Insulin Secretion Depends on Intra-islet Glucagon Signaling

Svendsen, Berit; Larsen, Olav; Gabe, M; Christiansen, C.; Rosenkilde, Mette M.; Drucker, Daniel J.; Holst, Jens J.

doi:10.1016/j.celrep.2018.10.018

Cited by 273 publications

(318 citation statements)

References 43 publications

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“…The physiological interpretation of these earlier studies is difficult because the V1bR is the only receptor from the vasopressin receptor family expressed in mouse islets, and its expression is restricted to alpha-cells (DiGruccio et al, 2016;Taveau et al, 2017), something we also observe. An explanation for the reported increase in insulin could lie in the recently elucidated role of glucagon as a paracrine regulator of insulin (Svendsen et al, 2018). In particular, it could be that AVP stimulates glucagon secretion so potently (especially at the supraphysiological concentrations used in these aforementioned studies; > 10 nM) that it binds to the GLP-1 receptor on beta-cells, thereby increasing insulin secretion.…”

Section: Pg 18mentioning

confidence: 99%

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

Kim

Knudsen

Madara

et al. 2020

Preprint

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Hypoglycaemia is a major barrier to the treatment of diabetes. Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon -the body's principle blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. In isolated islets, varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor that stimulates glucagon secretion in vivo remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor (V1bR). Activation of AVP neurons in vivo increased circulating AVP, stimulated glucagon release and evoked hyperglycaemia; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of dehydration and hypoglycaemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata, which are known to be activated by hypoglycaemia, drive AVP neuron activation in response to insulin-induced hypoglycaemia.Hypoglycaemia also increases circulating levels of copeptin (derived from the same pre-pro hormone as AVP) levels in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with type 1 diabetes, hypoglycaemia failed to increase both plasma copeptin and glucagon. These findings provide a new mechanism for the central regulation of glucagon secretion in both health and disease.

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Section: Pg 18mentioning

confidence: 99%

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

Kim

Knudsen

Madara

et al. 2020

Preprint

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“…GRA increased plasma amino acid concentrations, and we believe that the GRA augmented glucagon secretion may be due to feedback mechanisms involving amino acids and/or beta-and delta-cell secretory products. The augmented insulin secretion in GRA treated mice in response to mixture 4 is surprising since glucagon has been shown to induce insulin secretion (9,59,70). We therefore expected GRA treatment to, if anything, decrease insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…; Bayer Animal Health, Leverkusen, Germany)) and the entire abdominal cavity was exposed. The pancreas was then isolated in situ from the circulation as previously described (59). After establishing the perfusion flow through the pancreas, the mouse was euthanized by perforating the diaphragm.…”

Section: Stimulation Of the Perfused Mouse Pancreas With Individual Amentioning

confidence: 99%

Alanine, arginine, and proline but not glutamine are the feed-back regulators in the liver-alpha cell axis in mice

Galsgaard

Jepsen

Kjeldsen

et al. 2019

Preprint

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Aim:To identify the amino acids that stimulate glucagon secretion in mice and whether the metabolism of these relies on glucagon receptor signaling.Methods: Pancreata of female C57BL/6JRj mice were perfused with 19 individual amino acids (1 mM) and secretion of glucagon was assessed using a specific glucagon radioimmunoassay. Separately, a glucagon receptor antagonist (GRA; 25-2648, 100 mg/kg) or vehicle was administered to female C57BL/6JRj mice three hours prior to an intraperitoneal injection of four different isomolar (in total 7 µmol/g body weight) amino acid mixtures; mixture 1: alanine, arginine, cysteine, and proline; mixture 2: asparatate, glutamate, histidine, and lysine; mixture 3: citrulline, methionine, serine, and threonine; and mixture 4: glutamine, leucine, isoleucine, and valine. Blood glucose, plasma glucagon, amino acid, and insulin concentrations were measured using well characterized methodologies.Results: Alanine (P=0.03), arginine (P<0.001), and proline (P=0.03) but not glutamine (P=0.2) stimulated glucagon secretion from the perfused mouse pancreas. Cysteine had the numerically largest effect on glucagon secretion but did not reach statistical significance (P=0.08). However, when the four isomolar amino acid mixtures were administered there were no significant difference (P>0.5) in plasma concentrations of glucagon across mixture 1-4. Plasma concentrations of total amino acids were higher after administration of GRA when mixture 1 (P=0.004) or mixture 3 (P=0.04) were injected. Conclusion:Our data suggest that alanine, arginine, and proline but not glutamine are involved in the liveralpha cell axis in mice as they all increased glucagon secretion and their disappearance rate was altered by GRA.

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“…Glucagon receptors are abundantly expressed on pancreatic β-cells and coupled to stimulation of insulin secretion. [36][37][38] Svendsen et al examined glucagon-induced insulin secretion using mouse models with different ways of disrupting glucagon signalling confirming that insulin secretion depends on intra-islet glucagon activity, and glucagon receptor, along with GLP-1 receptor, is crucial for β-cell secretory responses. 38 Upregulation of these genes indicates enhanced insulin release.…”

Section: Effects Of 72-h Exposure To Svg On Gene Transcription In Mmentioning

confidence: 99%

Steviol glucuronide, a metabolite of steviol glycosides, potently stimulates insulin secretion from isolated mouse islets: Studies in vitro

Rebsdorf

Anker

et al. 2019

Endocrino Diabet & Metabol

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Aims Steviol glycosides are the sweet components extracted from medicinal plant Stevia rebaudiana Bertoni, which have antihyperglycaemic effects. Steviol glucuronide (SVG) is the metabolite excreted in human urine after oral administration of steviol glycosides. We aimed to clarify whether SVG exerts direct insulin stimulation from pancreatic islets and to explore its mode of action. Materials and Methods Insulin secretion was measured after 60 minutes static incubation of isolated mouse islets with (a) 10−9‐10−5 mol/L SVG at 16.7 mmol/L glucose and (b) 10−7 mol/L SVG at 3.3‐16.7 mmol/L glucose. Islets were perifused with 3.3 or 16.7 mmol/L glucose in the presence or absence of 10−7 mol/L SVG. Gene transcription was measured after 72 hours incubation in the presence or absence of 10−7 mol/L SVG. Results SVG dose‐dependently increased insulin secretion from mouse islets with 10−7 mol/L exerting the maximum effect in the presence of 16.7 mmol/L glucose (P < .001). The insulinotropic effect of SVG was critically dependent on the prevailing glucose concentration, and SVG (10−7 mol/L) enhanced insulin secretion at or above 11.1 mmol/L glucose (P < .001) and showed no effect at lower glucose concentrations. During perifusion of islets, SVG (10−7 mol/L) had a long‐acting and apparently reversible insulinotropic effect in the presence of 16.7 mmol/L glucose (P < .05). Gene‐transcript levels of B2m and Gcgr were markedly altered. Conclusion This is the first report to demonstrate that SVG stimulates insulin secretion in a dose‐ and glucose‐dependent manner from isolated mouse islets of Langerhans. SVG may be the main active metabolite after oral intake of steviol glycosides.

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Insulin Secretion Depends on Intra-islet Glucagon Signaling

Abstract: Highlights d Paracrine glucagon actions are required for maintenance of normal insulin secretion d Glucagon signaling in islets involves activation of glucagon and GLP-1 receptors d Beta cell GLP-1 receptors are activated by local glucagon in a paracrine manner

Cited by 273 publications

References 43 publications

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

Alanine, arginine, and proline but not glutamine are the feed-back regulators in the liver-alpha cell axis in mice

Steviol glucuronide, a metabolite of steviol glycosides, potently stimulates insulin secretion from isolated mouse islets: Studies in vitro

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