR and IS were analyzed. RESULTS The levels of total fasting GLP-1 (FGLP-1), 2h GLP-1 (2hGLP-1) and 2hGLP-1 increments (∆GLP-1) following OGTT reduced significantly in IFG+IGT and NDDM groups (P<0.005). HOMA-β , HOMA-IR, Gutt and Matsuda indexes demonstrated various patterns among NGT, isolated IFG, isolated IGT, IFG+IGT and NDDM groups (P<0.05). Spearman rank correlation analysis and multivariable linear regression model suggested that some levels of correlation between GLP-1 levels, ∆GLP-1 and β cell function, IR (P<0.05). CONCLUSIONS The total GLP-1 levels and its response to glucose load decreased significantly in IFG+IGT group, compared to isolated IFG or IGT group. They were even similar to that of NDDM group. Moreover, there were observable correlations between impaired GLP-1 secretion and β cell function, IR and IS.
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Affiliation(s)
- Fang Zhang
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Xialian Tang
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Hongyi Cao
- 2. Division of Endocrinology, The Fifth People's Hospital of Chengdu, Chengdu, Sichuan 610000, China
| | - Qingguo Lü
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Nali Li
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Yupu Liu
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Xiangxun Zhang
- 3. Research Laboratory of Endocrine and Metabolic Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuwei Zhang
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Mingming Cao
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Jun Wan
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Zhenmei An
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
| | - Nanwei Tong
- 1. Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang , Chengdu, Sichuan 610041, China
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Kota SK, Ugale S, Gupta N, Naik V, Kumar KVSH, Modi KD. Ileal interposition with sleeve gastrectomy for treatment of type 2 diabetes mellitus. Indian J Endocrinol Metab 2012; 16:589-98. [PMID: 22837922 PMCID: PMC3401762 DOI: 10.4103/2230-8210.98017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AIM Combination of laparoscopic ileal interposition (II) with sleeve gastrectomy (SG) is an upcoming procedure, which offers good metabolic improvement and weight reduction without causing significant malabsorption. The objective of this study was to evaluate the results of this novel procedure for control of type 2 diabetes, obesity, hypertension, and related metabolic abnormalities. MATERIALS AND METHODS The II and SG was performed in 43 patients (M:F = 25:18) from February 2008. Participants had a mean age of 47.2 ± 8.2 years (range 29-66 years), mean duration of diabetes of 10.1 ± 9.2 years (range 1-32 years), and mean preoperative body mass index (BMI) of 33.2 ± 7.8 kg/m2. All patients had poorly controlled type 2 diabetes mellitus (DM) [mean glycated hemoglobin (HbA1C) 9.6 ± 2.1%] despite use of oral hypoglycemic agents (OHAs) and/or insulin. Thirty (70%) patients had hypertension, 20 (46%) had dyslipidemia, and 18 (42%) had significant microalbuminuria. The primary outcome was remission of diabetes (HbA1C < 6.5% without OHAs/insulin) and the secondary outcomes were reduction in antidiabetic agent requirement and components of metabolic syndrome. RESULTS Mean follow-up was for 20.2 ± 8.6 months (range 4-40 months). Postoperatively, glycemic parameters (fasting and post-lunch blood sugar, HbA1C improved in all patients (P < 0.05) at all intervals. Twenty (47%) patients had remission in diabetes and the remaining patients showed significantly decreased OHA requirement. All patients had weight loss between 15 and 30% (P < 0.05). Twenty-seven (90%) patients had remission in hypertension. At 3 years, the mean fall in HbA1C (34%) was more than reduction in BMI (25%). There was a declining trend in lipids and microalbuminuria postoperatively, though it was significant for microalbuminuria only. CONCLUSIONS The laparoscopic II with SG seems to be a promising procedure for control of type 2 DM, hypertension, weight reduction, and associated metabolic abnormalities. A multicenter study with larger number of patients and a longer follow-up period is needed to substantiate our preliminary findings.
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Affiliation(s)
- Sunil Kumar Kota
- Department of Endocrinology, Medwin Hospitals, Hyderabad, Andhra Pradesh, India
| | - Surendra Ugale
- Department of Laparoscopic Surgery, Kirloskar Hospital, Hyderabad, Andhra Pradesh, India
| | - Neeraj Gupta
- Department of Laparoscopic Surgery, Kirloskar Hospital, Hyderabad, Andhra Pradesh, India
| | - Vishwas Naik
- Department of Laparoscopic Surgery, Kirloskar Hospital, Hyderabad, Andhra Pradesh, India
| | - K. V. S. Hari Kumar
- Department of Endocrinology, Command Hospital, Lucknow, Uttar Pradesh, India
| | - Kirtikumar D. Modi
- Department of Endocrinology, Medwin Hospitals, Hyderabad, Andhra Pradesh, India
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44
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Cao Z, Li Y, Tang L, Xu W, Liu C, Zhang J, Gong M. Formation of cyclic structure at amino-terminus of glucagon-like peptide-1 exhibited a prolonged half-life in vivo. Diabetes Res Clin Pract 2012; 96:362-70. [PMID: 22284602 DOI: 10.1016/j.diabres.2012.01.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 12/12/2011] [Accepted: 01/03/2012] [Indexed: 11/20/2022]
Abstract
The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the therapy of type 2 diabetes. However, the biological half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The stabilization of GLP-1 is critical for its utility in drug development. In this study, several GLP-1 mutants containing an N-terminal cyclic conformation were prepared in that the existence of cyclic conformation is predicted to increase the stabilization of GLP-1 in vivo. In this study, the binding capacities of the mutants were determined, the stabilities of the mutants were investigated and the physiological functions of the mutants were compared with those of wild-type GLP-1 in animals. The results indicated that the mutant (GLP1N8) remarkably raised the half-life in vivo; it also showed better glucose tolerance and higher HbA(1c) reduction than GLP-1 and exendin-4 in rodents. These results suggest that the GLP-1 analog (GLP1N8) which contains an N-terminal cyclic structure might be utilized as possible potent anti-diabetic drugs in the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Zhenghong Cao
- Department of Pharmacy, Tianjin University of Traditional Medicine, China
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45
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Abstract
The pathogenetic mechanisms causing type 2 diabetes are complex, and include a significant reduction of the incretin effect. In patients with type 2 diabetes, GLP-1 secretion may be impaired, while GIP secretion seems unaffected. In contrast, the insulinotropic activity of GIP is severely altered, whereas that of GLP-1 is maintained to a great extent. Better understanding of the role of incretin hormones in glucose homeostasis has led to the development of incretin-based therapies that complement and offer important advantages over previously used agents. Incretin-based agents have significant glucose-lowering effects, promote weight loss (or are weight-neutral), inhibit glucagon secretion while maintaining counter-regulatory mechanisms, exhibit cardiovascular benefits, and protect β-cells while possessing a low risk profile. At present, incretin-based therapies are most widely used as add on to metformin to provide sufficient glycemic control after metformin failure. However, they are also recommended as monotherapy early in the disease course, and later in triple combination. These agents may also be a promising therapeutic tool in prediabetic subjects. Therefore, a therapeutic algorithm is needed for their optimal application at different stages of diabetes, as suggested in this article.
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Affiliation(s)
- Simona Cernea
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Targu Mures, Romania.
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46
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Kitahara Y, Miura K, Yasuda R, Kawanabe H, Ogawa S, Eto Y. Nateglinide stimulates glucagon-like peptide-1 release by human intestinal L cells via a K(ATP) channel-independent mechanism. Biol Pharm Bull 2011; 34:671-6. [PMID: 21532155 DOI: 10.1248/bpb.34.671] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A reduced incretin effect is one of the well-known characteristics of patients with type 2 diabetes, and impaired release of glucagon-like peptide-1 (GLP-1) has been reported to be at least partly involved. In this study, we investigated the effect of nateglinide on GLP-1 release in vivo and in vitro. The GLP-1 level in the portal blood at 20 min after oral administration of nateglinide to Wistar rats was about twice that in vehicle-treated rats. To clarify whether this effect of nateglinide was related to direct stimulation of intestinal cells, in vitro studies were performed using human intestinal L cells (NCI-H716). Nateglinide stimulated GLP-1 release in a concentration-dependent manner from 500 µM, along with transient elevation of the intracellular calcium level. However, diazoxide, nitrendipine, and dantrolene did not block this effect of nateglinide. In addition, the major metabolite of nateglinide, tolbutamide, and mitiglinide, all of which augment insulin secretion by the pancreatic islets, had no effect on GLP-1 release by this cell line. On the other hand, capsazepine significantly inhibited the promotion of GLP-1 release by nateglinide in a concentration-dependent manner. These findings indicate that nateglinide directly stimulates GLP-1 release by intestinal L cells in a K(ATP) channel-independent manner. A novel target of nateglinide may be involved in increasing intracellular calcium to stimulate GLP-1 release, e.g., the transient receptor potential channels. Taken together, the present findings indicate that promotion of GLP-1 release from intestinal L cells may be another important mechanism by which nateglinide restores early-phase insulin secretion and regulates postprandial glucose metabolism.
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Affiliation(s)
- Yoshiro Kitahara
- Exploratory Research Laboratories, Ajinomoto Pharmaceuticals Co., Ltd, Kawasaki, Japan.
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47
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Mechanism-based population modelling for assessment of L-cell function based on total GLP-1 response following an oral glucose tolerance test. J Pharmacokinet Pharmacodyn 2011; 38:713-25. [PMID: 21922329 DOI: 10.1007/s10928-011-9216-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Accepted: 09/08/2011] [Indexed: 01/26/2023]
Abstract
GLP-1 is an insulinotropic hormone that synergistically with glucose gives rise to an increased insulin response. Its secretion is increased following a meal and it is thus of interest to describe the secretion of this hormone following an oral glucose tolerance test (OGTT). The aim of this study was to build a mechanism-based population model that describes the time course of total GLP-1 and provides indices for capability of secretion in each subject. The goal was thus to model the secretion of GLP-1, and not its effect on insulin production. Single 75 g doses of glucose were administered orally to a mixed group of subjects ranging from healthy volunteers to patients with type 2 diabetes (T2D). Glucose, insulin, and total GLP-1 concentrations were measured. Prior population data analysis on measurements of glucose and insulin were performed in order to estimate the glucose absorption rate. The individual estimates of absorption rate constants were used in the model for GLP-1 secretion. Estimation of parameters was performed using the FOCE method with interaction implemented in NONMEM VI. The final transit/indirect-response model obtained for GLP-1 production following an OGTT included two stimulation components (fast, slow) for the zero-order production rate. The fast stimulation was estimated to be faster than the glucose absorption rate, supporting the presence of a proximal-distal loop for fast secretion from L: -cells. The fast component (st₃) = 8.64·10⁻⁵ [mg⁻¹]) was estimated to peak around 25 min after glucose ingestion, whereas the slower component (st₄ = 26.2·10⁻⁵ [mg⁻¹]) was estimated to peak around 100 min. Elimination of total GLP-1 was characterised by a first-order loss. The individual values of the early phase GLP-1 secretion parameter (st₃) were correlated (r = 0.52) with the AUC(0-60 min.) for GLP-1. A mechanistic population model was successfully developed to describe total GLP-1 concentrations over time observed after an OGTT. The model provides indices related to different mechanisms of subject abilities to secrete GLP-1. The model provides a good basis to study influence of different demographic factors on these components, presented mainly by indices of the fast- and slow phases of GLP-1 response.
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48
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Zheng X, Li Y, Li X, Tang L, Xu W, Gong M. Peptide complex containing GLP-1 exhibited long-acting properties in the treatment of type 2 diabetes. Diabetes Res Clin Pract 2011; 93:410-20. [PMID: 21641071 DOI: 10.1016/j.diabres.2011.05.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 04/30/2011] [Accepted: 05/10/2011] [Indexed: 10/18/2022]
Abstract
The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, in vivo, the half-life of GLP-1 is short, which is caused by the degradation of dipeptidyl peptidase-IV (DPP-IV) and renal clearance. Thus, the stabilization of GLP-1 is critical for its utility in drug development. Peptides known as GLP-1 protectors are predicted to increase the half-life of GLP-1 in vivo. Protecting peptides are able to form stable complexes by non-covalent interactions with human GLP-1. In this study, the stability of the complex was investigated, and the physiological functions of the GLP-1/peptide 1 complex were compared to those of exenatide and liraglutide in animals. The results indicated that the GLP-1/peptide 1 complex remarkably raised the half-life of GLP-1 in vivo and showed better glucose tolerance and higher HbA(1c) reduction than exenatide and liraglutide in rodents. Based upon these results, it is suggested that the GLP-1/peptide 1 complex might be utilized as a possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Xuemin Zheng
- Department of Pharmaceutical Analysis, Tianjin University of Traditional Chinese Medicine, China
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49
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Li Y, Li X, Zheng X, Tang L, Xu W, Gong M. Disulfide bond prolongs the half-life of therapeutic peptide-GLP-1. Peptides 2011; 32:1400-7. [PMID: 21600946 DOI: 10.1016/j.peptides.2011.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Revised: 05/04/2011] [Accepted: 05/04/2011] [Indexed: 11/19/2022]
Abstract
The multiple physiological characterization of glucagon-like peptide-1 (GLP-1) makes it a promising drug candidate for the therapy of type 2 diabetes. However, the half-life of GLP-1 is short in vivo due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. This indicates that the stabilization of GLP-1 is critical for its utility in drug development. In this study, we developed a cluster of GLP-1 homodimeric analogs, which fused the mutated GLP-1 monomer by an intra-disulfide bridge. The stabilities of the GLP-1 homodimeric analogs were investigated and the physiological functions of the analogs were compared with those of wild-type GLP-1 in rats and human serum. Single dose glucose tolerance test was performed to investigate the administration frequency which satisfied the efficient glucose regulatory in rats. Multiple dose glucose tolerance tests were employed also to study the long-acting anti-diabetic activity of GLP-1 homodimeric analog. The results indicated that the GLP-1 homodimeric analog (hdGLP1G10C) remarkably raised the biological half-life of GLP-1; also HDGLP1G10C showed better glucose tolerance and higher HbA(1c) reduction than GLP-1 in rodents. Based upon the results in this study, it was suggested that hdGLP1G10C prolonged the stability of GLP-1 and retained the biological activity of GLP-1. The improved physiological characterization of hdGLP1G10C makes it as possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Ying Li
- School of Biosciences, University of Birmingham, United Kingdom
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50
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Li Y, Xu W, Tang L, Gong M, Zhang J. A novel GLP-1 analog exhibits potent utility in the treatment of type 2 diabetes with an extended half-life and efficient glucose clearance in vivo. Peptides 2011; 32:1408-14. [PMID: 21664938 DOI: 10.1016/j.peptides.2011.05.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Revised: 05/26/2011] [Accepted: 05/26/2011] [Indexed: 11/24/2022]
Abstract
The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the therapy of type 2 diabetes. However, the half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. Therefore, the stabilization of GLP-1 is critical for its utility in drug development. Based on our previous research, a GLP-1 analog that contained an intra-disulfide bond exhibited a prolonged biological half-life. In this study, we improved upon previous analogs with a novel GLP-1 analog that contained a tryptophan cage-like sequence for an improved binding affinity to the GLP-1 receptor. The binding capacities and the stabilities of GLP715a were investigated, and the physiological functions of the GLP715a were compared to those of the wild-type GLP-1 in animals. The results demonstrated that the new GLP-1 analog (GLP715a) increased its biological half-life to approximately 48h in vivo; GLP715a also exhibited a higher binding affinity to the GLP-1 receptor than the wild-type GLP-1. The increased binding capacity of GLP715a to its receptor resulted in a quick response to glucose administration. The long-acting anti-diabetic property of GLP715a was revealed by its increased glucose tolerance, higher HbA(1c) reduction, more efficient glucose clearance and quicker insulin stimulation upon glucose administration compared to the wild-type GLP-1 in rodents. The improved physiological characterizations of GLP715a make it a possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Ying Li
- School of Bioscience, University of Birmingham, UK
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