In the rat pancreas, somatostatin tonically inhibits glucagon secretion and is required for glucose-induced inhibition of glucagon secretion.
GABA
glucagon secretion
insulin
intrinsic regulation
isolated perfused rat pancreas
paracrine regulation
somatostatin
Journal
Acta physiologica (Oxford, England)
ISSN: 1748-1716
Titre abrégé: Acta Physiol (Oxf)
Pays: England
ID NLM: 101262545
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
26
08
2019
revised:
28
02
2020
accepted:
04
03
2020
pubmed:
8
3
2020
medline:
27
7
2021
entrez:
8
3
2020
Statut:
ppublish
Résumé
It is debated whether the inhibition of glucagon secretion by glucose results from direct effects of glucose on the α-cell (intrinsic regulation) or by paracrine effects exerted by beta- or delta-cell products. To study this in a more physiological model than isolated islets, we perfused isolated rat pancreases and measured glucagon, insulin and somatostatin secretion in response to graded increases in perfusate glucose concentration (from 3.5 to 4, 5, 6, 7, 8, 10, 12 mmol/L) as well as glucagon responses to blockage/activation of insulin/GABA/somatostatin signalling with or without addition of glucose. Glucagon secretion was reduced by about 50% (compared to baseline secretion at 3.5 mmol/L) within minutes after increasing glucose from 4 to 5 mmol/L (P < .01, n = 13). Insulin secretion was increased minimally, but significantly, compared to baseline (3.5 mmol/L) at 4 mmol/L, whereas somatostatin secretion was not significantly increased from baseline until 7 mmol/L. Hereafter secretion of both increased gradually up to 12 mmol/L glucose. Neither recombinant insulin (1 µmol/L), GABA (300 µmol/L) or the insulin-receptor antagonist S961 (at 1 µmol/L) affected basal (3.5 mmol/L) or glucose-induced (5.0 mmol/L) attenuation of glucagon secretion (n = 7-8). Somatostatin-14 attenuated glucagon secretion by ~ 95%, and blockage of somatostatin-receptor (SSTR)-2 or combined blockage of SSTR-2, -3 and -5 by specific antagonists increased glucagon output (at 3.5 mmol/L glucose) and prevented glucose-induced (from 3.5 to 5.0 mmol/L) suppression of secretion. Somatostatin is a powerful and tonic inhibitor of glucagon secretion from the rat pancreas and is required for glucose to inhibit glucagon secretion.
Substances chimiques
Insulin
0
Somatostatin
51110-01-1
Glucagon
9007-92-5
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13464Informations de copyright
© 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
Références
Ohneda A, Aguilar-Parada E, Eisentraut AM, Unger RH. Control of pancreatic glucagon secretion by glucose. Diabetes. 1969;18(1):1-10.
Gylfe E. Glucose control of glucagon secretion-'There's a brand-new gimmick every year'. Upsala J Med Sci. 2016;121(2):120-132.
Walker JN, Ramracheya R, Zhang Q, Johnson PR, Braun M, Rorsman P. Regulation of glucagon secretion by glucose: paracrine, intrinsic or both? Diabetes Obes Metab. 2011;13(Suppl 1):95-105.
Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev. 2007;28(1):84-116.
Gerich JE, Lorenzi M, Schneider V, et al. Inhibition of pancreatic glucagon responses to arginine by somatostatin in normal man and in insulin-dependent diabetics. Diabetes. 1974;23(11):876-880.
Klaff LJ, Taborsky GJ Jr. Pancreatic somatostatin is a mediator of glucagon inhibition by hyperglycemia. Diabetes. 1987;36(5):592-596.
Farhy LS, Du Z, Zeng Q, et al. Amplification of pulsatile glucagon counterregulation by switch-off of alpha-cell-suppressing signals in streptozotocin-treated rats. Am J Physiol Endocrinol Metab. 2008;295(3):E575-E585.
Orgaard A, Holst JJ. The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice. Diabetologia. 2017;60(9):1731-1739.
Adriaenssens AE, Svendsen B, Lam BYH, et al. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets. Diabetologia. 2016;59(10):2156-2165.
Lai BK, Chae H, Gomez-Ruiz A, et al. Somatostatin is only partly required for the glucagonostatic effect of glucose but is necessary for the glucagonostatic effect of KATP channel blockers. Diabetes. 2018;67(11):2239-2253.
Cejvan K, Coy DH, Efendic S. Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. Diabetes. 2003;52(5):1176-1181.
Li J, Yu Q, Ahooghalandari P, et al. Submembrane ATP and Ca2+ kinetics in alpha-cells: unexpected signaling for glucagon secretion. FASEB J. 2015;29(8):3379-3388.
Hauge-Evans AC, King AJ, Carmignac D, et al. Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes. 2009;58(2):403-411.
Vergari E, Knudsen JG, Ramracheya R, et al. Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion. Nat Commun. 2019;10(1):139.
Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH. Insulin within islets is a physiologic glucagon release inhibitor. J Clin Investig. 1984;74(6):2296-2299.
Cooperberg BA, Cryer PE. Insulin reciprocally regulates glucagon secretion in humans. Diabetes. 2010;59(11):2936-2940.
Franklin I, Gromada J, Gjinovci A, Theander S, Wollheim CB. Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes. 2005;54(6):1808-1815.
Olsen HL, Theander S, Bokvist K, Buschard K, Wollheim CB, Gromada J. Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells. Endocrinology. 2005;146(11):4861-4870.
Wendt A, Birnir B, Buschard K, et al. Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. Diabetes. 2004;53(4):1038-1045.
Hardy AB, Serino AS, Wijesekara N, Chimienti F, Wheeler MB. Regulation of glucagon secretion by zinc: lessons from the beta cell-specific Znt8 knockout mouse model. Diabetes Obes Metab. 2011;13(Suppl 1):112-117.
Gedulin BR, Rink TJ, Young AA. Dose-response for glucagonostatic effect of amylin in rats. Metabolism. 1997;46(1):67-70.
Salehi A, Vieira E, Gylfe E. Paradoxical stimulation of glucagon secretion by high glucose concentrations. Diabetes. 2006;55(8):2318-2323.
Vieira E, Salehi A, Gylfe E. Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia. 2007;50(2):370-379.
Cheng-Xue R, Gomez-Ruiz A, Antoine N, et al. Tolbutamide controls glucagon release from mouse islets differently than glucose: involvement of K(ATP) channels from both alpha-cells and delta-cells. Diabetes. 2013;62(5):1612-1622.
Kuhre RE, Ghiasi SM, Adriaenssens AE, et al. No direct effect of SGLT2 activity on glucagon secretion. Diabetologia. 2019;62(6):1011-1023.
Kuhre RE, Wewer Albrechtsen NJ, Larsen O, et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metabol. 2018;11:84-95.
Ludvigsen E, Olsson R, Stridsberg M, Janson ET, Sandler S. Expression and distribution of somatostatin receptor subtypes in the pancreatic islets of mice and rats. J Histochem Cytochem. 2004;52(3):391-400.
DiGruccio MR, Mawla AM, Donaldson CJ, et al. Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Mol Metabol. 2016;5(7):449-458.
de Heer J, Rasmussen C, Coy DH, Holst JJ. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia. 2008;51(12):2263-2270.
Halban PA, Berger M, Gjinovci A, Renold AE. Biologic activity and pharmacokinetics of biosynthetic human insulin in the rat. Diabet Care. 1981;4(2):238-243.
Qinna NA, Badwan AA. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats. Drug Des Devel Ther. 2015;9:2515-2525.
Le Marchand SJ, Piston DW. Glucose suppression of glucagon secretion: metabolic and calcium responses from alpha-cells in intact mouse pancreatic islets. J Biol Chem. 2010;285(19):14389-14398.
Christiansen E, Vestergaard H, Tibell A, et al. Impaired insulin-stimulated nonoxidative glucose metabolism in pancreas-kidney transplant recipients: dose-response effects of insulin on glucose turnover. Diabetes. 1996;45(9):1267-1275.
Menge BA, Gruber L, Jorgensen SM, et al. Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes. Diabetes. 2011;60(8):2160-2168.
Gerich JE, Charles MA, Grodsky GM. Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas. J Clin Investig. 1974;54(4):833-841.
Greenbaum CJ, Havel PJ, Taborsky GJ Jr, Klaff LJ. Intra-islet insulin permits glucose to directly suppress pancreatic A cell function. J Clin Investig. 1991;88(3):767-773.
Diao J, Asghar Z, Chan CB, Wheeler MB. Glucose-regulated glucagon secretion requires insulin receptor expression in pancreatic alpha-cells. J Biol Chem. 2005;280(39):33487-33496.
Xu E, Kumar M, Zhang YI, et al. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab. 2006;3(1):47-58.
Kaneko K, Shirotani T, Araki E, et al. Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells. Diabetes Res Clin Pract. 1999;44(2):83-92.
Bonner-Weir S, Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes. 1982;31(10):883-889.
Jansson L, Barbu A, Bodin B, et al. Pancreatic islet blood flow and its measurement. Upsala J Med Sci. 2016;121(2):81-95.
Cieniewicz AM, Kirchner T, Hinke SA, et al. Novel monoclonal antibody is an allosteric insulin receptor antagonist that induces insulin resistance. Diabetes. 2017;66(1):206-217.
Schäffer L, Brand CL, Hansen BF, et al. A novel high-affinity peptide antagonist to the insulin receptor. Biochem Biophys Res Comm. 2008;376(2):380-383.
Galsgaard KD, Winther-Sørensen M, Pedersen J, et al. Glucose and amino acid metabolism in mice depend mutually on glucagon and insulin receptor signaling. Am J Physiol Endocrinol Metab. 2019;316(4):E660-E673.
Rorsman P, Berggren P-O, Bokvist K, et al. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature. 1989;341(6239):233-236.
Bansal P, Wang S, Liu S, Xiang YY, Lu WY, Wang Q. GABA coordinates with insulin in regulating secretory function in pancreatic INS-1 beta-cells. PLoS ONE. 2011;6(10):e26225.
Pizarro-Delgado J, Braun M, Hernandez-Fisac I, Martin-Del-Rio R, Tamarit-Rodriguez J. Glucose promotion of GABA metabolism contributes to the stimulation of insulin secretion in beta-cells. Biochem J. 2010;431(3):381-389.
Bolli G, Feo PD, Compagnucci P, et al. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes. 1983;32(2):134-141.
Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science (New York, NY). 1973;182(4108):171-173.
Yue JT, Burdett E, Coy DH, Giacca A, Efendic S, Vranic M. Somatostatin receptor type 2 antagonism improves glucagon and corticosterone counterregulatory responses to hypoglycemia in streptozotocin-induced diabetic rats. Diabetes. 2012;61(1):197-207.
Karimian N, Qin T, Liang T, et al. Somatostatin receptor type 2 antagonism improves glucagon counterregulation in biobreeding diabetic rats. Diabetes. 2013;62(8):2968-2977.
Yue JT, Riddell MC, Burdett E, Coy DH, Efendic S, Vranic M. Amelioration of hypoglycemia via somatostatin receptor type 2 antagonism in recurrently hypoglycemic diabetic rats. Diabetes. 2013;62(7):2215-2222.
Bosco D, Armanet M, Morel P, et al. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes. 2010;59(5):1202-1210.
Persson PB. Good publication practice in physiology 2019. Acta Physiologica (Oxford, England). 2019;227(4):e13405.
Christiansen CB, Svendsen B, Holst JJ. The VGF-derived neuropeptide TLQP-21 shows no impact on hormone secretion in the isolated perfused rat pancreas. Horm Metabol Res. 2015;47(7):537-543.
de Heer J, Holst JJ. Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide 1. Diabetes. 2007;56(2):438-443.
Svensson AM, Abdel-Halim SM, Efendic S, Jansson L, Ostenson CG. Pancreatic and islet blood flow in F1-hybrids of the non-insulin-dependent diabetic GK-Wistar rat. Eur J Endocrinol. 1994;130(6):612-616.
Iwase M, Sandler S, Carlsson PO, Hellerstrom C, Jansson L. The pancreatic islets in spontaneously hypertensive rats: islet blood flow and insulin production. Eur J Endocrinol. 2001;144(2):169-178.
Orskov C, Jeppesen J, Madsbad S, Holst JJ. Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. J Clin Investig. 1991;87(2):415-423.
Brand CL, Jorgensen PN, Knigge U, et al. Role of glucagon in maintenance of euglycemia in fed and fasted rats. Am J Physiol. 1995;269(3 Pt 1):E469-E477.
Holst JJ, Bersani M. Assays for peptide products of somatostatin gene expression. Metods Neurosci. 1991;5:3-22.
Segerstolpe Å, Palasantza A, Eliasson P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab. 2016;24(4):593-607.
Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36(5):411-420.
Stuart T, Butler A, Hoffman P, et al. Comprehensive integration of single cell data. bioRxiv. 2018:460147.