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Rees TA, Buttle BJ, Tasma Z, Yang SH, Harris PWR, Walker CS. Tirzepatide, GIP(1-42) and GIP(1-30) display unique signaling profiles at two common GIP receptor variants, E354 and Q354. Front Pharmacol 2024; 15:1463313. [PMID: 39464637 PMCID: PMC11502443 DOI: 10.3389/fphar.2024.1463313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 10/02/2024] [Indexed: 10/29/2024] Open
Abstract
Type 2 diabetes (T2D) and obesity are prevalent metabolic disorders affecting millions of individuals worldwide. A new effective therapeutic drug called tirzepatide for the treatment of obesity and T2D is a dual agonist of the GIP receptor and GLP-1 receptor. Tirzepatide is clinically more effective than GLP-1 receptor agonists but the reasons why are not well understood. Tirzepatide reportedly stimulates the GIP receptor more potently than the GLP-1 receptor. However, tirzepatide signaling has not been thoroughly investigated at the E354 (wildtype) or Q354 (E354Q) GIP receptor variants. The E354Q variant is associated increased risk of T2D and lower body mass index. To better understand GIP receptor signaling we characterized the activity of endogenous agonists and tirzepatide at both GIP receptor variants. Using Cos7 cells we examined wildtype and E354Q GIP receptor signaling, analyzing cAMP and IP1 accumulation as well as AKT, ERK1/2 and CREB phosphorylation. GIP(1-42) and GIP(1-30)NH2 displayed equipotent effects on these pathways excluding CREB phosphorylation where GIP(1-30)NH2 was more potent than GIP(1-42) at the E354Q GIP receptor. Tirzepatide favored cAMP signaling at both variants. These findings indicate that tirzepatide is a biased agonist towards Gαs signaling and suggests it equally activates the wildtype and E354Q GIP receptor variants. We also observed differences between the pharmacology of the GIP receptor variants with endogenous peptides, which may help to explain differences in phenotype. These findings contribute to a comprehensive understanding of GIP receptor signaling, and will aid development of therapies combating T2D and obesity.
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Affiliation(s)
- Tayla A. Rees
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
- Headache Group, Wolfson Sensory Pain and Regeneration Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Benjamin J. Buttle
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
| | - Zoe Tasma
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
| | - Sung-Hyun Yang
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
| | - Paul W. R. Harris
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
- School of Chemical Sciences, The University of Auckland, Auckland, New Zealand
| | - Christopher S. Walker
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
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Li RJ, Yang T, Zeng YH, Natsuyama Y, Ren K, Li J, Nagakawa Y, Yi SQ. Impacts of different pancreatic resection ranges on endocrine function in Suncus murinus. World J Gastrointest Surg 2024; 16:2308-2318. [PMID: 39087135 PMCID: PMC11287669 DOI: 10.4240/wjgs.v16.i7.2308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/23/2024] [Accepted: 06/12/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND Surgical intervention involving the pancreas can lead to impaired glucose tolerance and other types of endocrine dysfunction. The scope of pancreatectomy and whether it includes the ventral pancreas are the key factors in the development of postoperative diabetes. The ventral and dorsal pancreases are almost separated in Suncus murinus (S. murinus). AIM To investigate the effects of different extents of pancreatic resection on endocrine function in S. murinus. METHODS Eight-week-old male S. murinus shrews were randomly divided into three experimental groups according to different pancreatic resection ranges as follows: ventral pancreatectomy (VPx) group; partial pancreatectomy (PPx) group; subtotal pancreatectomy (SPx) group; and a sham-operated group. Postprandial serum insulin, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and somatostatin (SST) levels, as well as food intake, weight, blood glucose, and glucose tolerance were regularly measured for each animal. RESULTS S. murinus treated with PPx and SPx suffered from varying degrees of impaired glucose tolerance, but only a small proportion of the SPx group developed diabetes. Only S. murinus in the SPx group showed a significant decrease in food intake accompanied by severe weight loss, as well as a significant increase in postprandial serum GLP-1 levels. Postprandial serum PP levels decreased in both the VPx and PPx groups, but not in the SPx group. Postprandial serum SST levels decreased in both VPx and PPx groups, but the decrease was marginal. CONCLUSION Severe weight loss after pancreatectomy may be related to loss of appetite caused by compensatory elevation of GLP-1. PP and GLP-1 may play a role in resisting blood glucose imbalance.
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Affiliation(s)
- Ru-Jia Li
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Ting Yang
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Yu-Hao Zeng
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Yutaro Natsuyama
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Ke Ren
- Faculty of Physical Education, Qujing Normal University, Qujing 655000, Yunnan Province, China
| | - Jun Li
- School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo 160-0023, Japan
| | - Shuang-Qin Yi
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
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3
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Pacini G, Ahrén B. The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice. Peptides 2024; 171:171117. [PMID: 37984684 DOI: 10.1016/j.peptides.2023.171117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/27/2023] [Accepted: 11/15/2023] [Indexed: 11/22/2023]
Abstract
Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUCinsulin divided by AUCglucose. Insulin sensitivity (SI) and glucose effectiveness (SG) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUCinsulin versus AUCglucose was increased 7-fold by tirzepatide from 0.014 ± 0.004 with glucose only to 0.099 ± 0.016 (P < 0.001). SI was not affected by tirzepatide, whereas SG was increased by 78% (P < 0.001). The increase in SG contributed to an increase in KG by 74 ± 4% after glucose alone and by 67 ± 8% after glucose+ tirzepatide, whereas contribution by SI times AUCinsulin insulin (i.e., disposition index) was 26 ± 4% and 33 ± 8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.
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Affiliation(s)
| | - Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
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4
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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5
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Contribution of GIP and GLP-1 to the Insulin Response to Oral Administration of Glucose in Female Mice. Biomedicines 2023; 11:biomedicines11020591. [PMID: 36831127 PMCID: PMC9953110 DOI: 10.3390/biomedicines11020591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/09/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
It has previously been shown that the incretin effect accounts for ≈50% of the insulin response to oral glucose in normal mice. Now, I have proceeded and studied the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) to the insulin response to oral glucose in female mice by using receptor antagonists. A specific GIP receptor antagonist (mGIP(3-30); 50 or 500 nmol/kg), a specific GLP-1 receptor antagonist (exendin(9-39); 3 or 30 nmol/kg), the combination of mGIP (500 nmol/kg) and exendin(9-39) (30 nmol/kg), or saline was given intravenously four minutes after administration of glucose (50 mg) through a gastric tube in anesthetized C57/BL6J mice (n = 95) with samples obtained before glucose administration and after 15, 30 and 60 min. The insulinogenic index, determined as the area under the 60 min curve for insulin (AUCinsulin) divided by the AUCglucose, was used to reflect the insulin response. It was found that the insulinogenic index was reduced by 67 ± 4% by mGIP(3-30) (p < 0.001), by 60 ± 14% by exendin(9-39) (p = 0.007) and by 61 ± 14% by the combination of mGIP(3-30) and exendin(9-39) (p = 0.043), both at their highest doses, compared to animals injected with glucose in the same experimental series. It is concluded that both GIP and GLP-1 are required for a normal incretin effect in female mice, that they contribute similarly to the insulin response, and that it is unlikely that there is another incretin hormone in this species.
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Atanasova-Panchevska N, Stojchevski R, Hadzi-Petrushev N, Mitrokhin V, Avtanski D, Mladenov M. Antibacterial and Antiviral Properties of Tetrahydrocurcumin-Based Formulations: An Overview of Their Metabolism in Different Microbiotic Compartments. Life (Basel) 2022; 12:1708. [PMID: 36362863 PMCID: PMC9696410 DOI: 10.3390/life12111708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/13/2022] [Accepted: 10/23/2022] [Indexed: 08/29/2023] Open
Abstract
In this review, the basic metabolic characteristics of the curcuminoid tetrahydrocurcumin (THC) at the level of the intestinal microbiota were addressed. Special attention was given to the bactericidal effects of one of the THC-phospholipid formulations, which has shown greater bioavailability and activity than pure THC. Similarly, quinoline derivatives and amino acid conjugates of THC have also shown antibacterial effects in the gut. The microbial effect of pure THC is particularly pronounced in pathophysiological conditions related to the function of the intestinal microbiota, such as type II diabetes. Furthermore, the antiviral characteristics of Cur compared to those of THC are more pronounced in preventing the influenza virus. In the case of HIV infections, the new microemulsion gel formulations of THC possess high retention during preventive application in the vagina and, at the same time, do not disturb the vaginal microbiota, which is critical in maintaining low vaginal pH. Based on the reviewed literature, finding new formulations of THC which can increase its bioavailability and activity and emphasize its antibacterial and antiviral characteristics could be very important. Applying such THC formulations in preventing and treating ailments related to the microbiotic compartments in the body would be beneficial from a medical point of view.
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Affiliation(s)
- Natalija Atanasova-Panchevska
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, P.O. Box 162, 1000 Skopje, North Macedonia
| | - Radoslav Stojchevski
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, P.O. Box 162, 1000 Skopje, North Macedonia
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY 10022, USA
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, P.O. Box 162, 1000 Skopje, North Macedonia
| | - Vadim Mitrokhin
- Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, 117997 Moscow, Russia
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY 10022, USA
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, P.O. Box 162, 1000 Skopje, North Macedonia
- Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, 117997 Moscow, Russia
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7
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Ahrén B. The Glucose Sensitivity of Insulin Secretion-Lessons from In Vivo and In Vitro Studies in Mice. Biomolecules 2022; 12:biom12070976. [PMID: 35883532 PMCID: PMC9312818 DOI: 10.3390/biom12070976] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/27/2022] [Accepted: 07/08/2022] [Indexed: 02/05/2023] Open
Abstract
This study explored the relationship between the glucose dose and insulin response from beta cells in vivo and in vitro in mice. Glucose was administered intravenously at different dose levels (from 0 to 0.75 g/kg) in anesthetized C57BL/6J mice, and the glucose and insulin concentrations were determined in samples taken after 50 min. Furthermore, freshly isolated mouse islets were incubated for 60 min in the presence of different concentrations of glucose (from 2.8 to 22.2 mmol/L) and insulin levels were analyzed in the medium. It was found that insulin levels increased after an intravenous injection of glucose with the maximal increase seen after 0.35 g/kg with no further increase after 0.5 or 0.75 g/kg. The acute increase in insulin levels (during the first 5 min) and the maximum glucose level (achieved after 1 min) showed a curvilinear relation with the half-maximal increase in insulin levels achieved at 11.4 mmol/L glucose and the maximal increase in insulin levels at 22.0 mmol/L glucose. In vitro, there was also a curvilinear relation between glucose concentrations and insulin secretion. Half maximal increase in insulin concentrations was achieved at 12.5 mmol/L glucose and the maximal increase in insulin concentrations was achieved at 21.5 mmol/L. Based on these data, we concluded that the glucose-insulin relation was curvilinear both in vivo and in vitro in mice with similar characteristics in relation to which glucose levels that achieve half-maximal and maximal increases in insulin secretion. Besides the new knowledge of knowing these relations, the results have consequences on how to design studies on insulin secretion to obtain the most information.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, 22185 Lund, Sweden
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8
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Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab 2021; 23 Suppl 3:5-29. [PMID: 34310013 DOI: 10.1111/dom.14496] [Citation(s) in RCA: 188] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 11/27/2022]
Abstract
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.
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Affiliation(s)
- Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Daniel R Quast
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Jakob Wefers
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Andreas F H Pfeiffer
- Charité - Universitätsmedizin Berlin, Klinik für Endokrinologie, Stoffwechsel- und Ernährungsmedizin, Berlin, Germany
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9
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Ovlund T, Pacini G, Ahrén B. Impact of Incretin Hormone Receptors on Insulin-Independent Glucose Disposal in Model Experiments in Mice. Front Endocrinol (Lausanne) 2021; 12:680153. [PMID: 34168617 PMCID: PMC8217865 DOI: 10.3389/fendo.2021.680153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/19/2021] [Indexed: 12/14/2022] Open
Abstract
A large contribution to glucose elimination from the circulation is achieved by insulin-independent processes. We have previously shown that the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) increase this process and, therefore, seem to contribute to glucose disposal both through this effect and through the classical incretin effect resulting in enhanced insulin levels. We have now explored in more detail the potential contribution by incretin hormone receptors to insulin-independent processes for glucose elimination. To that end, we have performed intravenous glucose tests (0.35g/kg) in C57BL/6J mice and analyzed glucose elimination rate and glucose effectiveness (i.e., insulin-independent glucose disposal, SG) in wildtype mice and in mice with genetic deletion of GIP receptors or GLP-1 receptors. We performed studies with or without complete blockade of insulin secretion by the drug diazoxide (25 mg/kg). The mice were anesthetized with a novel fentanyl citrate/fluanisone formulation, called Fluafent, together with midazolam. Initially we demonstrated that glucose and insulin data after intravenous and oral glucose were not different using this anesthesia compared to the previously commonly used combination of HypnormR and midazolam. The results show that SG was reduced in GLP-1 receptor knockout mice, whereas there was no difference between GIP receptor knockout mice and wildtype mice, and this was evident both under normal conditions and after complete inhibition of insulin secretion. The study therefore indicates that insulin-independent glucose elimination requires active GLP-1 receptors and thus that the two incretin hormone receptor types show dissociated relevance for this process.
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Affiliation(s)
- Tina Ovlund
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | | | - Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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10
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Kilanowska A, Szkudelski T. Effects of inhibition of phosphodiesterase 3B in pancreatic islets on insulin secretion: a potential link with some stimulatory pathways. Arch Physiol Biochem 2021; 127:250-257. [PMID: 31240952 DOI: 10.1080/13813455.2019.1628071] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Elevated intracellular cAMP concentrations potentiate insulin secretion from pancreatic β cells. Phosphodiesterase 3B (PDE3B) is highly expressed in these cells and plays a role in the regulation of insulin secretion. MATERIALS AND METHODS In this study, effects of amrinone, an inhibitor of PDE3B on insulin release from isolated pancreatic islets, were determined. RESULTS Exposure of islets to amrinone for 15, 30 and 90 min markedly increased secretion induced by 6.7 mM glucose. Amrinone enhanced also secretion stimulated by 6.7 mM glucose and DB-cAMP, an activator of PKA. It was also demonstrated that amrinone potentiated insulin secretion induced by 6.7 mM glucose in the combination with PMA (activator of PKC) or acetylcholine. However, the insulin-secretory response to glucose and glibenclamide was unchanged by amrinone. CONCLUSIONS These results indicate that amrinone is capable of increasing insulin secretion; however, its action is restricted.
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Affiliation(s)
- Agnieszka Kilanowska
- Department of Anatomy and Histology, University of Zielona Gora, Zielona Gora, Poland
| | - Tomasz Szkudelski
- Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Poznan, Poland
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11
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Ahrén B, Pacini G. Glucose effectiveness: Lessons from studies on insulin-independent glucose clearance in mice. J Diabetes Investig 2021; 12:675-685. [PMID: 33098240 PMCID: PMC8088998 DOI: 10.1111/jdi.13446] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/15/2020] [Accepted: 10/19/2020] [Indexed: 01/07/2023] Open
Abstract
Besides insulin-mediated transport of glucose into the cells, an important role is also played by the non-insulin-mediated transport. This latter process is called glucose effectiveness (acronym SG ), which is estimated by modeling of glucose and insulin data after an intravenous glucose administration, and accounts for ≈70% of glucose disposal. This review summarizes studies on SG , mainly in humans and rodents with focus on results achieved in model experiments in mice. In humans, SG is reduced in type 2 diabetes, in obesity, in liver cirrhosis and in some elderly populations. In model experiments in mice, SG is independent from glucose levels, but increases when insulin secretion is stimulated, such as after administration of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. SG is reduced in insulin resistance induced by high-fat feeding and by exogenous administration of glucagon. Glucose-dependent (insulin-independent) glucose disposal is therefore important for glucose elimination, and it is also well regulated. It might be of pathophysiological relevance for the development of type 2 diabetes, in particular during insulin resistance, and might also be a target for glucose-reducing therapy. Measuring SG is essentially important when carrying out metabolic studies to understand glucose homeostasis.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences LundLund UniversityLundSweden
| | - Giovanni Pacini
- Metabolic UnitInstitute of Neurosciences (IN‐CNR)PadovaItaly
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12
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Ahrén B, Yamada Y, Seino Y. The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice. Peptides 2021; 135:170434. [PMID: 33172827 DOI: 10.1016/j.peptides.2020.170434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/20/2020] [Accepted: 10/20/2020] [Indexed: 12/28/2022]
Abstract
To study whether activation of GLP-1 receptors importantly contributes to the insulinotropic action of exogenously administered glucagon, we have performed whole animal experiments in normal mice and in mice with GLP-1 receptor knockout. Glucagon (1, 3 or 10 μg/kg), the GLP-1 receptor antagonist exendin 9-39 (30 nmol/kg), glucose (0.35 g/kg) or the incretin hormone glucose-dependent insulinotropic polypeptide (GIP; 3 nmol/kg) was injected intravenously or glucose (75 mg) was given orally through gavage. Furthermore, islets were isolated and incubated in the presence of glucose with or without glucagon. It was found that the insulin response to intravenous glucagon was preserved in GLP-1 receptor knockout mice but that glucagon-induced insulin secretion was markedly suppressed in islets from GLP-1 receptor knockout mice. Similarly, the GLP-1 receptor antagonist markedly suppressed glucagon-induced insulin secretion in wildtype mice. These data suggest that GLP-1 receptors contribute to the insulinotropic action of glucagon and that there is a compensatory mechanism in GLP-1 receptor knockout mice that counteracts a reduced effect of glucagon. Two potential compensatory mechanisms (glucose and GIP) were explored. However, neither of these seemed to explain why the insulin response to glucagon is not suppressed in GLP-1 receptor knockout mice. Based on these data we confirm the hypothesis that glucagon-induced insulin secretion is partially mediated by GLP-1 receptors on the beta cells and we propose that a compensatory mechanism, the nature of which remains to be established, is induced in GLP-1 receptor knockout mice to counteract the expected impaired insulin response to glucagon in these mice.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, C11 BMC, Sölvegatan 19, 221 84 Lund, Sweden.
| | - Yuichiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Graduate School of Medicine, Akita University, Akita, Japan
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Yuan T, Yin Z, Yan Z, Hao Q, Zeng J, Li L, Zhao J. Tetrahydrocurcumin ameliorates diabetes profiles of db/db mice by altering the composition of gut microbiota and up-regulating the expression of GLP-1 in the pancreas. Fitoterapia 2020; 146:104665. [DOI: 10.1016/j.fitote.2020.104665] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/06/2020] [Accepted: 06/07/2020] [Indexed: 01/09/2023]
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Ahrén B, Yamada Y, Seino Y. Islet adaptation in GIP receptor knockout mice. Peptides 2020; 125:170152. [PMID: 31522751 DOI: 10.1016/j.peptides.2019.170152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/01/2019] [Accepted: 09/02/2019] [Indexed: 12/27/2022]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) receptor knockout (KO) mice are tools for studying GIP physiology. Previous results have demonstrated that these mice have impaired insulin response to oral glucose. In this study, we examined the insulin response to intravenous glucose by measuring glucose, insulin and C-peptide after intravenous glucose (0.35 g/kg) in 5-h fasted female GIP receptor KO mice and their wild-type (WT) littermates. The 1 min insulin and C-peptide responses to intravenous glucose were significantly enhanced in GIP receptor KO mice (n = 26) compared to WT mice (n = 30) as was beta cell function (area under the 50 min C-peptide curve divided by area under the 50 min curve for glucose) (P = 0.001). Beta cell function after intravenous glucose was also enhanced in GIP receptor KO mice in the presence of the glucagon-like peptide-1 receptor antagonist exendin 9 (30 nmol/kg; P = 0.007), the muscarinic antagonist atropine (5 mg/kg; P = 0.007) and the combination of the alpha-adrenoceptor antagonist yohimbine (1.4 mg/kg) and the beta-adrenoceptor antagonist propranolol (2.5 mg/kg; P = 0.042). Analysis of the regression between fasting glucose (6.8 ± 0.1 mmol/l in GIP receptor KO mice and 7.5 ± 0.2 mmol/l in WT mice, P = 0.003) and the 1 min C-peptide response to intravenous glucose showed a negative linear regression between these variables in both WT (n = 60; r = -0.425, P = 0.001) and GIP receptor KO mice (n = 56; r = -0.474, P < 0.001). We conclude that there is a beta cell adaptation in GIP receptor KO mice resulting in enhanced insulin secretion after intravenous glucose to which slight long-term reduction in circulating glucose in these mice may contribute.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund university, Lund, Sweden.
| | - Yuchiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Graduate School of Medicine, Akita University, Akita, Japan
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Morettini M, Di Nardo F, Ingrillini L, Fioretti S, Göbl C, Kautzky-Willer A, Tura A, Pacini G, Burattini L. Glucose effectiveness and its components in relation to body mass index. Eur J Clin Invest 2019; 49:e13099. [PMID: 30838644 DOI: 10.1111/eci.13099] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 02/14/2019] [Accepted: 03/03/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Obesity is known to induce a deterioration of insulin sensitivity (SI ), one of the insulin-dependent components of glucose tolerance. However, few studies investigated whether obesity affects also the insulin-independent component, that is glucose effectiveness (SG ). This cross-sectional study aimed to analyse SG and its components in different body mass index (BMI) categories. MATERIALS AND METHODS Three groups of subjects spanning different BMI (kg m-2 ) categories underwent a 3-h frequently sampled intravenous glucose tolerance test: Lean (LE; 18.5 ≤ BMI < 25, n = 73), Overweight (OW; 25 ≤ BMI < 30, n = 90), and Obese (OB; BMI ≥ 30, n = 41). OB has been further divided into two subgroups, namely Obese I (OB-I; 30 ≤ BMI < 35, n = 27) and Morbidly Obese (OB-M; BMI ≥ 35, n = 14). Minimal model analysis provided SG and its components at zero (GEZI) and at basal (BIE) insulin. RESULTS Values for SG were 1.98 ± 1.30 × 10-2 ·min-1 in all subjects grouped and 2.38 ± 1.23, 1.84 ± 0.82, 1.59 ± 0.61 10-2 ·min-1 in LE, OW and OB, respectively. In all subjects grouped, a significant inverse linear correlation was found between the log-transformed values of SG and BMI (r = -0.3, P < 0.0001). SG was significantly reduced in OW and OB with respect to LE (P < 0.001) but no significant difference was detected between OB and OW (P = 0.35) and between OB-I and OB-M (P = 0.25). Similar results were found for GEZI. BIE was not significantly different among NW, OW and OB (P = 0.11) and between OB-I and OB-M (P ≥ 0.07). CONCLUSIONS SG and its major component GEZI deteriorate in overweight individuals compared to those in the normal BMI range, without further deterioration when BMI increases above 30 kg m-2 .
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Affiliation(s)
- Micaela Morettini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Francesco Di Nardo
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Laura Ingrillini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Sandro Fioretti
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Christian Göbl
- Department of Obstetrics and Gynecology, Division of Obstetrics and Feto-maternal Medicine, Medical University of Vienna, Vienna, Austria
| | - Alexandra Kautzky-Willer
- Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Andrea Tura
- Metabolic Unit, CNR Institute of Neuroscience, Padova, Italy
| | - Giovanni Pacini
- Metabolic Unit, CNR Institute of Neuroscience, Padova, Italy
| | - Laura Burattini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
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Tura A, Pacini G, Yamada Y, Seino Y, Ahrén B. Glucagon and insulin secretion, insulin clearance, and fasting glucose in GIP receptor and GLP-1 receptor knockout mice. Am J Physiol Regul Integr Comp Physiol 2019; 316:R27-R37. [DOI: 10.1152/ajpregu.00288.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
It is not known whether GIP receptor and GLP-1 receptor knockout (KO) mice have perturbations in glucagon secretion or insulin clearance, and studies on impact on fasting glycemia have previously been inconsistent in these mice. We therefore studied glucagon secretion after oral whey protein (60 mg) and intravenous arginine (6.25 mg), insulin clearance after intravenous glucose (0.35 g/kg) and fasting glucose, insulin, and glucagon levels after standardized 5-h fasting in female GIP receptor and GLP-1 receptor KO mice and their wild-type (WT) littermates. Compared with WT controls, GIP receptor KO mice had normal glucagon responses to oral protein and intravenous arginine, except for an enhanced 1-min response to arginine, whereas glucagon levels after oral protein and intravenous arginine were enhanced in GLP-1 receptor KO mice. Furthermore, the intravenous glucose test revealed normal insulin clearance in both GIP receptor and GLP-1 receptor KO mice, whereas β-cell glucose sensitivity was enhanced in GIP receptor KO mice and reduced in GLP-1 receptor KO mice. Finally, GIP receptor KO mice had reduced fasting glucose (6.7 ± 0.1, n = 56, vs. 7.4 ± 0.1 mmol/l, n = 59, P = 0.001), whereas GLP-1 receptor KO mice had increased fasting glucose (9.1 ± 0.2, n = 44, vs. 7.7 ± 0.1 mmol/l, n = 41, P < 0.001). We therefore suggest that GIP has a limited role for glucagon secretion in mice, whereas GLP-1 is of importance for glucagon regulation, that GIP and GLP-1 are of importance for the regulation of β-cell function beyond their role as incretin hormones, and that they are both of importance for fasting glucose.
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Affiliation(s)
- Andrea Tura
- Metabolic Unit, National Research Council Institute of Neuroscience, Padua, Italy
| | - Giovanni Pacini
- Metabolic Unit, National Research Council Institute of Neuroscience, Padua, Italy
| | - Yuchiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Graduate School of Medicine, Akita University, Akita, Japan
| | | | - Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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Morettini M, Di Nardo F, Burattini L, Fioretti S, Göbl C, Kautzky-Willer A, Pacini G, Tura A. Assessment of glucose effectiveness from short IVGTT in individuals with different degrees of glucose tolerance. Acta Diabetol 2018; 55:1011-1018. [PMID: 29931422 DOI: 10.1007/s00592-018-1182-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 06/12/2018] [Indexed: 02/06/2023]
Abstract
AIMS Minimal model analysis of intravenous glucose tolerance test (IVGTT) data represents the reference method to assess insulin sensitivity (SI) and glucose effectiveness (SG) that quantify the insulin-dependent and insulin-independent processes of glucose disappearance, respectively. However, test duration (3 h) and need for modeling expertise limit the applicability of this method. Aim of this study was providing a simple predictor of SG applicable to short test (1 h), as previously done with SI. METHODS Three groups of subjects reflecting different glucose tolerance degrees underwent a 3 h IVGTT: subjects with normal glucose tolerance (NGT, n = 164), with defective glucose regulation (DGR, n = 191), and with type 2 diabetes (T2D, n = 39). Minimal model analysis provided reference SG and its components at zero (GEZI) and basal (BIE) insulin. The simple predictor CSG (calculated SG) was described by the formula CSG = α0 + α1 × KG/Gpeak, being KG the glucose disappearance rate (between 10 and 50 min) and Gpeak the maximum of the glucose curve during the test; α0 and α1 coefficients were provided by linear regression analysis. RESULTS CSG and SG showed a markedly significant relationship in the whole dataset (r = 0.72, p < 0.0001) and in the single groups (r = 0.70 in NGT, r = 0.71 in DGR and r = 0.70 in T2D, p < 0.0001 for all); α1 × KG/Gpeak was significantly related to GEZI (r ≥ 0.60). CONCLUSIONS The interest for insulin-independent glucose disappearance is increasing, due to the recent availability of SGLT2 pharmacological agents, lowering glycemic levels without requiring insulin action. This study proposes a reliable predictor of SG based on IVGTT lasting 1 h only, and not requiring mathematical modeling skills.
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Affiliation(s)
- Micaela Morettini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Francesco Di Nardo
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Laura Burattini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Sandro Fioretti
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Christian Göbl
- Division of Obstetrics and Feto-maternal Medicine, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Alexandra Kautzky-Willer
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Giovanni Pacini
- Metabolic Unit, CNR Institute of Neuroscience, Corso Stati Uniti 4, 35127, Padova, Italy
| | - Andrea Tura
- Metabolic Unit, CNR Institute of Neuroscience, Corso Stati Uniti 4, 35127, Padova, Italy.
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Pacini G, Ahrén B. Glucagon-like peptide-1 and glucose-dependent insulinotropic peptide: effects alone and in combination on insulin secretion and glucose disappearance in mice. Physiol Rep 2018; 5:5/11/e13280. [PMID: 28611149 PMCID: PMC5471432 DOI: 10.14814/phy2.13280] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 04/06/2017] [Accepted: 04/12/2017] [Indexed: 12/30/2022] Open
Abstract
Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) stimulate insulin secretion. They are both released after meal ingestion, and therefore they might cooperate in their actions. However, whether there is a cooperative action of the two incretins is not known. This study therefore investigated the effects on insulin secretion and glucose disappearance of GLP‐1 and GIP when given together with intravenous glucose both alone and in combination in mice. Four different doses were used (0.003, 0.03, 0.3 and 3.0 nmol/kg), which ranged from subthreshold to maximal doses to stimulate first‐phase insulin secretion as evident from initial dose–response studies. It was found that at 0.03 nmol/kg and higher doses, glucose‐stimulated insulin secretion was augmented by both incretins. When they were given in combination, no further increase was observed, indicating no synergistic effect. Also, glucose disappearance rate was increased by 0.03 and 3.0 nmol/kg of the two incretins, both when they were given alone and in combination with, again, no synergy. Finally, glucose effectiveness (an index of noninsulin‐mediated processes) was enhanced by the two incretins, in particular GIP. We also found that insulin‐dependent and insulin‐independent mechanisms contributed 38% and 62%, respectively, to glucose tolerance after glucose alone; with GIP, the contribution by noninsulin‐dependent processes was remarkably dominant and with GLP‐1, insulin‐dependent processes were prevailing. In conclusion, GIP and GLP‐1 stimulate insulin secretion and glucose effectiveness in mice with no synergistic action, but with a dissociated contributory effector on glucose disposal: with GLP‐1 being more active on insulin‐dependent processes and GIP more active on noninsulin‐dependent processes.
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Affiliation(s)
- Giovanni Pacini
- Metabolic Unit, Institute of Neuroscience (IN-CNR), Padova, Italy
| | - Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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