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Horm Metab Res 2010; 42(9): 657-662
DOI: 10.1055/s-0030-1253421
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

GLP-1 (9–36) Amide Metabolite Suppression of Glucose Production in Isolated Mouse Hepatocytes

E. Tomas1 , V. Stanojevic1 , J. F. Habener1
  • 1Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston, USA
Further Information

Publication History

received 15.01.2010

accepted 14.04.2010

Publication Date:
28 May 2010 (online)

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Abstract

The glucoincretin hormone glucagon-like peptide-1 (GLP-1) augments glucose-stimulated insulin secretion and is in use as an effective treatment for diabetes. However, after its secretion from the intestine, the insulinotropic GLP-1 (7–36) amide hormone is rapidly inactivated by enzymatic cleavage by the diaminopeptidyl peptidase-4 giving rise to GLP-1 (9–36) amide. Inasmuch as most of the circulating GLP-1 is in the form of the metabolite GLP-1 (9–36) amide it has been suggested that it has insulin-like actions on peripheral insulin-sensitive tissues. In earlier studies, infusions of GLP-1 (9–36) amide in obese insulin-resistant subjects showed a marked suppression of hepatic glucose production. However, it remained uncertain whether the effects on glucose production were due to direct effects on hepatocytes, involved central or portal vein-mediated actions, or were mediated by insulin secretion. Here we show that GLP-1 (9–36) amide directly suppresses glucose production in isolated mouse hepatocytes ex vivo independent of the GLP-1 receptor. These findings support direct insulinomimetic actions of the GLP-1 metabolite on gluconeogenesis in hepatocytes that are independent of insulin action and the GLP-1 receptor, and suggest that GLP-1 (9–36) amide-based peptides might present a novel therapy for the treatment of excessive hepatic glucose production in individuals with insulin-resistant diabetes.

Key words

hepatic insulin resistance - hyperglycemia - diabetes

References

  • 1 Lovshin JA, Drucker DJ. Incretin-based therapies for type 2 diabetes mellitus.  Nat Rev Endocrinol. 2009;  5 262-269
    Google Scholar
  • 2 Kieffer TJ, Habener JF. The glucagon-like peptides.  Endocr Rev. 1999;  20 876-913
    Google Scholar
  • 3 Deacon CF. Circulation and degradation of GIP and GLP-1.  Horm Metab Res. 2004;  36 761-765
    Google Scholar
  • 4 Abu-Hamdah R, Rabiee A, Meneilly GS, Shannon RP, Andersen DK, Elahi D. Clinical review: The extrapancreatic effects of glucagon-like peptide-1 and related peptides.  J Clin Endocrinol Metab. 2009;  94 1843-1852
    Google Scholar
  • 5 Tomas E, Habener JF. Insulin-like actions of glucagon-like peptide-1: A dual receptor hypothesis.  Trends Endocrinol Metab. 2010;  21 59-67
    Google Scholar
  • 6 Nikolaidis LA, Elahi D, Shen YT, Shannon RP. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy.  Am J Physiol Heart Circ Physiol. 2005;  289 H2401-H2408
    Google Scholar
  • 7 Sonne DP, Engstrøm T, Treiman M. Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart.  Regul Pept. 2008;  146 243-249
    Google Scholar
  • 8 Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways.  Circulation. 2008;  117 2340-2350
    Google Scholar
  • 9 Green BD, Hand KV, Dougan JE, McDonnell BM, Cassidy RS, Grieve DJ. GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP.  Arch Biochem Biophys. 2008;  478 136-142
    Google Scholar
  • 10 Elahi D, Egan JM, Shannon RP, Meneilly GS, Khatri A, Habener JF, Andersen DK. Glucagon-like peptide-1 (9–36) amide, cleavage product of glucagon-like peptide-1 (7–36) is a glucoregulatory peptide.  Obesity. 2008;  16 1501-1509
    Google Scholar
  • 11 Ayala JE, Bracy DP, James FD, Julien BM, Wasserlman DH, Drucker DJ. The glucagons-like petide-1 receptor regulated endogenous glucose production and muscle glucose uptake independent of its incretin action.  Endocrinology. 2009;  150 1155-1164
    Google Scholar
  • 12 Nishizawa M, Nakabayashi H, Dawai K, Ito T, Dawakami S, Nakagawa A, Niijima A, Uchida K. The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor.  J Auton Nerv Syst. 2000;  80 14-21
    Google Scholar
  • 13 Estall JL, Kahn M, Cooper MP, Fisher FM, Wu MK, Laznik D, Qu L, Cohen DE, Shulman GI, Spiegelman BM. Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression.  Diabetes. 2009;  58 1499-1508
    Google Scholar
  • 14 Liu HY, Collins QF, Xiong Y, Moukdar F, Lupo Jr EG, Liu Z, Cao W. Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase.  J Biol Chem. 2007;  282 14205-14212
    Google Scholar
  • 15 Ban K, Kim KH, Cho CK, Sauvé M, Diamandis EP, Backx PH, Drucker DJ, Husain M. Glucagon-Like Peptide (GLP)-1(9–36)Amide-Mediated Cytoprotection Is Blocked by Exendin(9–39) Yet Does Not Require the Known GLP-1 Receptor.  Endocrinology. 2010;  151 1520-1531
    Google Scholar
  • 16 Lee YS, Shin S, Shigihara T, Hahm E, Liu MJ, Han J, Yoon JW, Jun HS. Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis.  Diabetes. 2007;  56 1671-1479
    Google Scholar
  • 17 Flock G, Baggio LL, Longuet C, Drucker DJ. Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice.  Diabetes. 2007;  56 3006-3013
    Google Scholar
  • 18 Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences.  FEBS Lett. 1995;  358 219-224
    Google Scholar
  • 19 Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor.  Endocrinology. 1996;  137 2968-2978
    Google Scholar
  • 20 Dunphy JL, Taylor RG, Fuller PJ. Tissue distribution of rat glucagon receptor and GLP-1 receptor gene expression.  Mol Cell Endocrinol. 1998;  141 179-186
    Google Scholar
  • 21 Aviv V, Meivar-Levy I, Rachmut IH, Rubinek T, Mor E, Ferber S. Exendin-4 promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process.  J Biol Chem. 2009;  284 33509-33520
    Google Scholar
  • 22 Raab EL, Vuguin PM, Stoffers DA, Simmons RA. Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats.  Am J Physiol Regul Integr Comp Physiol. 2009;  297 R1785-R1794
    Google Scholar
  • 23 Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice.  Hepatology. 2006;  43 173-181
    Google Scholar
  • 24 Campos RV, Lee YC, Drucker DJ. Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse.  Endocrinology. 1994;  134 2156-2164
    Google Scholar
  • 25 Egan JM, Montrose-Rafizadeh C, Wang Y, Bernier M, Roth J. Glucagon-like peptide-1(7–36) amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-L1 adipocytes: one of several potential extrapancreatic sites of GLP-1 action.  Endocrinology. 1994;  135 2070-2075
    Google Scholar
  • 26 Meier JJ, Gethmann A, Nauck MA, Gotze O, Schmitz F, Deacon CF, Gallwitz B, Schmidt WE, Holst JJ. The glucagon-like peptide-1 metabolite GLP-1-(9–36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans.  Am J Physiol Endocrinol Metab. 2006;  290 E1118-E1123
    Google Scholar
  • 27 Vahl TP, Paty BW, Fuller BD, Pridgeon RL, D’Alession DA. Effects of GLP-1-(7–37), and GLP-1-(9–36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans.  J Clin Endocrinol Metab. 2003;  88 1772-1779
    Google Scholar
  • 28 Valverde AM, Burks DJ, Fabregat I, Fisher TL, Carretero J, White MF, Benito M. Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes.  Diabetes. 2003;  52 2239-2248
    Google Scholar
  • 29 Koonen DP, Jacobs RL, Febbraio M, Young ME, Soltys CL, Ong H, Vance DE, Dyck JR. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity.  Diabetes. 2007;  56 2863-2871
    Google Scholar
  • 30 Moore KJ, El Khoury J, Medeiros LA, Terada K, Geula C, Luster AD, Freeman MW. A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid.  J Biol Chem. 2002;  277 47373-47379
    Google Scholar

Correspondence

Prof. J. F. Habener

Laboratory of Molecular

Endocrinology

Thier 306

55 Fruit Street

Massachusetts General Hospital

Boston MA 02114

USA

Phone: +1/617/726 3420

Fax: +1/617/726 6954

Email: jhabener@partners.org

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