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BASIC AND TRANSLATIONAL—PANCREAS Glucose-Dependent Insulinotropic Peptide Stimulates Glucagon-Like Peptide 1 Production by Pancreatic Islets via Interleukin 6, Produced by a Cells

Published on Jan 1, 2016
Katharina Timper12
Estimated H-index: 12
,
Elise Dalmas8
Estimated H-index: 8
+ 9 AuthorsMarc Y. Donath60
Estimated H-index: 60
Abstract
BACKGROUND & AIMS: Glucose-dependent insulinotropic peptide (GIP) induces production of interleukin 6 (IL6) by adipocytes. IL6 increases production of glucagon-like peptide (GLP)-1 by L cells and a cells, leading to secretion of insulin from b cells. We investigated whether GIP regulates GLP1 and glycemia via IL6. METHODS: We obtained samples of human pancreatic islets and isolated islets from mice; human a cells and b cells were sorted by flow cytometry and incubated with GIP. Islets were analyzed by quantitative polymerase chain reaction and immunohistochemistry. BKS.Cg-Dock7mþ/þ Leprdb/J db/db mice (diabetic mice) and db/þ mice, as well as C57BL/6J IL6-knockout mice (IL6-KO) and C57BL/6J mice with the full-length Il6 gene (controls), were fed a chow or a high-fat diet; some mice were given injections of recombinant GIP, IL6, GLP, a neutralizing antibody against IL6 (anti-IL6), lipopolysaccharide, and/or IL1B. Mice were given a glucose challenge and blood samples were collected and analyzed. RESULTS: Incubation of mouse and human pancreatic a cells with GIP induced their production of IL6, leading to production of GLP1 and insulin secretion from pancreatic islets. This did not occur in islets from IL6-KO mice or in islets incubated with anti-IL6. Incubation of islets with IL1B resulted in IL6 production but directly reduced GLP1 production. Incubation of mouse islets with the sodium glucose transporter 2 inhibitor dapagliflozin induced production of GLP1 and IL6. Injection of control mice with GIP increased plasma levels of GLP1, insulin, and glucose tolerance; these effects were amplified in mice given lipopolysaccharide but reduced in IL6-KO mice or in mice given anti-IL6. Islets from diabetic mice had increased levels of IL1B and IL6, compared with db/þ mice, but injection of GIP did not lead to production of GLP1 or reduce glycemia.CONCLUSIONS: In studies of pancreatic islets from human beings and mice, we found that GIP induces production of IL6 by a cells, leading to islet production of GLP1 and insulin. This process is regulated by inflammation, via IL1B, and by sodium glucose transporter 2. In diabetic mice, increased islet levels of IL6 and IL1B might increase or reduce the production of GLP1 and affect glycemia.
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  • Citations (1)
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References43
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#1Berit Svendsen (UCPH: University of Copenhagen)H-Index: 16
#2Jens J. Holst (UCPH: University of Copenhagen)H-Index: 152
Abstract The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from enteroendocrine cells in the intestine along with other gut hormones (PYY, CCK and neurotensin) shown to affect metabolism and/or appetite. The secretion of many gut hormones is highly increased after gastric bypass operations, which have turned out to be an effective therapy of not only obesity but also type 2 diabetes. These effects are likely to be due, at le...
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#1Caroline BonnerH-Index: 16
#2Julie Kerr-ConteH-Index: 40
Last. François PattouH-Index: 63
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The recently approved drug dapagliflozin is now shown to increase glucagon secretion by acting on pancreatic alpha cells, which has implications for the potency of its antidiabetic effects
255 CitationsSource
#1Siri Malmgren (Lund University)H-Index: 9
#2Bo Ahrén (Lund University)H-Index: 88
Aims/hypothesis Glucose-lowering therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors is associated with a low risk of hypoglycaemia. We hypothesise that DPP-4 inhibition prevents hypoglycaemia via increased glucagon counterregulation through the incretin hormone glucose-dependent insulinotropic polypeptide (GIP).
26 CitationsSource
#1Kasper Aaboe (UCPH: University of Copenhagen)H-Index: 8
#2S. Akram (UCPH: University of Copenhagen)H-Index: 1
Last. Thure Krarup (UCPH: University of Copenhagen)H-Index: 42
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Aims To examine whether 12 weeks of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, influences the insulin secretion induced by glucose, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during a hyperglycaemic clamp in patients with type 2 diabetes (T2DM). Methods A randomized, double-blind, placebo-controlled study was conducted over 12 weeks, during which 25 patients with T2DM completed treatment with either sitagliptin (100 mg once...
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Inflammation is now appreciated to have an important role in the pathogenesis of type 2 diabetes and associated complications. Donath describes the underlying mechanisms and discusses the rationale for the use of anti-inflammatory agents — such as those that have been developed for rheumatoid arthritis and other diseases driven by inflammatory processes — in patients with diabetes.
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#2Elza MuscelliH-Index: 27
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Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. Methods. We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m2, HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients rece...
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#2Vilborg Palsdottir (University of Gothenburg)H-Index: 9
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Glucagon-like peptide 1 (GLP-1), produced in the intestine and the brain, can stimulate insulin secretion from the pancreas and alleviate type 2 diabetes. The cytokine interleukin-6 (IL-6) may enhance insulin secretion from β-cells by stimulating peripheral GLP-1 production. GLP-1 and its analogs also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS, but otherwise are poorly understood. The cytokines IL-6 and interleukin 1β (IL-1β)...
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The role of the immune system is to restore functionality in response to stress. Increasing evidence shows that this function is not limited to insults by infection or injury and plays a role in response to overnutrition. Initially, this metabolic activation of the immune system is a physiological response, but it may become deleterious with time. Therefore, therapeutic interventions should aim at modulating the immune system rather than simply damping it. In this article, we describe the physio...
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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine on ingestion of various nutrients to stimulate insulin secretion from pancreatic β-cells glucose-dependently. GIP and GLP-1 undergo degradation by dipeptidyl peptidase-4 (DPP-4), and rapidly lose their biological activities. The actions of GIP and GLP-1 are mediated by their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP...
133 CitationsSource
#1Elisa Fernández-Millán (Complutense University of Madrid)H-Index: 10
#2J. de Toro-Martín (Complutense University of Madrid)H-Index: 2
Last. Carmen Álvarez (Complutense University of Madrid)H-Index: 17
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Aims/hypothesis Plasma glucagon concentrations rise sharply during the early postnatal period. This condition is associated with increased alpha cell mass. However, the trophic factors that regulate alpha cell turnover during the perinatal period have not been studied. Macrophage infiltrations are present in the neonatal pancreas, and this cell type releases cytokines such as IL-6. Alpha cells have been identified as a primary target of IL-6 actions. We therefore investigated the physiological r...
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#1Brian Finan (TUM: Technische Universität München)H-Index: 22
#2Timo D. Müller (TUM: Technische Universität München)H-Index: 32
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Glucagon-like peptide-1 (GLP-1) analogs are considered the best current medicines for type 2 diabetes (T2D) and obesity due to their actions in lowering blood glucose and body weight. Despite similarities to GLP-1, glucose-dependent insulinotropic polypeptide (GIP) has not been extensively pursued as a medical treatment for T2D. This is largely based on observations of diminished responses of GIP to lower blood glucose in select patients, as well as evidence from rodent knockout models implying ...
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