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Horm Metab Res 2004; 36(11/12): 795-803
DOI: 10.1055/s-2004-826166
Original
© Georg Thieme Verlag KG Stuttgart · New York

Glucagon-like Peptide-1 and Islet Lipolysis

M.  Sörhede Winzell1 , B.  Ahrén1
  • 1 Department of Medicine, Lund University, Lund, Sweden
Further Information

Publication History

Received 14 July 2004

Accepted after revision 1 September 2004

Publication Date:
18 January 2005 (online)

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Abstract

A role for glucagon-like peptide 1 (GLP-1) has been suggested in stimulating β-cell lipolysis via elevation of cAMP and activation of protein kinase A, which in turn may activate hormone-sensitive lipase (HSL), thereby contributing to fatty acid generation (FFA) from intracellular triglyceride stores. FFAs may then be metabolized to a lipid signal, which is required for optimal glucose-stimulated insulin secretion. Since HSL is expressed in islet β-cells, this effect could contribute to the stimulation of insulin secretion by GLP-1, provided that a lipid signal of importance for insulin secretion is generated. To examine this hypothesis, we have studied the acute effect of GLP-1 on isolated mouse islets from normal mice and from mice with high-fat diet induced insulin resistance. We found, however, that although GLP-1 (100 nM) markedly potentiated glucose-stimulated insulin secretion from islets of both feeding groups, the peptide was not able to stimulate islet palmitate oxidation or increase lipolysis measured as glycerol release. This indicates that a lipid signal does not contribute to the acute stimulation of insulin secretion by GLP-1. To test whether lipolysis might be involved in the islet effects of long-term GLP-1 action, mice from the two feeding groups were chronically treated with exendin-4, a peptide that lowers blood glucose by interacting with GLP-1 receptors, in order to stimulate insulin secretion, for 16 days before isolation of the islets. The insulinotropic effects of GLP-1 and forskolin were exaggerated in isolated islets from exendin-4 treated mice given a high-fat diet, with a augmented palmitate oxidation as well as islet lipolysis at high glucose levels in these islets. Exendin-4 treatment had less impact on mice fed a normal diet. From these results we conclude that while GLP-1 does not seem to induce β-cell lipolysis acutely in mouse islets, the peptide affects β-cell fat metabolism after long-term adaptation to GLP-1 receptor stimulation.

Key words

Insulin secretion - Exendin-4 - Islet - Lipid metabolism

References

  • 1 Boden G, Shulman G I. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction.  Eur J Clin Invest. 2002;  32 14-23
    CrossrefPubMedGoogle Scholar
  • 2 Shimabukuro M, Zhou Y T, Levi M, Unger R H. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes.  Proc Natl Acad Sci USA. 1998;  95 2498-2502
    CrossrefPubMedGoogle Scholar
  • 3 Warnotte C, Gilon P, Nenquin M, Henquin J C. Mechanisms of the stimulation of insulin release by saturated fatty acids. A study of palmitate effects in mouse beta-cells.  Diabetes. 1994;  43 703-711
    CrossrefPubMedGoogle Scholar
  • 4 Dobbins R L, Chester M W, Stevenson B E, Daniels M B, Stein D T, McGarry J D. A fatty acid- dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion.  J Clin Invest. 1998;  101 2370-2376
    CrossrefPubMedGoogle Scholar
  • 5 Elks M L. Chronic perifusion of rat islets with palmitate suppresses glucose-stimulated insulin release.  Endocrinology. 1993;  133 208-214
    CrossrefPubMedGoogle Scholar
  • 6 Sako Y, Grill V E. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation.  Endocrinology. 1990;  127 1580-1589
    PubMedGoogle Scholar
  • 7 Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, Bergamini E, Mosca F, Di Mario U, Del Prato S, Marchetti P. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated.  Diabetes. 2002;  51 1437-1442
    CrossrefPubMedGoogle Scholar
  • 8 Grill V, Cerasi E. Activation by glucose of adenyl cyclase in pancreatic islets of the rat.  FEBS Lett. 1973;  33 311-314
    CrossrefPubMedGoogle Scholar
  • 9 Schuit F C, Pipeleers D G. Regulation of adenosine 3′,5′-monophosphate levels in the pancreatic B cell.  Endocrinology. 1985;  117 834-840
    PubMedGoogle Scholar
  • 10 Ahren B. Glucagon-like peptide-1(7-36)amide increases cyclic AMP accumulation in normal islets.  Pancreas. 1996;  12 211-213
    PubMedGoogle Scholar
  • 11 Gao Z Y, Gilon P, Henquin J C. The role of protein kinase-C in signal transduction through vasopressin and acetylcholine receptors in pancreatic B-cells from normal mouse.  Endocrinology. 1994;  135 191-199
    CrossrefPubMedGoogle Scholar
  • 12 Weng L, Davies M, Ashcroft S J. Effects of cholinergic agonists on diacylglycerol and intracellular calcium levels in pancreatic beta-cells.  Cell Signal. 1993;  5 777-786
    CrossrefPubMedGoogle Scholar
  • 13 Corkey B E, Glennon M C, Chen K S, Deeney J T, Matschinsky F M, Prentki M. A role for malonyl-CoA in glucose-stimulated insulin secretion from clonal pancreatic beta-cells.  J Biol Chem. 1989;  264 21608-21612
    PubMedGoogle Scholar
  • 14 Chen S, Ogawa A, Ohneda M, Unger R H, Foster D W, McGarry J D. More direct evidence for a malonyl-CoA-carnitine palmitoyltransferase I interaction as a key event in pancreatic beta-cell signaling.  Diabetes. 1994;  43 878-883
    PubMedGoogle Scholar
  • 15 Corkey B E, Deeney J T, Yaney G C, Tornheim K, Prentki M. The role of long-chain fatty acyl-CoA esters in beta-cell signal transduction.  J Nutr. 2000;  130 (2S Suppl) 299S-304S
    PubMedGoogle Scholar
  • 16 Briaud I, Harmon J S, Kelpe C L, Segu V B, Poitout V. Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids.  Diabetes. 2001;  50 315-321
    CrossrefPubMedGoogle Scholar
  • 17 Segall L, Lameloise N, Assimacopoulos-Jeannet F, Roche E, Corkey P, Thumelin S, Corkey B E, Prentki M. Lipid rather than glucose metabolism is implicated in altered insulin secretion caused by oleate in INS-1 cells.  Am J Physiol. 1999;  277 E521-E528
    PubMedGoogle Scholar
  • 18 Deeney J T, Tornheim K, Korchak H M, Prentki M, Corkey B E. Acyl-CoA esters modulate intracellular Ca2+ handling by permeabilized clonal pancreatic beta-cells.  J Biol Chem. 1992;  267 19840-19845
    PubMedGoogle Scholar
  • 19 Larsson O, Deeney J T, Branstrom R, Berggren P O, Corkey B E. Activation of the ATP-sensitive K+ channel by long chain acyl-CoA. A role in modulation of pancreatic beta-cell glucose sensitivity.  J Biol Chem. 1996;  271 10623-10626
    CrossrefPubMedGoogle Scholar
  • 20 Yaney G C, Korchak H M, Corkey B E. Long-chain acyl CoA regulation of protein kinase C and fatty acid potentiation of glucose-stimulated insulin secretion in clonal beta-cells.  Endocrinology. 2000;  141 1989-1998
    CrossrefPubMedGoogle Scholar
  • 21 Mulder H, Holst L S, Svensson H, Degerman E, Sundler F, Ahren B, Rorsman P, Holm C. Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells.  Diabetes. 1999;  48 228-232
    PubMedGoogle Scholar
  • 22 Roduit R, Masiello P, Wang S P, Li H, Mitchell G A, Prentki M. A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice.  Diabetes. 2001;  50 1970-1975
    PubMedGoogle Scholar
  • 23 Mulder H, Sörhede-Winzell M, Contreras J A, Fex M, Strom K, Ploug T, Galbo H, Arner P, Lundberg C, Sundler F, Ahren B, Holm C. Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact.  J Biol Chem. 2003;  278 36380-36388
    CrossrefPubMedGoogle Scholar
  • 24 Fex M, Olofsson C S, Fransson U, Bacos K, Lindvall H, Sörhede-Winzell M, Rorsman P, Holm C, Mulder H. Hormone-sensitive Lipase deficiency in mouse islets abolishes neutral cholesterol ester hydrolase activity but leaves lipolysis, acylglycerides, fat oxidation, and insulin secretion intact.  Endocrinology. 2004;  145 3746-3753
    CrossrefPubMedGoogle Scholar
  • 25 Holm C, Osterlund T, Laurell H, Contreras J A. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis.  Annu Rev Nutr. 2000;  20 365-393
    CrossrefPubMedGoogle Scholar
  • 26 Holst J J, Orskov C. Incretin hormones - an update.  Scand J Clin Lab Invest Suppl. 2001;  234 75-85
    PubMedGoogle Scholar
  • 27 Thorens B, Porret A, Buhler L, Deng S P, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.  Diabetes. 1993;  42 1678-1682
    CrossrefPubMedGoogle Scholar
  • 28 Fehmann H C, Bode H P, Ebert T, Karl A, Goke B. Interaction of GLP-I and leptin at rat pancreatic B-cells: effects on insulin secretion and signal transduction.  Horm Metab Res. 1997;  29 572-576
    PubMedGoogle Scholar
  • 29 Yaney G C, Civelek V N, Richard A M, Dillon J S, Deeney J T, Hamilton J A, Korchak H M, Tornheim K, Corkey B E, Boyd A E 3rd. Glucagon-like peptide 1 stimulates lipolysis in clonal pancreatic beta-cells (HIT).  Diabetes. 2001;  50 56-62
    PubMedGoogle Scholar
  • 30 Eng J, Kleinman W A, Singh L, Singh G, Raufman J P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas.  J Biol Chem. 1992;  267 7402-7405
    PubMedGoogle Scholar
  • 31 Goke R, Fehmann H C, Linn T, Schmidt H, Krause M, Eng J, Goke B. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells.  J Biol Chem. 1993;  268 19 650-19 655
    PubMedGoogle Scholar
  • 32 Nielsen L L, Baron A D. Pharmacology of exenatide (synthetic exendin-4) for the treatment of type 2 diabetes.  Curr Opin Investig Drugs. 2003;  4 401-405
    PubMedGoogle Scholar
  • 33 Surwit R S, Kuhn C M, Cochrane C, McCubbin J A, Feinglos M N. Diet-induced type II diabetes in C57BL/6J mice.  Diabetes. 1988;  37 1163-1167
    CrossrefPubMedGoogle Scholar
  • 34 Ahren B, Simonsson E, Scheurink A J, Mulder H, Myrsen U, Sundler F. Dissociated insulinotropic sensitivity to glucose and carbachol in high-fat diet-induced insulin resistance in C57BL/6J mice.  Metabolism. 1997;  46 97-106
    CrossrefPubMedGoogle Scholar
  • 35 Pacini G, Thomaseth K, Ahren B. Contribution to glucose tolerance of insulin-independent vs. insulin-dependent mechanisms in mice.  Am J Physiol Endocrinol Metab. 2001;  281 E693-E703
    PubMedGoogle Scholar
  • 36 Sörhede Winzell M, Ahren B. High-fat diet fed mice - a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes.  Diabetes. 2004;  53 S215-S219
    PubMedGoogle Scholar
  • 37 Young A A, Gedulin B R, Bhavsar S, Bodkin N, Jodka C, Hansen B, Denaro M. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).  Diabetes. 1999;  48 1026-1034
    PubMedGoogle Scholar
  • 38 Wang Q, Brubaker P L. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice.  Diabetologia. 2002;  45 1263-1273
    CrossrefPubMedGoogle Scholar
  • 39 Antinozzi P A, Segall L, Prentki M, McGarry J D, Newgard C B. Molecular or pharmacologic perturbation of the link between glucose and lipid metabolism is without effect on glucose-stimulated insulin secretion. A re-evaluation of the long-chain acyl-CoA hypothesis.  J Biol Chem. 1998;  273 16146-16154
    CrossrefPubMedGoogle Scholar
  • 40 Noel R J, Antinozzi P A, McGarry J D, Newgard C B. Engineering of glycerol-stimulated insulin secretion in islet beta cells. Differential metabolic fates of glucose and glycerol provide insight into mechanisms of stimulus-secretion coupling.  J Biol Chem. 1997;  272 18621-18627
    CrossrefPubMedGoogle Scholar
  • 41 Hellmer J, Arner P, Lundin A. Automatic luminometric kinetic assay of glycerol for lipolysis studies.  Anal Biochem. 1989;  177 132-137
    CrossrefPubMedGoogle Scholar
  • 42 Kreymann B, Williams G, Ghatei M A, Bloom S R. Glucagon-like peptide-1 7-36: a physiological incretin in man.  Lancet. 1987;  2 1300-1304
    PubMedGoogle Scholar
  • 43 Fehmann H C, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide.  Endocr Rev. 1995;  16 390-410
    CrossrefPubMedGoogle Scholar
  • 44 Drucker D J. Biological actions and therapeutic potential of the glucagon-like peptides.  Gastroenterology. 2002;  122 531-544
    PubMedGoogle Scholar
  • 45 Simonsson E, Ahren B. Potentiated beta-cell response to non-glucose stimuli in insulin-resistant C57BL/6J mice.  Eur J Pharmacol. 1998;  350 243-250
    CrossrefPubMedGoogle Scholar
  • 46 Malaisse W J, Best L, Kawazu S, Malaisse-Lagae F, Sener A. The stimulus-secretion coupling of glucose-induced insulin release: fuel metabolism in islets deprived of exogenous nutrient.  Arch Biochem Biophys. 1983;  224 102-110
    CrossrefPubMedGoogle Scholar
  • 47 Deeney J T, Gromada J, Hoy M, Olsen H L, Rhodes C J, Prentki M, Berggren P O, Corkey B E. Acute stimulation with long chain acyl-CoA enhances exocytosis in insulin-secreting cells (HIT T-15 and NMRI beta-cells).  J Biol Chem. 2000;  275 9363-9368
    CrossrefPubMedGoogle Scholar
  • 48 Prentki M, Joly E, El-Assaad W, Roduit R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes.  Diabetes. 2002;  51 S405-S413
    CrossrefPubMedGoogle Scholar
  • 49 Roduit R, Nolan C, Alarcon C, Moore P, Barbeau A, Delghingaro-Augusto V, Przybykowski E, Morin J, Masse F, Massie B, Ruderman N, Rhodes C, Poitout V, Prentki M. A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli.  Diabetes. 2004;  53 1007-1019
    PubMedGoogle Scholar
  • 50 Ahren B, Pacini G. Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and glucose effectiveness in mice.  Am J Physiol. 1999;  277 E996-E1004
    PubMedGoogle Scholar
  • 51 Greig N H, Holloway H W, de Ore K A, Jani D, Wang Y, Zhou J, Garant M J, Egan J M. Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations.  Diabetologia. 1999;  42 45-50
    CrossrefPubMedGoogle Scholar
  • 52 Winzell M S, Svensson H, Arner P, Ahren B, Holm C. The expression of hormone-sensitive lipase in clonal beta-cells and rat islets is induced by long-term exposure to high glucose.  Diabetes. 2001;  50 2225-2230
    PubMedGoogle Scholar
  • 53 Mulder H, Yang S, Winzell M S, Holm C, Ahren B. Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion.  Diabetes. 2004;  53 122-128
    PubMedGoogle Scholar
  • 54 Egan J M, Bulotta A, Hui H, Perfetti R. GLP-1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells.  Diabetes Metab Res Rev. 2003;  19 115-123
    CrossrefPubMedGoogle Scholar
  • 55 Perry T, Greig N H. The glucagon-like peptides: a double-edged therapeutic sword?.  Trends Pharmacol Sci. 2003;  24 377-383
    CrossrefPubMedGoogle Scholar
  • 56 Ahren B. Gut peptides and type 2 diabetes mellitus treatment.  Curr Diab Rep. 2003;  3 365-372
    PubMedGoogle Scholar
  • 57 Vilsboll T, Holst J J. Incretins, insulin secretion and Type 2 diabetes mellitus.  Diabetologia. 2004;  47 357-366
    CrossrefPubMedGoogle Scholar

M. Sörhede Winzell

Dept of Medicine, Lund University

BMC, B11 · SE-221 84 Lund · Sweden ·

Phone: +46 (46) 222 0760

Fax: +46 (46) 222 0757

Email: maria.sorhede_winzell@med.lu.se

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