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Müller TD, Adriaenssens A, Ahrén B, Blüher M, Birkenfeld AL, Campbell JE, Coghlan MP, D'Alessio D, Deacon CF, DelPrato S, Douros JD, Drucker DJ, Figueredo Burgos NS, Flatt PR, Finan B, Gimeno RE, Gribble FM, Hayes MR, Hölscher C, Holst JJ, Knerr PJ, Knop FK, Kusminski CM, Liskiewicz A, Mabilleau G, Mowery SA, Nauck MA, Novikoff A, Reimann F, Roberts AG, Rosenkilde MM, Samms RJ, Scherer PE, Seeley RJ, Sloop KW, Wolfrum C, Wootten D, DiMarchi RD, Tschöp MH. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab 2025; 95:102118. [PMID: 40024571 PMCID: PMC11931254 DOI: 10.1016/j.molmet.2025.102118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. MAJOR CONCLUSIONS Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.
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Affiliation(s)
- Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany.
| | - Alice Adriaenssens
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Bo Ahrén
- Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
| | - Matthias Blüher
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Matthew P Coghlan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - David D'Alessio
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Carolyn F Deacon
- School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano DelPrato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | | | - Daniel J Drucker
- The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Natalie S Figueredo Burgos
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Brian Finan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Fiona M Gribble
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christian Hölscher
- Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Patrick J Knerr
- Indianapolis Biosciences Research Institute, Indianapolis, IN, USA
| | - Filip K Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christine M Kusminski
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arkadiusz Liskiewicz
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France
| | | | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany
| | - Frank Reimann
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Anna G Roberts
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Ricardo J Samms
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Philip E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kyle W Sloop
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland
| | - Denise Wootten
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | | | - Matthias H Tschöp
- Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
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Parra Villasmil MG, Bellin MD. Risk Factors and Mechanisms for Diabetes in Pancreatitis. Gastroenterol Clin North Am 2025; 54:175-188. [PMID: 39880526 PMCID: PMC11780253 DOI: 10.1016/j.gtc.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
Diabetes (DM) can occur as a complication of acute, acute recurrent, or chronic pancreatitis, affecting more than 30% of adults with chronic pancreatitis. Data on the pathophysiology and management are limited, especially in pediatric population. Proposed mechanisms include insulin deficiency, insulin resistance, decreased pancreatic polypeptide, and possible beta-cell autoimmunity (in a small subset). Risk factors for developing diabetes in those with pancreatitis may include hypertriglyceridemia, obesity, necrotizing pancreatitis, exocrine pancreatic insufficiency, and pancreatic calcifications, among others. Further studies are required to understand pathophysiology of pancreatogenic DM, in order to define optimal treatment approaches.
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Affiliation(s)
- María Graciela Parra Villasmil
- Department of Pediatrics, Stead Family Children's Hospital, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA
| | - Melena D Bellin
- Department of Pediatrics, University of Minnesota, MMC 391, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA.
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Lv Y, Lu X, Liu G, Qi L, Zhong Z, Wang X, Zhang W, Shi R, Goodarzi MO, Pandol SJ, Li L. Differential Diagnosis of Post Pancreatitis Diabetes Mellitus Based on Pancreatic and Gut Hormone Characteristics. J Clin Endocrinol Metab 2024; 109:2003-2011. [PMID: 38344778 DOI: 10.1210/clinem/dgae080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/20/2024] [Accepted: 02/06/2024] [Indexed: 03/20/2024]
Abstract
CONTEXT Distinguishing different types of diabetes is important in directing optimized treatment strategies and correlated epidemiological studies. OBJECTIVE Through detailed analysis of hormone responses to mixed meal tolerance test (MMTT), we aimed to find representing characteristics of post-acute pancreatitis diabetes mellitus (PPDM-A) and post-chronic pancreatitis diabetes mellitus (PPDM-C). METHODS Participants with PPDM-A, PPDM-C, type 1 diabetes, type 2 diabetes, and normal controls (NCs) underwent MMTT. Fasting and postprandial responses of serum glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, gastric inhibitory peptide (GIP), glucagon like peptide-1 (GLP-1), and peptide YY (PYY) were detected and compared among different groups. Focused analysis on calculated insulin sensitivity and secretion indices were performed to determine major causes of hyperglycemia in different conditions. RESULTS Participants with PPDM-A were characterized by increased C-peptide, insulin, glucagon, and PP, but decreased ghrelin, GIP, and PYY compared with NCs. Patients with PPDM-C showed secretion insufficiency of C-peptide, insulin, ghrelin, and PYY, and higher postprandial responses of glucagon and PP than NCs. In particular, both fasting and postprandial levels of ghrelin in PPDM-C were significantly lower than other diabetes groups. PYY responses in patients with PPDM-A and PPDM-C were markedly reduced. Additionally, the insulin sensitivity of PPDM-A was decreased, and the insulin secretion for PPDM-C was decreased. CONCLUSION Along with the continuum from acute to chronic pancreatitis, the pathological mechanism of PPDM changes from insulin resistance to insulin deficiency. Insufficient PYY secretion is a promising diagnostic marker for distinguishing PPDM from type 1 and type 2 diabetes. Absent ghrelin secretion to MMTT may help identify PPDM-C.
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Affiliation(s)
- Yingqi Lv
- Division of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Xuejia Lu
- School of Medicine, Nanjing Medical University, Nanjing 210009, China
- Division of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Gaifang Liu
- Division of Gastroenterology, Hebei General Hospital, Shijiazhuang 050000, China
| | - Liang Qi
- Division of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Zihang Zhong
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210009, China
| | - Xiaoyuan Wang
- Division of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Ruihua Shi
- School of Medicine, Nanjing Medical University, Nanjing 210009, China
- Division of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Mark O Goodarzi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Stephen J Pandol
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ling Li
- Division of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
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Helsted MM, Schaltz NL, Gasbjerg LS, Christensen MB, Vilsbøll T, Knop FK. Safety of native glucose-dependent insulinotropic polypeptide in humans. Peptides 2024; 177:171214. [PMID: 38615716 DOI: 10.1016/j.peptides.2024.171214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/04/2024] [Accepted: 04/09/2024] [Indexed: 04/16/2024]
Abstract
In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1-42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1-42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78% did not mention safety events, 10% of the studies reported that no safety events were observed in relation to GIP administration, and 15% of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1-42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1-42) and reported safety events. Clearance rates of GIP(1-42) were similar between participant groups. In conclusion, the available data indicate that GIP(1-42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1-42) administration is unknown.
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Affiliation(s)
- Mads M Helsted
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Nina L Schaltz
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Herlev, Denmark.
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Jagomäe T, Gaur N, Seppa K, Reimets R, Pastak M, Plaas M, Kaasik A, Vasar E, Plaas M. Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome. Front Endocrinol (Lausanne) 2023; 14:1234925. [PMID: 37900147 PMCID: PMC10611518 DOI: 10.3389/fendo.2023.1234925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/27/2023] [Indexed: 10/31/2023] Open
Abstract
Aim Wolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS. Methods Eight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis. Results DA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats. Conclusion We present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.
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Affiliation(s)
- Toomas Jagomäe
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Nayana Gaur
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Kadri Seppa
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Riin Reimets
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Marko Pastak
- Eye Clinic of Tartu University Hospital, Tartu, Estonia
| | - Mihkel Plaas
- Ear Clinic of Tartu University Hospital, Tartu, Estonia
| | - Allen Kaasik
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Eero Vasar
- Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Mario Plaas
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
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Goodarzi MO, Petrov MS. Diabetes of the Exocrine Pancreas: Implications for Pharmacological Management. Drugs 2023:10.1007/s40265-023-01913-5. [PMID: 37410209 PMCID: PMC10361873 DOI: 10.1007/s40265-023-01913-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/12/2023] [Indexed: 07/07/2023]
Abstract
Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development.
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Affiliation(s)
- Mark O Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Maxim S Petrov
- School of Medicine, University of Auckland, Auckland, New Zealand.
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Várkonyi TT, Pósa A, Pávó N, Pavo I. Perspectives on weight control in diabetes - Tirzepatide. Diabetes Res Clin Pract 2023:110770. [PMID: 37279858 DOI: 10.1016/j.diabres.2023.110770] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/30/2023] [Accepted: 06/01/2023] [Indexed: 06/08/2023]
Abstract
Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (GIP/GLP-1 RA) improves glycemic control. Besides improvement of glycemic control, tirzepatide treatment is associated with significantly more weight loss as compared to potent selective GLP-1 receptor agonists as well as other beneficial changes in cardio-metabolic parameters, such as reduced fat mass, blood pressure, improved insulin sensitivity, lipoprotein concentrations, and circulating metabolic profile in individuals with type 2 diabetes (T2D). Some of these changes are partially associated with weight reduction. We review here the putative mechanisms of GIP receptor agonism contributing to GLP-1 receptor agonism-induced weight loss and respective findings with GIP/GLP-1 RAs, including tirzepatide in T2D preclinical models and clinical studies. Subsequently, we summarize the clinical data on weight loss and related non-glycemic metabolic changes of tirzepatide in T2D. These findings suggest that the robust weight loss and associated changes are important contributors to the clinical profile of tirzepatide for the treatment of T2D diabetes and serve as the basis for further investigations including clinical outcomes.
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Affiliation(s)
- Tamas T Várkonyi
- Department of Internal Medicine, University of Szeged, Kálvária sgt. 57, H-6725 Szeged, Hungary.
| | - Anikó Pósa
- Department of Oral Biology and Experimental Dental Research, University of Szeged, Tisza Lajos krt. 64-66, H-6720 Szeged, Hungary.
| | - Noémi Pávó
- Department of Internal Medicine II, Clinical Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
| | - Imre Pavo
- Eli Lilly Regional Operations GmbH, Erdberger Lände 26/A, A-1030 Vienna, Austria.
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Nyirjesy SC, Peleckis AJ, Eiel JN, Gallagher K, Doliba A, Tami A, Flatt AJ, De Leon DD, Hadjiliadis D, Sheikh S, Stefanovski D, Gallop R, D’Alessio DA, Rubenstein RC, Kelly A, Rickels MR. Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis. Diabetes 2022; 71:2153-2165. [PMID: 35796669 PMCID: PMC9501647 DOI: 10.2337/db22-0399] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/01/2022] [Indexed: 01/07/2023]
Abstract
Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.
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Affiliation(s)
- Sarah C. Nyirjesy
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Amy J. Peleckis
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Jack N. Eiel
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Kathryn Gallagher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Andriana Doliba
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Abigail Tami
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Anneliese J. Flatt
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Diva D. De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Saba Sheikh
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Darko Stefanovski
- New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA
| | - Robert Gallop
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA
- Department of Mathematics, West Chester University of Pennsylvania, West Chester, PA
| | - David A. D’Alessio
- Division of Endocrinology and Metabolism, Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Ronald C. Rubenstein
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
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Gao Z, Yang J, Liang Y, Yang S, Zhang T, Gong Z, Li M. Changes in Gastric Inhibitory Polypeptide (GIP) After Roux-en-Y Gastric Bypass in Obese Patients: a Meta-analysis. Obes Surg 2022; 32:2706-2716. [PMID: 35597875 DOI: 10.1007/s11695-022-05959-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/25/2022] [Accepted: 02/03/2022] [Indexed: 01/19/2023]
Abstract
This meta-analysis aimed to evaluate changes in GIP after RYGB in obese patients. We searched PubMed, EMBASE, and CENTRAL for relevant studies from database inception through July 2021. Articles were eligible for inclusion if they reported pre-operative and post-operative fasting GIP levels. We found fasting GIP levels had a decreasing tendency. The decrease in fasting glucose and postprandial GIP levels was also observed. Subgroup analysis indicated diabetic subjects tended to have a more obvious fasting GIP reduction compared to non-diabetic individuals. Meta-regression showed that the amount of weight loss (% total body weight), gastric pouch volume, alimentary limb length, and biliopancreatic limb length were not related to fasting GIP decrease. Fasting GIP levels decreased significantly after RYGB in obese people, especially in diabetic patients.
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Affiliation(s)
- Zhiguang Gao
- Department of Gastrointestinal Surgery, The affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, 523320, China.
| | - Jingge Yang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yuzhi Liang
- Department of Medical Imaging, The affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, 523320, China
| | - Sen Yang
- Guangdong Medical University, Zhanjiang, Guangdong Province, China
| | - Tao Zhang
- Department of Gastrointestinal Surgery, The affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, 523320, China
| | - Zuyuan Gong
- Department of Gastrointestinal Surgery, The affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, 523320, China
| | - Min Li
- Department of Gastrointestinal Surgery, The affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, 523320, China
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10
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Bellin MD. Pancreatogenic Diabetes in Children With Recurrent Acute and Chronic Pancreatitis: Risks, Screening, and Treatment (Mini-Review). Front Pediatr 2022; 10:884668. [PMID: 35558377 PMCID: PMC9086714 DOI: 10.3389/fped.2022.884668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 03/25/2022] [Indexed: 11/18/2022] Open
Abstract
Up to 9% of children with acute recurrent pancreatitis (ARP) or chronic pancreatitis have pancreatogenic diabetes mellitus (DM), and this risk likely increases as they age into adulthood. Risk factors for pancreatogenic DM in children vary depending on the clinical cohort but may include pancreatic atrophy, exocrine insufficiency, pancreatic calcifications, obesity/metabolic syndrome features, or autoimmune diseases. Knowledge regarding disease pathology is extrapolated nearly entirely from studies in adults. Insulin deficiency is the primary defect, resulting from islet loss associated with pancreatic fibrosis and cytokine-mediated β-cell dysfunction. Beta cell autoimmunity (type 1 diabetes) should also be considered as markers for this have been identified in a small subset of children with pancreatogenic DM. Hepatic insulin resistance, a deficient pancreatic polypeptide state, and dysfunctional incretin hormone response to a meal are all potential contributors in adults with pancreatogenic DM but their significance in pediatrics is yet unknown. Current guidelines recommend yearly screening for diabetes with fasting glucose and hemoglobin A1c (HbA1c). Insulin in the first-line pharmacologic therapy for treatment of pancreatogenic DM in children. Involvement of a multidisciplinary team including a pediatric endocrinologist, gastroenterologist, and dietitian are important, and nutritional health and exocrine insufficiency must also be addressed for optimal DM management.
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Affiliation(s)
- Melena D Bellin
- University of Minnesota Medical School and Masonic Children's Hospital, Minneapolis, MN, United States
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11
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Chueire VB, Muscelli E. Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect - a narrative review. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:24-31. [PMID: 33320449 PMCID: PMC10528699 DOI: 10.20945/2359-3997000000313] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 09/26/2020] [Indexed: 11/23/2022]
Abstract
Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.
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Affiliation(s)
- Valeria Bahdur Chueire
- Departamento de Endocrinologia, Hospital da Pontifícia Universidade Católica de Campinas, Campinas, SP, Brasil,
| | - Elza Muscelli
- Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
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12
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Abstract
PURPOSE OF REVIEW In children, chronic pancreatitis is infrequent but may be associated with serious complications, including severe pain that limits activities, exocrine and endocrine pancreatic insufficiency and malnutrition. Investigation into pediatric chronic pancreatitis has transitioned from single center reports to multicenter, protocol-driven studies. As a result, we now have information on much larger numbers of children with chronic pancreatitis, allowing a more reliable understanding of the complications of chronic pancreatitis. RECENT FINDINGS A high percentage of children with chronic pancreatitis use opioids frequently to control pain. About a quarter of children with chronic pancreatitis have exocrine pancreatic insufficiency, and about 6% have pancreatogenic diabetes. Mild malnutrition and low bone density are both common in children with chronic pancreatitis. SUMMARY Large multicenter and single-center observational studies have allowed us to more accurately assess complications of chronic pancreatitis in children. These studies demonstrate the need for examination of therapies for these complications in children.
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Affiliation(s)
- Emily Perito
- Department of Pediatrics, University of California, San Francisco
| | - Tanja Gonska
- Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Translational Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Melena D. Bellin
- Department of Pediatrics, University of Minnesota Medical Center and Schulze Diabetes Institute, Minneapolis, MN
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13
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Freeman AJ, Maqbool A, Bellin MD, Goldschneider KR, Grover AS, Hartzell C, Piester TL, Szabo F, Kiernan BD, Khalaf R, Kumar R, Rios M, Husain SZ, Morinville VD, Abu-El-Haija M. Medical Management of Chronic Pancreatitis in Children: A Position Paper by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee. J Pediatr Gastroenterol Nutr 2021; 72:324-340. [PMID: 33230082 PMCID: PMC8054312 DOI: 10.1097/mpg.0000000000003001] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
ABSTRACT This position paper summarizes the current understanding of the medical management of chronic pancreatitis (CP) in children in light of the existing medical literature, incorporating recent advances in understanding of nutrition, pain, lifestyle considerations, and sequelae of CP. This article complements and is intended to integrate with parallel position papers on endoscopic and surgical aspects of CP in children. Concepts and controversies related to pancreatic enzyme replacement therapy (PERT), the use of antioxidants and other CP medical therapies are also reviewed. Highlights include inclusion of tools for medical decision-making for PERT, CP-related diabetes, and multimodal pain management (including an analgesia ladder). Gaps in our understanding of CP in children and avenues for further investigations are also reviewed.
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Affiliation(s)
- A. Jay Freeman
- Department of Gastroenterology, Hepatology and Nutrition, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA
| | - Asim Maqbool
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Melena D. Bellin
- Department of Pediatrics, Division of Endocrinology and Diabetes, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN
| | | | - Amit S. Grover
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - Cheryl Hartzell
- Division of Pediatric Anesthesiology, Department of Anesthesiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA
| | - Travis L. Piester
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA
| | - Flora Szabo
- Division of Pediatric Gastroenterology and Nutrition, Children’s Hospital of Richmond, Virginia Commonwealth University, Richmond, VA
| | - Bridget Dowd Kiernan
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Racha Khalaf
- Digestive Health Institute, Children’s Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
| | - Rakesh Kumar
- Department of Gastroenterology, Hepatology and Nutrition, Promedica Toledo Children’s Hospital, Toledo, OH
| | - Mirta Rios
- Food and Nutrition Department, Nicklaus Children’s Hospital, Miami, FL
| | - Sohail Z. Husain
- Department of Pediatrics, Stanford University, and the Lucile Packard Children’s Hospital, Palo Alto, CA
| | - Veronique D. Morinville
- Division of Pediatric Gastroenterology and Nutrition, Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec, Canada
| | - Maisam Abu-El-Haija
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
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14
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Grespan E, Giorgino T, Natali A, Ferrannini E, Mari A. Different mechanisms of GIP and GLP-1 action explain their different therapeutic efficacy in type 2 diabetes. Metabolism 2021; 114:154415. [PMID: 33137379 DOI: 10.1016/j.metabol.2020.154415] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 06/08/2020] [Accepted: 10/28/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects. METHODS We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the β-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data. RESULTS a) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion. CONCLUSION We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.
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Affiliation(s)
- Eleonora Grespan
- Institute of Neuroscience, National Research Council, Padua 35127, Italy
| | - Toni Giorgino
- Biophysics Institute, National Research Council, Milan 20133, Italy; Department of Biosciences, University of Milan, Milan 20133, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
| | - Ele Ferrannini
- Institute of Clinical Physiology, National Research Council, Pisa 56124, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua 35127, Italy.
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15
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Wei Q, Qi L, Lin H, Liu D, Zhu X, Dai Y, Waldron RT, Lugea A, Goodarzi MO, Pandol SJ, Li L. Pathological Mechanisms in Diabetes of the Exocrine Pancreas: What's Known and What's to Know. Front Physiol 2020; 11:570276. [PMID: 33250773 PMCID: PMC7673428 DOI: 10.3389/fphys.2020.570276] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 10/07/2020] [Indexed: 12/17/2022] Open
Abstract
The clinical significance of diabetes arising in the setting of pancreatic disease (also known as diabetes of the exocrine pancreas, DEP) has drawn more attention in recent years. However, significant improvements still need to be made in the recognition, diagnosis and treatment of the disorder, and in the knowledge of the pathological mechanisms. The clinical course of DEP is different from type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). DEP develops in patients with previous existing exocrine pancreatic disorders which damage both exocrine and endocrine parts of pancreas, and lead to pancreas exocrine insufficiency (PEI) and malnutrition. Therefore, damage in various exocrine and endocrine cell types participating in glucose metabolism regulation likely contribute to the development of DEP. Due to the limited amount of clinical and experimental studies, the pathological mechanism of DEP is poorly defined. In fact, it still not entirely clear whether DEP represents a distinct pathologic entity or is a form of T2DM arising when β cell failure is accelerated by pancreatic disease. In this review, we include findings from related studies in T1DM and T2DM to highlight potential pathological mechanisms involved in initiation and progression of DEP, and to provide directions for future research studies.
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Affiliation(s)
- Qiong Wei
- Department of Endocrinology, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China.,Institute of Pancreas, Southeast University, Nanjing, China
| | - Liang Qi
- Department of Endocrinology, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Hao Lin
- Institute of Pancreas, Southeast University, Nanjing, China.,Department of Clinical Science and Research, ZhongDa Hospital, Southeast University, Nanjing, China
| | - Dechen Liu
- Institute of Pancreas, Southeast University, Nanjing, China.,Department of Clinical Science and Research, ZhongDa Hospital, Southeast University, Nanjing, China
| | - Xiangyun Zhu
- Department of Endocrinology, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China.,Institute of Pancreas, Southeast University, Nanjing, China
| | - Yu Dai
- Nanjing Foreign Language School, Nanjing, China
| | - Richard T Waldron
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Aurelia Lugea
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Mark O Goodarzi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Stephen J Pandol
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Ling Li
- Department of Endocrinology, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China.,Institute of Pancreas, Southeast University, Nanjing, China
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16
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Pottakkat B. Islet cell dysfunction in patients with chronic pancreatitis. World J Diabetes 2020; 11:280-292. [PMID: 32843931 PMCID: PMC7415230 DOI: 10.4239/wjd.v11.i7.280] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/02/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency. Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption. Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP. Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP. However, the emerging evidence is varied probably because of dependence on the study procedure, the study population as well as on the stage of the disease. The mechanism behind islet cell dysfunction in CP is multifactorial. The intra-islet alpha and beta cell regulation of each other is often lost. Moreover, secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated. This significantly contributes to islet cell disturbances. Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP. In addition, the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function. Hence, different factors such as chronic inflammation, dysregulated incretin axis, surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP. Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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17
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Nauck MA, Holle H, Kahle M, Tytko A, Deacon CF, Holst JJ, Meier JJ. No evidence of tachyphylaxis for insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) in subjects with type 2 diabetes, their first-degree relatives, or in healthy subjects. Peptides 2020; 125:170176. [PMID: 31669136 DOI: 10.1016/j.peptides.2019.170176] [Citation(s) in RCA: 3] [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: 08/29/2019] [Revised: 10/12/2019] [Accepted: 10/14/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND, AIMS In patients with type 2 diabetes, the lost insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is more apparent after continuous versus bolus administration. To test whether the difference might be explained by rapid tachyphylaxis in response to elevated concentrations of GIP, and whether patients with type 2 diabetes and their relatives are more susceptible to tachyphylaxis than healthy subjects. PATIENTS AND METHODS In a two-way crossover design, insulinotropic responses to repeated bolus injection (50 pmol/kg body weight at 30 and 120 min) and continuous infusion of GIP (2 pmol.kg-1.min-1 from 30 to 180 min) under hyperglycaemic clamp conditions (8.5 mmol/l) was compared in age- gender- and weight-matched patients with type 2 diabetes, first degree relatives of such patients, and healthy subjects. RESULTS Insulin secretory responses to the first and second GIP bolus were not significantly different in any of the subject groups. Subjects with type 2 diabetes had a significant relative impairment versus healthy subjects with continuous (C-peptide, -13.2 %, p < 0.05), but not with repeated bolus administration of GIP (+11.1 %, n.s.). First-degree relatives tended to hyper-secrete insulin with bolus or continuous administrations of GIP. CONCLUSIONS Rapid tachyphylaxis in response to continuous exposure to slightly supraphysiological concentrations of GIP does not explain the reduced insulinotropic response to GIP infusions in patients with type 2 diabetes or their first-degree relatives.
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Affiliation(s)
- M A Nauck
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany; Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
| | - H Holle
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - M Kahle
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany; Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - A Tytko
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - C F Deacon
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - J J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - J J Meier
- Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
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18
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Christensen MB, Gasbjerg LS, Heimbürger SM, Stensen S, Vilsbøll T, Knop FK. GIP's involvement in the pathophysiology of type 2 diabetes. Peptides 2020; 125:170178. [PMID: 31682875 DOI: 10.1016/j.peptides.2019.170178] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023]
Abstract
During the past four decades derangements in glucose-dependent insulinotropic polypeptide (GIP) biology has been viewed upon as contributing factors to various parts of the pathophysiology type 2 diabetes. This overview outlines and discusses the impaired insulin responses to GIP as well as the effect of GIP on glucagon secretion and the potential involvement of GIP in the obesity and bone disease associated with type 2 diabetes. As outlined in this review, it is unlikely that the impaired insulinotropic effect of GIP occurs as a primary event in the development of type 2 diabetes, but rather develops once the diabetic state is present and beta cells are unable to maintain normoglycemia. In various models, GIP has effects on glucagon secretion, bone and lipid homeostasis, but whether these effects contribute substantially to the pathophysiology of type 2 diabetes is at present controversial. The review also discusses the substantial uncertainty surrounding the translation of preclinical data relating to the GIP system and outline future research directions.
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Affiliation(s)
- Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sebastian M Heimbürger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Signe Stensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte Hospital, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte Hospital, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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19
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Bergmann NC, Gasbjerg LS, Heimbürger SM, Krogh LSL, Dela F, Hartmann B, Holst JJ, Jessen L, Christensen MB, Vilsbøll T, Lund A, Knop FK. No Acute Effects of Exogenous Glucose-Dependent Insulinotropic Polypeptide on Energy Intake, Appetite, or Energy Expenditure When Added to Treatment With a Long-Acting Glucagon-Like Peptide 1 Receptor Agonist in Men With Type 2 Diabetes. Diabetes Care 2020; 43:588-596. [PMID: 31949084 DOI: 10.2337/dc19-0578] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 12/18/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Dual incretin receptor agonists in clinical development have shown reductions in body weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes, but the impact of glucose-dependent insulinotropic polypeptide (GIP) receptor activation remains unclear. Here, we evaluated the effects of high-dose exogenous GIP on energy intake, energy expenditure, plasma glucose, and glucose-regulating hormones in patients with type 2 diabetes treated with a long-acting glucagon-like peptide 1 receptor (GLP-1R) agonist. RESEARCH DESIGN AND METHODS In a randomized, double-blind design, men with type 2 diabetes (n = 22, mean ± SEM HbA1c 6.8 ± 0.1% [51 ± 1.5 mmol/mol]) treated with metformin and long-acting GLP-1R agonists were subjected to two 5-h continuous infusions (separated by a washout period of ≥3 days): one with GIP (6 pmol/kg/min) and another with saline (placebo). After 60 min of infusion, a liquid mixed-meal test was performed, and after 270 min of infusion, an ad libitum meal was served for evaluation of energy intake (primary end point). RESULTS Energy intake was similar during GIP and placebo infusion (648 ± 74 kcal vs. 594 ± 55 kcal, respectively; P = 0.480), as were appetite measures and energy expenditure. Plasma glucagon and glucose were higher during GIP infusion compared with placebo infusion (P = 0.026 and P = 0.017) as assessed by area under the curve. CONCLUSIONS In patients with type 2 diabetes, GIP infusion on top of treatment with metformin and a long-acting GLP-1R agonist did not affect energy intake, appetite, or energy expenditure but increased plasma glucose compared with placebo. These results indicate no acute beneficial effects of combining GIP and GLP-1.
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Affiliation(s)
- Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Zealand Pharma A/S, Glostrup, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sebastian M Heimbürger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Liva S L Krogh
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Flemming Dela
- Xlab, Center for Healthy Ageing, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Geriatrics, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Asger Lund
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark .,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Steno Diabetes Center Copenhagen, Gentofte, Denmark
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Lin CH, Yeh NC, Wang JJ, Ho CH, Her SH, Tsay WI, Chien CC. Effect of Chronic Pancreatitis on Complications and Mortality in DM Patients: A 10-year Nationwide Cohort Study. J Clin Endocrinol Metab 2020; 105:5715202. [PMID: 31974550 DOI: 10.1210/clinem/dgaa035] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/23/2020] [Indexed: 02/08/2023]
Abstract
CONTEXT Chronic pancreatitis (CP), is a long-term inflammation of the pancreatic parenchyma, and might increase risk of a hyperglycemia crisis or hypoglycemia in patients with diabetes mellitus (DM); however, the relationship has not been previously investigated. OBJECTIVE To investigate the risk of diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), hypoglycemia, and long-term outcomes in DM patients with CP. DESIGN A population-based cohort study. SETTING AND PARTICIPANTS Tapping Taiwan's National Health Insurance Research Database, we identified 506 DM patients with newly diagnosed CP from 1999 to 2010 and created a control cohort consisting of 5060 age- and sex-matched DM patients without CP from the same time period. We followed those 2 cohorts from the index date to occurrence of outcomes, the date of death or 31 December 2012. MAIN OUTCOME MEASURES DKA, HHS, hypoglycemia and mortality. RESULTS DM patients with CP, who were predominantly male (88%) and younger (60% < 45 years old), had a 9.5-, 5.0-, and 3.0-fold higher risk for DKA (95% confidence interval [CI]: 6.51-13.91), HHS (95% CI: 2.85-8.62), and hypoglycemia (95% CI: 2.23-4.08), respectively. They also had lower 1-, 5-, and 10-year cumulative survival rates (98.4% vs 99.0%, 87.7% vs 96.6%, and 78.7% vs 93.6%, respectively) (log-rank test: P < .001), and a 2.43-fold higher risk for death (HR: 2.43, 95% CI: 1.82-3.27). CONCLUSIONS In Taiwan, DM patients with CP have a higher incidence of DKA, HHS, hypoglycemia, and mortality. More attention is needed for preventing hyperglycemia crisis and hypoglycemia prevention in this population.
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Affiliation(s)
- Cheng-Heng Lin
- Department of Gastroenterology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan
| | - Nai-Cheng Yeh
- Department of Endocrinology and Metabolism, Chi-Mei Medical Center, Tainan, Taiwan
| | - Jhi-Joung Wang
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chung-Han Ho
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
| | - Shwu-Huey Her
- Division of Controlled Drugs, Food and Drug Administration, Ministry of Health and Welfare, Taiwan
| | - Wen-Ing Tsay
- Division of Controlled Drugs, Food and Drug Administration, Ministry of Health and Welfare, Taiwan
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Rebello CJ, Greenway FL. Obesity medications in development. Expert Opin Investig Drugs 2020; 29:63-71. [PMID: 31847611 PMCID: PMC6990416 DOI: 10.1080/13543784.2020.1705277] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/12/2019] [Indexed: 12/21/2022]
Abstract
Introduction: Obesity is compounded by a neurobiology that is resistant to weight loss. Therefore, the development of pharmacotherapies to address the pathology underlying the dysregulation of energy homeostasis is critical.Areas covered: This review examines selected clinical trial evidence for the pharmacologic treatment of obesity and provides an expert opinion on anti-obesity drug development. The article includes the outcomes of anti-obesity medications that have been evaluated in clinical trials but have not yet received approval from the U.S. Food and Drug Administration. The mechanisms of action of glucagon-like peptide-1 agonists and co-agonists, diabetes medications being investigated for weight loss, and medications acting on the central nervous system as well as peripherally are reviewed. A search was conducted on PubMed using the terms 'Obesity AND Medications' restricted to clinical trials reported in English. Using similar terms, a search was also conducted on ClinicalTrials.gov.Expert opinion: The goal of anti-obesity therapy is finding compounds that are effective and have minimal side effects. Combining medications targeting more than one of the redundant mechanisms driving obesity increases efficacy. However, targeting peripheral mechanisms to overcome the trickle-down effects of centrally acting drugs may be the key to success in treating obesity.
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Affiliation(s)
- Candida J. Rebello
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
| | - Frank L. Greenway
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
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22
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Abstract
OBJECTIVE Little data exist describing the change over time in islet function and glycemic control in patients with chronic pancreatitis (CP). METHODS In 325 CP patients who underwent 2 mixed meal tolerance tests and/or glycated hemoglobin (HbA1c) levels, we estimated the rate of change in metabolic measures per 6 months and assessed the association between potential risk factors for diabetes and rate of change using multivariate regression models. RESULTS Per 6-month time, HbA1c increased by 0.062% with a standard error of 0.029% (P = 0.037) and the ratio (area under the curve (AUC) C-peptide to AUC glucose from mixed meal tolerance testing) decreased by 0.0028 with a standard error of 0.0011 (P = 0.014). We observed more rapid decline in smokers (AUC C-peptide, P = 0.043) and patients with surgical drainage (AUC glucose, P = 0.001; ratio, P = 0.03) or with calcific pancreatitis (HbA1c, P = 0.003). In multivariate models, AUC C-peptide and ratio declined at a greater rate in smokers and HbA1c in those with pancreatic calcifications (both P < 0.05). CONCLUSIONS We observed a measurable decline in β-cell function and glycemic control in patients with CP. Patients with a history of tobacco smoking, surgical drainage, or pancreatic calcification may be at highest risk.
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Schmitt C, Portron A, Jadidi S, Sarkar N, DiMarchi R. Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 in people with type 2 diabetes mellitus. Diabetes Obes Metab 2017; 19:1436-1445. [PMID: 28730694 DOI: 10.1111/dom.13024] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 05/19/2017] [Accepted: 05/29/2017] [Indexed: 12/19/2022]
Abstract
AIMS To investigate the pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in patients with type 2 diabetes mellitus (T2D). METHODS A total of 56 patients with T2D received once-daily subcutaneous (s.c.) injection of RG7697 (0.25-2.5 mg) or placebo for 14 days in a randomized, double-blind, dose-escalation study. Adverse events (AEs), vital signs, ECGs and routine laboratory variables were intensively monitored. Drug concentrations, fasting glycaemic variables, 24-hour glucose profiles, glycated haemoglobin (HbA1c) and antibody formation were measured. Several meal tolerance and gastric emptying tests were performed during the study. RESULTS Daily s.c. injections of RG7697 were well tolerated by the majority of participants with T2D. The most frequently reported AEs with RG7697 were diarrhoea, nausea and decreased appetite. Asymptomatic events of hypoglycaemia were relatively uniformly distributed across dose groups including placebo. Pharmacokinetic steady-state was achieved within 1 week. Meaningful reductions in fasting, postprandial and 24-hour plasma glucose profile were observed at doses ≥0.75 mg, and were associated with numerical decreases in HbA1c (-0.67% [2.5-mg dose] vs -0.21% [placebo]). Decrease in postprandial insulin at doses ≥1.1 mg suggested improvement in insulin sensitivity. Minimum delay in gastric emptying and body weight reductions numerically greater than placebo (- 3.0 kg vs -0.9 kg) were seen at the highest dose of 2.5 mg. CONCLUSIONS Daily doses of RG7697 for 2 weeks were well tolerated by the majority of patients with T2D. Pharmacokinetic data supported once-daily dosing and pharmacodynamic effect displayed dose-dependent reductions in fasting and postprandial plasma glucose, without increasing the risk of hypoglycaemia.
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Affiliation(s)
- Christophe Schmitt
- Department of Clinical Pharmacology, F. Hoffmann-La Roche AG, Basel, Switzerland
| | - Agnès Portron
- Department of Clinical Pharmacology, F. Hoffmann-La Roche AG, Basel, Switzerland
| | - Shirin Jadidi
- Department of Safety Science, Roche Innovation Center, New York, New York
| | - Neena Sarkar
- Department of Biostatistics, Roche Innovation Center, New York, New York
| | - Richard DiMarchi
- Department of Chemistry, Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana
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24
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Mumme L, Breuer TGK, Rohrer S, Schenker N, Menge BA, Holst JJ, Nauck MA, Meier JJ. Defects in α-Cell Function in Patients With Diabetes Due to Chronic Pancreatitis Compared With Patients With Type 2 Diabetes and Healthy Individuals. Diabetes Care 2017; 40:1314-1322. [PMID: 28751547 DOI: 10.2337/dc17-0792] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 07/03/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Diabetes frequently develops in patients with chronic pancreatitis. We examined the alterations in the glucagon response to hypoglycemia and to oral glucose administration in patients with diabetes due to chronic pancreatitis. RESEARCH DESIGN AND METHODS Ten patients with diabetes secondary to chronic pancreatitis were compared with 13 patients with type 2 diabetes and 10 healthy control subjects. A stepwise hypoglycemic clamp and an oral glucose tolerance test (OGTT) were performed. RESULTS Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (P < 0.0001). Insulin and C-peptide levels were reduced, and the glucose-induced suppression of glucagon was impaired in both groups with diabetes (all P < 0.0001 vs. control subjects). During hypoglycemia, glucagon concentrations were reduced in patients with chronic pancreatitis and with type 2 diabetes (P < 0.05). The increase in glucagon during the clamp was inversely related to the glucose-induced glucagon suppression and positively related to β-cell function. Growth hormone responses to hypoglycemia were lower in patients with type 2 diabetes (P = 0.0002) but not in patients with chronic pancreatitis. CONCLUSIONS α-Cell responses to oral glucose ingestion and to hypoglycemia are disturbed in patients with diabetes and chronic pancreatitis and in patients with type 2 diabetes. The similarities between these defects suggest a common etiology.
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Affiliation(s)
- Lena Mumme
- Diabetes Division, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Thomas G K Breuer
- Diabetes Division, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Stephan Rohrer
- Diabetes Division, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Nina Schenker
- Diabetes Division, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Björn A Menge
- Diabetes Division, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Jens J Holst
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Michael A Nauck
- Diabetes Division, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Juris J Meier
- Diabetes Division, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
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Frias JP, Bastyr EJ, Vignati L, Tschöp MH, Schmitt C, Owen K, Christensen RH, DiMarchi RD. The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes. Cell Metab 2017; 26:343-352.e2. [PMID: 28768173 DOI: 10.1016/j.cmet.2017.07.011] [Citation(s) in RCA: 239] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 07/04/2017] [Accepted: 07/17/2017] [Indexed: 12/12/2022]
Abstract
Unimolecular dual incretins derived from hybridized glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) sequences have demonstrated synergistic reduction of adiposity in animal models and reductions of hyperglycemia in short-duration human trials. Here, we extend the characterization of NNC0090-2746 (also known as RG7697), a fatty-acylated dual agonist possessing in vitro balanced GIPR and GLP-1R agonism. In this 12-week, randomized, placebo-controlled, double-blind phase 2a trial, patients with type 2 diabetes inadequately controlled with metformin received 1.8 mg of NNC0090-2746 or placebo subcutaneously once daily. Liraglutide 1.8 mg (Victoza), starting with 2-week dose escalation, was administered subcutaneously once daily as an open-label reference arm. Measurements were collected at regular intervals after randomization. NNC0090-2746 significantly improved glycemic control and reduced body weight compared with placebo. Total cholesterol, alone among a range of lipid parameters, and leptin were both significantly reduced compared with placebo. Treatment with NNC0090-2746 was generally safe and well tolerated.
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Affiliation(s)
| | - Edward J Bastyr
- Division of Endocrinology & Metabolism, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Louis Vignati
- Former scientific advisor to MB2 LLC, Carmel, IN 46032, USA
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich 80333, Germany; German Center for Diabetes Research (DZD), Neuherberg 85764, Germany
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Hart PA, Bellin MD, Andersen DK, Bradley D, Cruz-Monserrate Z, Forsmark CE, Goodarzi MO, Habtezion A, Korc M, Kudva YC, Pandol SJ, Yadav D, Chari ST. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. Lancet Gastroenterol Hepatol 2016; 1:226-237. [PMID: 28404095 DOI: 10.1016/s2468-1253(16)30106-6] [Citation(s) in RCA: 315] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 07/25/2016] [Accepted: 07/26/2016] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.
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Affiliation(s)
- Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Melena D Bellin
- Division of Pediatric Endocrinology and Schulze Diabetes Institute, University of Minnesota Medical Center, Minneapolis, MN, USA
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David Bradley
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Christopher E Forsmark
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL, USA
| | - Mark O Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Murray Korc
- Departments of Medicine, Biochemistry, and Molecular Biology, Indiana University School of Medicine, Indiana University Simon Cancer Center, Indianapolis, IN, USA; Pancreatic Cancer Signature Center, Indiana University Simon Cancer Center, Indianapolis, IN, USA
| | - Yogish C Kudva
- Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA
| | - Stephen J Pandol
- Department of Veterans Affairs, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh and UPMC Medical Center, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh and UPMC Medical Center, Pittsburgh, PA, USA
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Lundberg R, Beilman GJ, Dunn TB, Pruett TL, Freeman ML, Ptacek PE, Berry KL, Robertson RP, Moran A, Bellin MD. Early Alterations in Glycemic Control and Pancreatic Endocrine Function in Nondiabetic Patients With Chronic Pancreatitis. Pancreas 2016; 45:565-71. [PMID: 26918872 PMCID: PMC4783201 DOI: 10.1097/mpa.0000000000000491] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES Diabetes mellitus is a frequent consequence of chronic pancreatitis (CP). Little is known about pancreatic endocrine function before the development of diabetes mellitus in CP, particularly in females, or those without calcific and/or alcoholic pancreatitis. METHODS Twenty-five nondiabetic adult patients with CP (19 female; mean [SE] age, 34.2 [2.4] years) were compared with 25 healthy controls matched for age, sex, and body mass index. Subjects underwent frequent sample intravenous glucose tolerance testing (FSIVGTT) and mixed meal tolerance testing (MMTT). RESULTS Mean (SE) fasting glucose was higher in patients with CP (89.5 [2.3] mg/dL) than in controls (84.4 [1.2] mg/dL, P = 0.04). On MMTT, patients with CP had a higher area under the curve (AUC) glucose and AUC glucagon compared with controls (P ≤ 0.01). The AUC C-peptide was equivalent (P = 0.6) but stimulated C-peptide at 30 minutes was lower in patients with CP (P = 0.04). Mean insulin sensitivity index calculated from the FSIVGTT was lower in CP group, indicating reduced insulin sensitivity (P ≤ 0.01). Disposition index (insulin secretion adjusted for insulin sensitivity on FSIVGTT) was lower in patients with CP (P = 0.01). CONCLUSIONS Patients with CP had higher fasting and MMTT glucose levels, without a compensatory increase in insulin secretion suggesting subtle early islet dysfunction. Our cohort had relative hyperglucagonemia and was less insulin sensitive than controls.
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Affiliation(s)
- Rachel Lundberg
- From the Departments *Pediatrics, †Surgery, and ‡Medicine, University of Minnesota, Minneapolis, MN
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Lozinska L, Weström B, Prykhodko O, Lindqvist A, Wierup N, Ahrén B, Szwiec K, Pierzynowski SG. Decreased insulin secretion and glucose clearance in exocrine pancreas-insufficient pigs. Exp Physiol 2015; 101:100-12. [PMID: 26663041 DOI: 10.1113/ep085431] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 10/30/2015] [Indexed: 12/26/2022]
Abstract
The effect of exocrine pancreatic function on the glucose-mediated insulin response and glucose utilization were studied in an exocrine pancreas-insufficient (EPI) pig model. Five 10-week-old EPI pigs after pancreatic duct ligation and 6 age-matched, non-operated control pigs were used in the study. Blood glucose, plasma insulin and C-peptide concentrations were monitored during meal (MGTT), oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. Upon post-mortem examination, the pancreatic remnants of the EPI pigs showed acinar fibrotic atrophy but normal islets and β-cell morphology. The EPI pigs displayed increased fasting glucose concentrations compared with control animals (6.4 ± 0.4 versus 4.8 ± 0.1 mmol l(-1) , P < 0.0001) but unchanged insulin concentrations (2.4 ± 0.6 versus 2.1 ± 0.2 pmol l(-1) ). During the OGTT and IVGTT, the EPI pigs showed slower, impaired glucose utilization, with the disruption of a well-timed insulin response. Plasma C-peptide concentrations confirmed the delayed insulin response during the IVGTT in EPI pigs. Oral pancreatic enzyme supplementation (PES) of EPI pigs improved glucose clearance during IVGTT [AUC(glucose) 1295 ± 70 mmol l(-1) × (120 min) in EPI versus 1044 ± 32 mmol l(-1) × (120 min) in EPI + PES, P < 0.0001] without reinforcing the release of insulin [AUC(C-peptide) 14.4 ± 3.8 nmol l(-1) × (120 min) in EPI versus 6.4 ± 1.3 nmol l(-1) × (120 min) in EPI + PES, P < 0.002]. The results suggest the existence of an acino-insular axis regulatory communication. The presence of pancreatic enzymes in the gut facilitates glucose utilization in an insulin-independent manner, indicating the existence of a gut-derived pancreatic enzyme-dependent mechanism involved in peripheral glucose utilization.
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Affiliation(s)
| | - Björn Weström
- Department of Biology, Lund University, Lund, Sweden
| | | | - Andreas Lindqvist
- Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden
| | - Nils Wierup
- Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden
| | - Bo Ahrén
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | | | - Stefan G Pierzynowski
- Department of Biology, Lund University, Lund, Sweden.,Department of Medical Biology, Institute of Rural Health, Lublin, Poland
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Abstract
PURPOSE OF REVIEW A relevant number of patients with pancreatic disorders suffer from secondary diabetes. Recent data have shed light on the link between pancreatic damage and subsequent impairments in glucose homeostasis. Furthermore, epidemiological studies provided insights into the relationship between diabetes and the risk of pancreatic carcinoma or pancreatitis. Pancreaticogenic diabetes requires a tailored therapeutic approach taking into account the individual properties of the available glucose-lowering drugs. RECENT FINDINGS We review the available literature concerning diabetes in patients with acute or chronic pancreatitis or pancreatic carcinoma. The relationship between the pancreatic damage and alterations in insulin and glucose homeostasis is summarized as well as the effect of diabetes mellitus on the risk of pancreatic cancer and pancreatitis. Caveats in the treatment of pancreaticogenic diabetes with currently available drugs are being discussed. SUMMARY Patients with pancreatic diseases should be screened for diabetes by means of an oral glucose tolerance test. There is a close inverse relationship between pancreatic β-cell loss and postchallenge hyperglycemia. The risk of hypoglycemia may be increased in patients with pancreaticogenic diabetes. Newly diagnosed diabetes may be a harbinger of pancreatic cancer. There is increasing evidence suggesting an increased risk for (pancreatic) cancer and pancreatitis in patients with diabetes mellitus. Further studies on the ideal glucose-lowering treatment of patients with pancreaticogenic diabetes will be required.
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Kar P, Cousins CE, Annink CE, Jones KL, Chapman MJ, Meier JJ, Nauck MA, Horowitz M, Deane AM. Effects of glucose-dependent insulinotropic polypeptide on gastric emptying, glycaemia and insulinaemia during critical illness: a prospective, double blind, randomised, crossover study. Crit Care 2015; 19:20. [PMID: 25613747 PMCID: PMC4340673 DOI: 10.1186/s13054-014-0718-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 12/11/2014] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Insulin is used to treat hyperglycaemia in critically ill patients but can cause hypoglycaemia, which is associated with poorer outcomes. In health glucose-dependent insulinotropic polypeptide (GIP) is a potent glucose-lowering peptide that does not cause hypoglycaemia. The objectives of this study were to determine the effects of exogenous GIP infusion on blood glucose concentrations, glucose absorption, insulinaemia and gastric emptying in critically ill patients without known diabetes. METHODS A total of 20 ventilated patients (Median age 61 (range: 22 to 79) years, APACHE II 21.5 (17 to 26), BMI 28 (21 to 40) kg/m(2)) without known diabetes were studied on two consecutive days in a randomised, double blind, placebo controlled, cross-over fashion. Intravenous GIP (4 pmol/kg/min) or placebo (0.9% saline) was infused between T = -60 to 300 minutes. At T0, 100 ml of liquid nutrient (2 kcal/ml) containing 3-O-Methylglucose (3-OMG), 100 mcg of Octanoic acid and 20 MBq Tc-99 m Calcium Phytate, was administered via a nasogastric tube. Blood glucose and serum 3-OMG (an index of glucose absorption) concentrations were measured. Gastric emptying, insulin and glucagon levels and plasma GIP concentrations were also measured. RESULTS While administration of GIP increased plasma GIP concentrations three- to four-fold (T = -60 23.9 (16.5 to 36.7) versus T = 0 84.2 (65.3 to 111.1); P <0.001) and plasma glucagon (iAUC300 4217 (1891 to 7715) versus 1232 (293 to 4545) pg/ml.300 minutes; P = 0.04), there were no effects on postprandial blood glucose (AUC300 2843 (2568 to 3338) versus 2819 (2550 to 3497) mmol/L.300 minutes; P = 0.86), gastric emptying (AUC300 15611 (10993 to 18062) versus 15660 (9694 to 22618) %.300 minutes; P = 0.61), glucose absorption (AUC300 50.6 (22.3 to 74.2) versus 64.3 (9.9 to 96.3) mmol/L.300 minutes; P = 0.62) or plasma insulin (AUC300 3945 (2280 to 6731) versus 3479 (2316 to 6081) mU/L.300 minutes; P = 0.76). CONCLUSIONS In contrast to its profound insulinotropic effect in health, the administration of GIP at pharmacological doses does not appear to affect glycaemia, gastric emptying, glucose absorption or insulinaemia in the critically ill patient. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry ACTRN12612000488808. Registered 3 May 2012.
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Affiliation(s)
- Palash Kar
- Intensive Care Unit, Level 4, Emergency Services Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia.
| | - Caroline E Cousins
- Intensive Care Unit, Level 4, Emergency Services Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia.
| | - Christopher E Annink
- Intensive Care Unit, Level 4, Emergency Services Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia.
| | - Karen L Jones
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Level 6 Eleanor Harrald Building, North Terrace, Adelaide, South Australia, 5000, Australia.
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Level 6, Eleanor Harrald Building, North Terrace, Adelaide, South Australia, 5000, Australia.
| | - Marianne J Chapman
- Intensive Care Unit, Level 4, Emergency Services Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia.
- Discipline of Acute Care Medicine, The University of Adelaide, North Terrace, Adelaide, South Australia, 5000, Australia.
| | - Juris J Meier
- Diabetes Division, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstraße 56, Bochum, 44791, Germany.
| | - Michael A Nauck
- Diabetes Centre, Bad Lauterberg, Kirchberg 21, Bad Lauterberg, Harz, 37431, Germany.
| | - Michael Horowitz
- Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Level 6 Eleanor Harrald Building, North Terrace, Adelaide, South Australia, 5000, Australia.
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Level 6, Eleanor Harrald Building, North Terrace, Adelaide, South Australia, 5000, Australia.
| | - Adam M Deane
- Intensive Care Unit, Level 4, Emergency Services Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia.
- Discipline of Acute Care Medicine, The University of Adelaide, North Terrace, Adelaide, South Australia, 5000, Australia.
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Malinska H, Kahleova H, Topolcan O, Vrzalova J, Oliyarnyk O, Kazdova L, Belinova L, Hill M, Pelikanova T. Postprandial oxidative stress and gastrointestinal hormones: is there a link? PLoS One 2014; 9:e103565. [PMID: 25141237 PMCID: PMC4139261 DOI: 10.1371/journal.pone.0103565] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 07/02/2014] [Indexed: 01/12/2023] Open
Abstract
Background Abnormal postprandial elevation of plasma glucose and lipids plays an important role in the pathogenesis of diabetes and strongly predicts cardiovascular mortality. In patients suffering from type 2 diabetes (T2D) postprandial state is associated with oxidative stress, cardiovascular risk and, probably, with impairment of both secretion and the effect of gastrointestinal peptides. Evaluating postprandial changes of gastrointestinal hormones together with changes in oxidative stress markers may help to understand the mechanisms behind the postprandial state in diabetes as well as suggest new preventive and therapeutical strategies. Methods A standard meal test has been used for monitoring the postprandial concentrations of gastrointestinal hormones and oxidative stress markers in patients with T2D (n = 50) compared to healthy controls (n = 50). Blood samples were drawn 0, 30, 60, 120 and 180 minutes after the standard meal. Results Both basal and postprandial plasma concentrations of glucose and insulin proved to be significantly higher in patients with T2D, whereas plasma concentrations of ghrelin showed significantly lower values during the whole meal test. In comparison with healthy controls, both basal and postprandial concentrations of almost all other gastrointestinal hormones and lipoperoxidation were significantly increased while ascorbic acid, reduced glutathione and superoxide dismutase activity were decreased in patients with T2D. A positive relationship was found between changes in GIP and those of glucose and immunoreactive insulin in diabetic patients (p<0.001 and p<0.001, respectively) and between changes in PYY and those of glucose (p<0.01). There was a positive correlation between changes in GIP and PYY and changes in ascorbic acid in patients with T2D (p<0.05 and p<0.001, respectively). Conclusion/Interpretation Apart from a positive relationship of postprandial changes in GIP and PYY with changes in ascorbic acid, there was no direct link observed between gastrointestinal hormones and oxidative stress markers in diabetic patients. Trial Registration ClinicalTrials.gov NCT01572402
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Affiliation(s)
- Hana Malinska
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Hana Kahleova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- * E-mail: (HK); (TP)
| | | | | | - Olena Oliyarnyk
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ludmila Kazdova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Lenka Belinova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Charles University, 1st Faculty of Medicine, Prague, Czech Republic
| | - Martin Hill
- Institute of Endocrinology, Prague, Czech Republic
| | - Terezie Pelikanova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- * E-mail: (HK); (TP)
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García-Martínez JM, Chocarro-Calvo A, De la Vieja A, García-Jiménez C. Insulin drives glucose-dependent insulinotropic peptide expression via glucose-dependent regulation of FoxO1 and LEF1/β-catenin. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1839:1141-50. [PMID: 25091498 DOI: 10.1016/j.bbagrm.2014.07.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2014] [Revised: 07/19/2014] [Accepted: 07/25/2014] [Indexed: 11/15/2022]
Abstract
Minutes after ingestion of fat or carbohydrates, vesicles stored in enteroendocrine cells release their content of incretin peptide hormones that, together with absorbed glucose, enhance insulin secretion by beta-pancreatic cells. Freshly-made incretins must therefore be packed into new vesicles in anticipation of the next meal with cells adjusting new incretin production to be proportional to the level of previous insulin release and absorbed blood glucose. Here we show that insulin stimulates the expression of the major human incretin, glucose-dependent insulinotropic peptide (GIP) in enteroendocrine cells but requires glucose to do it. Akt-dependent release of FoxO1 and glucose-dependent binding of LEF1/β-catenin mediate induction of Gip expression while insulin-induced phosphorylation of β-catenin does not alter its localization or transcriptional activity in enteroendocrine cells. Our results reveal a glucose-regulated feedback loop at the entero-insular axis, where glucose levels determine basal and insulin-induced Gip expression; GIP stimulation of insulin release, physiologically ensures a fine control of glucose homeostasis. How enteroendocrine cells adjust incretin production to replace incretin stores for future use is a key issue because GIP malfunction is linked to all forms of diabetes.
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Affiliation(s)
- Jose Manuel García-Martínez
- Department of Physiology, Biochemistry and Human Genetics, Faculty of Health Science, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain
| | - Ana Chocarro-Calvo
- Department of Physiology, Biochemistry and Human Genetics, Faculty of Health Science, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain
| | - Antonio De la Vieja
- Endocrine Tumor Unit (UFIEC), Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain
| | - Custodia García-Jiménez
- Department of Physiology, Biochemistry and Human Genetics, Faculty of Health Science, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
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MacNeil S, Rebry RM, Tetlow IJ, Emes MJ, McKeown B, Graham TE. Resistant starch intake at breakfast affects postprandial responses in type 2 diabetics and enhances the glucose-dependent insulinotropic polypeptide – insulin relationship following a second meal. Appl Physiol Nutr Metab 2013; 38:1187-95. [DOI: 10.1139/apnm-2013-0023] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Resistant starch (RS) consumption can modulate postprandial metabolic responses, but its effects on carbohydrate (CHO) handling in type 2 diabetics (T2D) are unclear. It was hypothesized that a bagel high in RS would improve glucose and insulin homeostasis following the 1st meal, regardless of the amount of available CHO, and that in association with incretins, the effects would carry over to a 2nd meal. Using a randomized crossover design, 12 T2D ingested four different bagel treatments (their 1st meal) determined by available CHO and the weight or amount of bagel consumed: treatment A, without RS (50 g of available CHO); treatment B, with RS (same total CHO as in A); treatment C, with RS (same available CHO as in A); and treatment D, with the same RS as in B and available CHO as in A and C. A standard 2nd meal was ingested 3 h later. Following the first meal, B elicited a lower glucose incremental area under the curve (iAUC) than C (P < 0.05), D (P < 0.05), and A (trend; P = 0.07), lower insulin iAUC than A (P < 0.05) and C (P < 0.05), and lower glucose-dependent insulinotropic polypeptide (GIP) iAUC than A (P < 0.05). There was a positive correlation (P < 0.05) between GIP and insulin iAUCs after the 2nd meal, and C had a 3 times greater slope than the other treatments (r = 0.91, P < 0.001), yet lacked a significant concomitant improvement in glucose disposal. These results show that for the 1st meal, RS was effective when it replaced a portion of the available CHO, while ingesting more RS influenced the GIP–insulin axis following the 2nd meal.
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Affiliation(s)
- Stacey MacNeil
- Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada
| | - Rachel M. Rebry
- Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada
| | - Ian J. Tetlow
- Department of Molecular and Cell Biology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Michael J. Emes
- Department of Molecular and Cell Biology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Bruce McKeown
- Canada Bread Company Limited, 10 Four Seasons Place, Toronto, ON M9B 6H7, Canada
| | - Terry E. Graham
- Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada
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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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Madsen KB, Askov-Hansen C, Naimi RM, Brandt CF, Hartmann B, Holst JJ, Mortensen PB, Jeppesen PB. Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1+GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study. ACTA ACUST UNITED AC 2013; 184:30-9. [PMID: 23511332 DOI: 10.1016/j.regpep.2013.03.025] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Revised: 03/02/2013] [Accepted: 03/11/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIMS The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of glucagon-like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients. METHODS SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1+2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast. RESULTS Nine SBS patients (5 women/4 men, aged 52±11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1+2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1+2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2. CONCLUSION GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1+2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the glucagon-like peptides or analogs, alone or in combination, in the treatment of SBS patients.
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Affiliation(s)
- K B Madsen
- Department of Gastroenterology CA-2121, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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Knop FK, Aaboe K, Vilsbøll T, Vølund A, Holst JJ, Krarup T, Madsbad S. Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab 2012; 14:500-10. [PMID: 22171657 DOI: 10.1111/j.1463-1326.2011.01549.x] [Citation(s) in RCA: 152] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
AIMS People with type 2 diabetes mellitus (T2DM) are characterized by reduced incretin effect and inappropriate glucagon levels. We evaluated α and β-cell responses to oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion (IIGI) in lean and obese persons with T2DM or normal glucose tolerance (NGT) to elucidate the impact of obesity on the incretin effect and incretin hormone and glucagon responses. METHODS Four hour 50-g OGTT and IIGI were performed in (i) Eight obese patients with T2DM [mean body mass index (BMI): 37 (range: 35-41) kg/m(2)]; (ii) Eight obese subjects with NGT [BMI: 33 (35-38) kg/m(2)]; (iii) Eight lean patients with T2DM [BMI: 24 (22-25) kg/m(2)]; and (iv) Eight lean healthy subjects [BMI: 23 (20-25) kg/m(2)]. RESULTS The incretin effect was significantly (p < 0.05) reduced in patients with T2DM {obese: 7 ± 7% [mean ± standard error of the mean (SEM)]; lean: 29 ± 8%; p = 0.06)} and was lower in obese subjects (41 ± 4%) than in lean subjects with NGT (53 ± 4%; p < 0.05). Obese subjects with NGT were also characterized by elevated fasting plasma glucagon levels, but the inappropriate glucagon responses to OGTT found in the T2DM patients were not evident in these subjects. CONCLUSIONS Our findings suggest that reduced incretin effect and fasting hyperglucagonaemia constitute very early steps in the pathophysiology of T2DM detectable even in obese people who despite their insulin-resistant state have NGT.
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Affiliation(s)
- Filip K Knop
- Department of Internal Medicine, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
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Metabolic surgery-principles and current concepts. Langenbecks Arch Surg 2011; 396:949-72. [PMID: 21870176 DOI: 10.1007/s00423-011-0834-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 08/01/2011] [Indexed: 12/19/2022]
Abstract
INTRODUCTION In the almost six decades of bariatric surgery, a variety of surgical approaches to treating morbid obesity have been developed. HISTORY AND EVOLUTION Rather than prior techniques being continually superseded by new ones, a broad choice of surgical solutions based on restrictive, malabsorptive, humoral effects, or combinations thereof, is now available. In fact, in recent years, the advent of surgically modifying human metabolism promises new approaches to ameliorate traditionally medically treated metabolic entities, i.e., diabetes, even in the non-obese. The understanding of the various metabolic effects have led to a paradigm shift from bariatric surgery as a solely weight-reducing procedure to metabolic surgery affecting whole body metabolism. CONCLUSION The bariatric surgeon now faces the challenge and opportunity of selecting the most suitable technique for each individual case. To assist in such decision-making, this review, Metabolic surgery-principles and current concepts, is presented, tracing the historical development; describing the various surgical techniques; elucidating the mechanisms by which glycemic control can be achieved that involve favorable changes in insulin secretion and insulin sensitivity, gut hormones, adipokines, energy expenditure, appetite, and preference for low glycemic index foods; as well as exploring the fascinating future potential of this new interdisciplinary field.
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Abstract
Exocrine pancreatic disease is thought to be uncommon in clinical practice and usually secondary to excess alcohol intake. Although excess alcohol intake does account for many cases of exocrine pancreatic disease, other conditions are associated with exocrine pancreatic insufficiency and such dysfunction perhaps occurs more frequently than conventionally expected. A reliable, patient-friendly, cheap and easy to use test for exocrine pancreatic disease is yet to be established; however, in many countries the main (and often only available) method of assessment of exocrine pancreatic function is the fecal-elastase-1 test. This Review examines the role of fecal-elastase-1 testing in detecting exocrine pancreatic insufficiency in a number of gastrointestinal and nongastrointestinal conditions and determines the value of pancreatic enzyme supplementation in these settings.
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Abstract
Bariatric surgery is the most effective modality of achieving weight loss as well as the most effective treatment for type 2 diabetes mellitus (T2DM). Glucose-dependent insulinotropic polypeptide (GIP) is an incretin and is implicated in the pathogenesis of obesity and T2DM. Its role in weight loss and resolution of T2DM after bariatric surgery is very controversial. We have made an attempt to review the physiology of GIP and its role in weight loss and resolution of T2DM after bariatric surgery. We searched PubMed and included all relevant original articles (both human and animal) in the review. Whereas most human studies have shown a decrease in GIP post-malabsorptive bariatric surgery, the role of GIP in bariatric surgery done in animal experiments remains inconclusive.
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Affiliation(s)
- Raghavendra S Rao
- Division of Metabolic, Endocrine and Minimally Invasive Surgery, Department of Surgery, Mount Sinai School of Medicine, New York, NY 10029, USA.
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Mentis N, Vardarli I, Köthe LD, Holst JJ, Deacon CF, Theodorakis M, Meier JJ, Nauck MA. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes 2011; 60:1270-6. [PMID: 21330636 PMCID: PMC3064100 DOI: 10.2337/db10-1332] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The incretin glucagon-like peptide 1 (GLP-1) exerts insulinotropic activity in type 2 diabetic patients, whereas glucose-dependent insulinotropic polypeptide (GIP) no longer does. We studied whether GIP can alter the insulinotropic or glucagonostatic activity of GLP-1 in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Twelve patients with type 2 diabetes (nine men and three women; 61 ± 10 years; BMI 30.0 ± 3.7 kg/m²; HbA(1c) 7.3 ± 1.5%) were studied. In randomized order, intravenous infusions of GLP-1(7-36)-amide (1.2 pmol · kg⁻¹ · min⁻¹), GIP (4 pmol · kg⁻¹ · min⁻¹), GLP-1 plus GIP, and placebo were administered over 360 min after an overnight fast (≥ 1 day wash-out period between experiments). Capillary blood glucose, plasma insulin, C-peptide, glucagon, GIP, GLP-1, and free fatty acids (FFA) were determined. RESULTS Exogenous GLP-1 alone reduced glycemia from 10.3 to 5.1 ± 0.2 mmol/L. Insulin secretion was stimulated (insulin, C-peptide, P < 0.0001), and glucagon was suppressed (P = 0.009). With GIP alone, glucose was lowered slightly (P = 0.0021); insulin and C-peptide were stimulated to a lesser degree than with GLP-1 (P < 0.001). Adding GIP to GLP-1 did not further enhance the insulinotropic activity of GLP-1 (insulin, P = 0.90; C-peptide, P = 0.85). Rather, the suppression of glucagon elicited by GLP-1 was antagonized by the addition of GIP (P = 0.008). FFA were suppressed by GLP-1 (P < 0.0001) and hardly affected by GIP (P = 0.07). CONCLUSIONS GIP is unable to further amplify the insulinotropic and glucose-lowering effects of GLP-1 in type 2 diabetes. Rather, the suppression of glucagon by GLP-1 is antagonized by GIP.
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Affiliation(s)
- Nikolaos Mentis
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - Irfan Vardarli
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - Lars D. Köthe
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - Jens J. Holst
- Department of Biomedical Sciences, Panum Institute, Copenhagen, Denmark
| | - Carolyn F. Deacon
- Department of Biomedical Sciences, Panum Institute, Copenhagen, Denmark
| | - Michael Theodorakis
- Department of Clinical Therapeutics, University of Athens Medical School, Athens, Greece
| | - Juris J. Meier
- Medizinische Klinik I, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Bochum, Germany
| | - Michael A. Nauck
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
- Corresponding author: Michael A. Nauck,
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Wang W, Guo Y, Liao Z, Zou DW, Jin ZD, Zou DJ, Jin G, Hu XG, Li ZS. Occurrence of and risk factors for diabetes mellitus in Chinese patients with chronic pancreatitis. Pancreas 2011; 40:206-212. [PMID: 21404458 DOI: 10.1097/mpa.0b013e31820032ae] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The aim of the study was to determine the occurrence and the risk factors of diabetes mellitus (DM) in Chinese patients with chronic pancreatitis (CP), with particular emphasis on those with endoscopic or surgical therapy for CP. METHODS Four hundred forty-five contacted CP patients in our hospital between January 1, 1997, and July 31, 2007, were followed up. Risk factors for DM were determined in a multivariate analysis after exclusion of 58 patients. RESULTS The cumulative rate of DM was 51.5% (SD, 8%) at 20 years after the onset of CP and 27.8% (SD, 6%) at 10 years after endotherapy or surgery, without significant difference between the 2 therapies (P = 0.243). The age at the onset of CP (hazard ratio, 1.032; 95% confidential interval, 1.012-1.052), smoking (2.859, 1.448-5.645), chronic pain (0.412, 0.180-0.945), and pancreatic calcifications (2.326, 1.203-4.496) were identified as independent risk factors for developing DM in the patients before any invasive therapy. Smoking (2.203, 1.153-4.209) and distal pancreatectomy (5.412, 2.506-11.690) were the independent risk factors for DM development in patients after invasive therapy. CONCLUSIONS The risk of DM seems to be mainly caused by progression of CP because it increased with older age, absence of chronic pain, and pancreatic calcifications, whereas this risk is influenced by smoking and distal pancreatectomy.
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Affiliation(s)
- Wei Wang
- Chronic Pancreatitis Study Group, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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Hansen KB, Vilsbøll T, Bagger JI, Holst JJ, Knop FK. Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet impairs the incretin effect in healthy subjects. J Clin Endocrinol Metab 2010; 95:3309-17. [PMID: 20410219 DOI: 10.1210/jc.2010-0119] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIMS/HYPOTHESIS The loss of incretin effect in patients with type 2 diabetes mellitus may be secondary to impaired glucose homeostasis. We investigated whether reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet in healthy young males would impair the incretin effect. METHODS The incretin effect was measured using 75 g oral glucose tolerance test (OGTT) and isoglycemic iv glucose infusion (IIGI) in 10 healthy Caucasian normal glucose-tolerant male subjects without any family history of diabetes [age 24 + or - 3 yr (mean + or - sd); body mass index 23 + or - 2 kg/m(2); glycosylated hemoglobin 5.4 + or - 0.1%] before and at the end of a 12-d period with oral administration of prednisolone (37.5 mg once daily), high-calorie diet, and relative physical inactivity. RESULTS The 12-d intervention period resulted in significant increases in body weight [79 + or - 5 vs. 80 + or - 6 kg (mean + or - sd), P = 0.03] and fasting plasma glucose (5.1 + or - 0.1 vs. 5.6 + or - 0.2 mm, P = 0.016), whereas insulin sensitivity (Matsuda index 17.6 + or - 1.7 vs. 9.2 + or - 1.0, P = 0.0001) decreased. Glucose tolerance [as assessed by the 120-min plasma glucose value after OGTT (4.9 + or - 1.1 vs. 7.8 + or - 2.5 mm, P < 0.0001) and area under curve (AUC) (152 + or - 45 vs. 384 + or - 53 mm.4 h, P = 0.002)] during the OGTT deteriorated. Also, the incretin effect [incretin effect (percent) = 100% x (AUC(insulin,OGTT) - AUC(insulin,IIGI))/AUC(insulin,OGTT))] deteriorated (72 + or - 5 vs. 43 + or - 7%, P = 0.002). An increase in glucose-dependent insulinotropic polypeptide response during OGTT, but no significant changes in glucagon-like peptide-1 or glucagon responses, was observed after glucose homeostatic dysregulation. CONCLUSIONS/INTERPRETATION Impairment of the incretin effect can be elicited by a short period of reduced glucose tolerance and insulin resistance in healthy male subjects not disposed for type 2 diabetes.
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Affiliation(s)
- K B Hansen
- Department of Clinical Physiology, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, DK-2600 Glostrup, Denmark.
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Knop FK, Vilsbøll T, Larsen S, Madsbad S, Holst JJ, Krarup T. Glucagon suppression during OGTT worsens while suppression during IVGTT sustains alongside development of glucose intolerance in patients with chronic pancreatitis. ACTA ACUST UNITED AC 2010; 164:144-50. [PMID: 20573586 DOI: 10.1016/j.regpep.2010.05.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2010] [Revised: 05/11/2010] [Accepted: 05/25/2010] [Indexed: 11/17/2022]
Abstract
AIMS To examine plasma glucagon responses to oral and intravenous (iv) glucose in patients with chronic pancreatitis (CP) and either normal glucose tolerance (NGT), secondary impaired glucose tolerance (IGT) or secondary diabetes mellitus (DM). METHODS Eleven patients with CP and NGT, 6 patients with CP and secondary IGT, 7 patients with CP and secondary non-insulin requiring DM, and 8 healthy subjects were examined with an oral glucose tolerance test (OGTT) and an iv glucose tolerance test (IVGTT). RESULTS In the CP groups, significant differences (increasing with the degree of glucose intolerance) in glucagon responses during the first hour of OGTT compared to IVGTT were observed (CP+NGT: -13 + or - 22 vs. -88 + or - 17, p = 0.02; CP+IGT: 3 + or - 17 vs. -87 + or - 19, p = 0.01; CP+DM: 94 + or - 27 vs. -78 + or - 16 1 h x pmol/l (mean + or - SEM), p<0.001). Glucagon was suppressed equally following OGTT and IVGTT in the healthy subjects (-103 + or - 22 vs. -131 + or - 19 1 h x pmol/l; p=NS). IVGTT suppressed glucagon similarly in all groups except for a slightly impaired suppression in the CP+DM-group compared to healthy subjects. CONCLUSIONS These results suggest that along with the development of secondary glucose intolerance in patients with CP, the suppression of glucagon by oral glucose is gradually lost and substituted by a paradoxical stimulation of secretion, while the suppression by iv glucose is maintained. This might indicate a glucagon stimulatory mechanism of gastrointestinal origin in CP patients.
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Affiliation(s)
- F K Knop
- Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Denmark
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Diab DL, D'Alessio DA. The contribution of enteroinsular hormones to the pathogenesis of type 2 diabetes mellitus. Curr Diab Rep 2010; 10:192-8. [PMID: 20425582 DOI: 10.1007/s11892-010-0114-6] [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] [Indexed: 02/07/2023]
Abstract
The gastrointestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), termed incretins, are essential regulators of normal glucose homeostasis. Research indicates that the incretin effect is impaired in type 2 diabetes, and this seems to be a consequence rather than a cause of type 2 diabetes. This review describes the defects in the incretin system seen in diabetic patients and discusses the potential roles of GIP and GLP-1 in the pathogenesis of type 2 diabetes. In addition, new information on clinical applications that exploit the enteroinsular axis to control blood glucose is discussed.
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Affiliation(s)
- Dima L Diab
- Division of Endocrinology/Metabolism, Cincinnati VA Medical Center, University of Cincinnati, ML 0547, Vontz Center, Cincinnati, OH 45220-0547, USA
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García-Martínez JM, Chocarro-Calvo A, Moya CM, García-Jiménez C. WNT/beta-catenin increases the production of incretins by entero-endocrine cells. Diabetologia 2009; 52:1913-24. [PMID: 19582394 DOI: 10.1007/s00125-009-1429-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Accepted: 05/21/2009] [Indexed: 01/09/2023]
Abstract
AIMS/HYPOTHESIS Glucose-dependent insulinotropic peptide (GIP) plays a pivotal role in the regulation of glucose homeostasis. Rates of diet-induced obesity, insulin resistance and type 2 diabetes are decreased when GIP signalling is disturbed in mice, suggesting that GIP plays a role in the onset of type 2 diabetes. WNT signalling is linked to type 2 diabetes and induces synthesis of the other incretin, glucagon-like peptide 1 (GLP-1). GLP-1 analogues improve treatment of type 2 diabetes patients in whom GLP-1 signalling is intact and have captured clinical attention. GIP levels are altered at the onset of type 2 diabetes and later on, while GIP signalling is impaired. Thus, GIP is not a candidate for treatment but might be an important target from a prevention perspective. Hypothesising that hypersecretion of GIP links altered WNT signalling to the onset of type 2 diabetes, we sought to determine whether WNT signalling induces GIP production by entero-endocrine cells. METHODS RT-PCR and chromatin immunoprecipitation (ChIP) were used to study Gip gene induction. Gip promoter elements mediating WNT/lithium induction were identified (electrophoretic mobility shift assay, co-transfection of deletion mutants, ChIP). RESULTS Lithium or WNT/beta-catenin signalling enhanced GIP production by entero-endocrine cells through a conserved site in the proximal Gip promoter. Lithium favours lymphoid enhancer factor-1/beta-catenin binding to Gip promoter and diminishes ChIP through T cell factor-4 and histone deacetylase 1. CONCLUSIONS/INTERPRETATION Lithium and WNT are incretin inducers in general. This work provides a novel link between WNT signalling, obesity and diabetes.
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Affiliation(s)
- J M García-Martínez
- Dptal I. Despacho 020, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922, Alcorcon, Madrid, Spain
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Højberg PV, Vilsbøll T, Rabøl R, Knop FK, Bache M, Krarup T, Holst JJ, Madsbad S. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 2009; 52:199-207. [PMID: 19037628 DOI: 10.1007/s00125-008-1195-5] [Citation(s) in RCA: 322] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2008] [Accepted: 09/19/2008] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. METHODS Eight obese patients with type 2 diabetes with poor glycaemic control (HbA(1c) 8.6 +/- 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 +/- 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. RESULTS Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0-10 min). The late phase C-peptide response (10-120 min) increased during GIP infusion from 33.0 +/- 8.5 to 103.9 +/- 24.2 (nmol/l) x (110 min)(-1) (p < 0.05) and during GLP-1 infusion from 48.7 +/- 11.8 to 126.6 +/- 32.5 (nmol/l) x (110 min)(-1) (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 +/- 11.2 vs 46.5 +/- 12.7 [nmol/l] x [110 min](-1)). CONCLUSIONS Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. CLINICALTRIALS.GOV ID NO.: NCT 00612950. FUNDING This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.
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Affiliation(s)
- P V Højberg
- Department of Endocrinology, Hvidovre Hospital, Kettegaards Allé 30, DK-2650 Hvidovre, Denmark.
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DePaula AL, Macedo ALV, Schraibman V, Mota BR, Vencio S. Hormonal evaluation following laparoscopic treatment of type 2 diabetes mellitus patients with BMI 20-34. Surg Endosc 2008; 23:1724-32. [PMID: 18830747 DOI: 10.1007/s00464-008-0168-6] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2008] [Accepted: 09/02/2008] [Indexed: 12/17/2022]
Abstract
BACKGROUND A group of patients with type 2 diabetes mellitus (T2DM) and body mass index (BMI) 20-34 kg/m(2) were submitted to laparoscopic interposition of a segment of ileum into the proximal jejunum or into the proximal duodenum associated to a sleeve gastrectomy. The objective of this study is to evaluate the hormonal changes in the pre- and postoperative period. MATERIALS AND METHODS Hormonal evaluation was done in 58 patients operated between April 2005 and July 2006. Mean age was 51.4 years (40-66 years). Mean BMI was 28.2 (20-34.8) kg/m(2). All patients had had the diagnosis of T2DM for at least 3 years. Mean duration of T2DM was 9.6 years (3-22 years). Two techniques were performed, consisting of different combinations of ileal interposition (II) associated to a sleeve gastrectomy (SG). The following hormones were assayed in the pre- and postoperative period (mean 16 months) at the baseline and following specific food stimulation (30, 60, 120 min): glucogen-like protein 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), insulin, glucagon, C-peptide, amylin, cholecystokinin (CCK), pancreatic polypeptide (PPP), somatostatin, peptide YY (PYY), ghrelin, adiponectin, resistin, leptin, and interleukin-6 (IL-6). RESULTS Thirty patients had II associated to sleeve gastrectomy (II-SG) and 28 had II with diverted sleeve gastrectomy (II-DSG). GLP1 exhibited an important rise following the two operations, especially after II-DSG (p < 0.001). GIP also exhibited an important rise, with both II-SG and II-DSG being equally effective (p < 0.001). Insulin and amylin showed a significant rise at 30 min. Glucagon decreased slightly. CCK measurements were very low after II-DSG. PPP was also slightly altered by the II-DSG. PYY showed an important increase with both operations (p < 0.001). Ghrelin showed a significant decrease following the two operations (p < 0.001). Somatostatin and IL-6 were not affected (p = 0.632). Both leptin and resistin blood levels decreased. Adiponectin showed a slight increase. Mean postoperative follow-up was 19.2 months. Both II-SG and II-DSG were effective in achieving adequate glycemic control (91.2%). CONCLUSIONS There was a significant hormonal change following laparoscopic ileal interposition. These alterations may explain the promising good results associated to these operations for the treatment of T2DM in the nonmorbidly obese population.
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Bibliography. Current world literature. Diabetes and the endocrine pancreas II. Curr Opin Endocrinol Diabetes Obes 2008; 15:383-93. [PMID: 18594281 DOI: 10.1097/med.0b013e32830c6b8e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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