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Glucagon-like peptide 1 (GLP-1) and metabolic diseases

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Abstract

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, mainly secreted after meals, which enhances glucose-induced insulin secretion and induces satiety. It has been reported that GLP-1 levels after a mixed meal and after an oral glucose load are reduced in patients with Type 2 diabetes. The reduction of oral glucose-stimulated active GLP-1 levels in patients with Type 2 diabetes has also been observed during euglycemic iper-insulinemic clamp. The reduction of post-prandial circulating active GLP-1 in Type 2 diabetic subjects, as a consequence of chronic hyperglycemia, could contribute to the reduction of early post-prandial insulin secretion; in fact, the administration of GLP-1 receptor antagonists to healthy volunteers elicits both an impairment of meal-induced insulin secretion and an increase of post-prandial glycemia similar to that observed in Type 2 diabetes. GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV), an enzyme produced by endothelial cells in different districts and that circulates in plasma. It is still not clear whether the reduction of meal-or oral-glucose stimulated GLP-1 levels in Type 2 diabetic patients is due to impairment of secretion, increase of degradation, or both. The major limitation of using GLP-1 to treat diabetic patients is the short half-life of the native compound. There are now several compounds in various stages of pre-clinical or clinical development for the treatment of Type 2 diabetes that utilize the GLP-1 signaling pathway; these include GLP-1 receptor agonists with extended half-lives, and inhibitors of DPP-IV that increase circulating levels of endogenous, intact and bioactive GLP-1.

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References

  1. Lopez LC, Frazier ML, Su CJ, Kumar A, Saunders GF. Mammalian pancreatic preproglucagon contains three glucagon-related peptides. Proc Natl Acad Sci USA 1983, 80: 5485–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  2. Heinrich G, Gros P, Lund PK, Bentley RC, Habener F. Preproglucagon messenger ribonucleic acid: nucleotide and encoded aminoacid sequence of the rat complementary deoxyribonucleic acid. Endocrinology 1984, 115: 2176–81.

    PubMed  CAS  Google Scholar 

  3. Orskov C, Bersani M, Johnsen AH, Hojrup P, Holst JJ. Complete sequences of glucagon-like peptide-1 from human and pig small intestine. J Biol Chem 1989, 264: 12826–9.

    PubMed  CAS  Google Scholar 

  4. Mojsov S, Heinrich G, Wilson IB, Ravazzola M, Orci L, Habener JF. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem 1986, 261: 11880–9.

    PubMed  CAS  Google Scholar 

  5. Printz H, Reiter S, Samadi N, Ebrahimsade S, Kirchner R, Arnold R, Goke B. GLP-1 release in man after lower large bowel resection or intrarectal glucose administration. Digestion 1998, 59: 689–95.

    PubMed  CAS  Google Scholar 

  6. Andrews PC, Hawke D, Lee TD, Legesse K, Noe BD, Shively JE. Isolation and structure of the principal products of preproglucagon processing, including an amidated glucagn-like peptide. J Biol Chem 1986, 261: 8128–33.

    PubMed  CAS  Google Scholar 

  7. Suzuki S, Kawai K, Ohashi S, Mukai H, Yamashita K. Comparison of the effects of various C-terminal and N-terminal fragment peptides of glucagon-like peptide-1 on insulin and glucagon release from the isolated perfused rat pancreas. Endocrinology 1989, 125: 3109–14.

    PubMed  CAS  Google Scholar 

  8. Mojsov S, Kopczynski MG, Habener JF. Both amidated and nonamidated forms of glucagon-like peptide I are synthesized in the rat intestine and the pancreas. J Biol Chem 1990, 15; 265: 8001–8.

    Google Scholar 

  9. Wettergren A, Pridal L, Wajdemann M, Holst JJ. Amidated and non-amidated glucagons-like peptide-1 (GLP-1): non pancreatic effects (cephalic phase acid secretion) and stability in plasma in humans. Regul Pept 1998, 77: 83–7.

    PubMed  CAS  Google Scholar 

  10. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yelds an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995, 80: 952–7.

    PubMed  CAS  Google Scholar 

  11. Orskov C, Rabenhoj L, Wettergren A, Kofod H, Holst JJ. Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide-1 in humans. Diabetes 1994, 43: 535–9.

    PubMed  CAS  Google Scholar 

  12. Brubaker PL, Schloos J, Drucker DJ. Regulation of glucagon-like peptide-1 in the GLUTag enteroendocrine cell line. Endocrinology 1998, 139: 4108–14.

    PubMed  CAS  Google Scholar 

  13. Gribble FM, Williams L, Simpson AK, Reimann F. A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell Line. Diabetes 2003, 52: 1147–54.

    PubMed  CAS  Google Scholar 

  14. Cordier-Bussat M, Bernard C, Levenez F, et al. Peptones stimulate both the secretion of the incretin hormone glucagon-like peptide-1 and the transcription of the poglucagon gene. Diabetes 1998, 47: 1038–45.

    PubMed  CAS  Google Scholar 

  15. Balks HJ, Holst JJ, von zur Muhlen A, Brabant G. Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors. J Clin Endocrinol Metab 1997, 82: 786–90.

    PubMed  CAS  Google Scholar 

  16. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-17–36: a physiological incretin in man. Lancet 1987, 2: 1300–4.

    PubMed  CAS  Google Scholar 

  17. Herrmann C, Goke R, Richter C, Fehmann HC, Arnold R, Goke B. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 1995, 56: 117–26.

    PubMed  CAS  Google Scholar 

  18. Thomsen C, Rasmussen O, Lousen T, et al. Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects. Am J Clin Nutr 1999, 69: 1135–43.

    PubMed  CAS  Google Scholar 

  19. Byrnes AE, Frost GS, Edwards CM, Ghatei MA, Bloom SR. Plasma glucagon-like peptide-1 (7–36) amide (GLP-1) response to liquid phase, solid phase, and meals of differing lipid composition. Nutrition 1998, 14: 433–6.

    Google Scholar 

  20. Schirra J, Katschinski M, Weidmann C, et al. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 1996, 97: 92–103.

    PubMed Central  PubMed  CAS  Google Scholar 

  21. Lavin JH, Wittert GA, Andrews J, et al. Interaction of insulin, glucagon-like peptide-1, gastric inhibitory polypeptide, and appetite in response to intraduodenal carbohydrate. Am J Clin Nutr 1998, 68: 591–8.

    PubMed  CAS  Google Scholar 

  22. Mannucci E, Ognibene A, Cremasco F, et al. Glucagon-like peptide-1 (GLP-1) amd leptin concentrations in obese patients with type 2 diabetes mellitus. Diabet Med 2000, 17: 713–9.

    PubMed  CAS  Google Scholar 

  23. Mannucci E, Ognibene A, Cremasco F, et al. Effect of Met-formin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care 2001, 24: 489–94.

    PubMed  CAS  Google Scholar 

  24. Ranganath L, Norris F, Morgan L, Wriht J, Marks V. The effect of circulating non-esterified fatty acids on the entero-insular axis. Eur J Clin Invest 1999, 29: 27–32.

    PubMed  CAS  Google Scholar 

  25. Gama R, Norris F, Morgan L, Hampton S, Wright J, Marks V. Elevated post-prandial gastric inhibitory polypeptide concentrations in hypertrygliceridaemic subjects. Clin Sci (Lond) 1997, 93: 343–7.

    CAS  Google Scholar 

  26. Orskov C, Poulsen SS, Moller M, Holst JJ. Glucagon-like peptide-1 receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide-1. Diabetes 1996, 45: 832–5.

    PubMed  CAS  Google Scholar 

  27. Takahashi H, Manaka H, Suda K, et al. Hyperglycemia but not hyperinsulinemia prevents the secretion of glucagon-like peptide-1-(7–36) amide. Scand J Clin Lab Invest 1991, 51: 499–507.

    PubMed  CAS  Google Scholar 

  28. Abello J, Ye F, Bosshard A, Bernard C, Cuber JC, Chayvialle JA. Stimulation of glucagon-like peptide-1 secretion by muscarinic agonist in a murine intestinal endocrine cell line. Endocrinology 1994, 134: 2011–7.

    PubMed  CAS  Google Scholar 

  29. Brubeker PL. Regulation of intestinal proglucagon-derived peptide secretion by intestinal regulatory peptides. Endocrinology 1991, 128: 3175–82.

    Google Scholar 

  30. Meneilly GS, Greig N, Tildesley H, Habener JF, Egan JM, Elahi D. Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care 2003, 26: 2835–41.

    PubMed  CAS  Google Scholar 

  31. Enc FY, Imeryuz N, Akin L, et al. Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release. Am J Physiol Gastrointest Liver Physiol 2001, 281: 752–63.

    Google Scholar 

  32. Drucker DJ, Asa S. Glucagon gene expression in vertebrate brain. J Biol Chem 1988, 263: 13475–8.

    PubMed  CAS  Google Scholar 

  33. O’Shea D, Gunn I, Chen X, Bloom S, Herbert J. A role for central glucagon-like peptide-1 in temperature regulation. Neuroreport 1996, 7: 830–2.

    PubMed  Google Scholar 

  34. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1-(7–36) amide, peptide histidine methionine, and is responsible for their degradation in human serum. Eur J Biochem 1993, 214: 829–35.

    PubMed  CAS  Google Scholar 

  35. Pauly RP, Demuth HU, Rosche F, et al. Improved glucose tolerance in rats treated with he dipeptydil peptidase IV (CD26) inhibitor Ile-thiazolidide. Metabolism 1999, 48: 385–9.

    PubMed  CAS  Google Scholar 

  36. Augustyns K, Bal G, Thonus G, et al. The unique properties of dipeptidyl-peptidase IV (DPP IV/CD 26) and the therapeutic potential of DPP-IV inhibitors. Curr Med Chem 1998, 6: 311–27.

    Google Scholar 

  37. Deacon CF, Nauck MA, Taft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcuaneously and intravenously administered glucagon-like peptide-1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995, 44: 1126–31.

    PubMed  CAS  Google Scholar 

  38. Kieffer TJ, McIntosh CH, Pedersen RA. Degradation of glucose-dependent insulinotropic peptide and truncated glucagon-like peptide-1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 1995, 136: 3585–96.

    PubMed  CAS  Google Scholar 

  39. Ritzel R, Orskov C, Holst JJ, Nauck MA. Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7–36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships. Diabetologia 1995, 38: 720–5.

    PubMed  CAS  Google Scholar 

  40. Rosenblum JF, Kozarich JW. Prolyl peptidases: a serine protease subfamily with high potential for drug discovery. Curr Opin Chem Biol 2003, 7: 496–504.

    PubMed  CAS  Google Scholar 

  41. Dillon JS, Tanizawa Y, Wheeler MC, et al. Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor. Endocrinology 1993, 133: 1907–10.

    PubMed  CAS  Google Scholar 

  42. Thorens B, Porret A, Buhler L, Deng SP, 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: 1678–82.

    PubMed  CAS  Google Scholar 

  43. Kieffer TJ and Habener JF. The glucagon-like peptides. Endocr Rev 1999, 20: 876–913.

    PubMed  CAS  Google Scholar 

  44. Graziano MP, Hey PJ, Borkowski D, Chicchi GG, Strader CD. Cloning and functional expression of a human glucagon-like peptide-1 receptor. Biochem Biophys Res Commun 1993 15, 196: 141–6.

    Google Scholar 

  45. Van Eyll B, Lank at-Buttgereit B, Bode HP, Goke R, Goke B. Signal transduction of the GLP-1 receptor cloned from a human insulinoma. FEBS Lett 1994, 348: 7–13.

    PubMed  Google Scholar 

  46. Wei Y, Mojsov S. Tissue-specific expression of the human re-ceptorfor glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett 1995, 358: 219–24.

    PubMed  CAS  Google Scholar 

  47. Turton MD, O’Shea D, Gunn I, et al. A role of glucagon-like peptide-1 in the central regulation of feeding. Nature 1996, 379: 69–72.

    PubMed  CAS  Google Scholar 

  48. Stoffel M, Espinosa R 3rd, Le Beau MM, Bell GI. Human glucagon-like peptide-1 receptor gene. Localization to chromosome band 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6. Diabetes 1993, 42: 1215–8.

    PubMed  CAS  Google Scholar 

  49. Tanizawa Y, Riggs AC, Elbein SC, Wheelan A, Donis-Keller H, Permutt MA. Human glucagon-like peptide-1 receptor gene in NIDDM. Identification and use of a simple sequence repeat polymorphism in genetic analysis. Diabetes 1994, 43: 752–7.

    PubMed  CAS  Google Scholar 

  50. Tokuyama Y, Matsui K, Egashira T, Nozaki O, Ishizuka T, Kanatsuka A. Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. Diabetes Res Clin Pract 2004, 66: 63–9.

    PubMed  CAS  Google Scholar 

  51. Goke R, Richter G, Goke B, Trautmann M, Arnold R. Inter-nalization of glucagon-like peptide-1-(7–36) amide in rat insulinoma cells. Res Exp Med (Berl) 1989, 189: 257–64.

    CAS  Google Scholar 

  52. Widmann C, Dolci W, Thorens B. Internalization and homologous desensitization of the GLP-1 receptor depend on phosphorylation of the receptor carboxyl tail at the same three sites. Mol Endocrinol 1997, 11: 1094–02.

    PubMed  CAS  Google Scholar 

  53. Widmann C, Dolci W, Thorens B. Agonist-induced internalization and recycling of the glucagon-like peptide-1 receptor in tranfected fibroblasts and insulinomas. Biochem J 1995 310: 203–14.

    PubMed Central  PubMed  CAS  Google Scholar 

  54. Wilmen A, Goke B, Goke R. The isolated N-terminal extracellular domain of the glucagon-like peptide-1 (GLP-1) receptor has intrinsic binding activity. FEBS Lett 1996, 398: 43–7.

    PubMed  CAS  Google Scholar 

  55. Van Eyll B, Goke B, Wilmen A, Goke R. Exchange of W39yA within the N-terminal extracellular domain of the GLP-1 receptor results in a loss of receptor function. Peptides 1996, 17: 565–70.

    PubMed  Google Scholar 

  56. Graziano MP, Hey PJ, Strader CD. The amino terminal domain of the glucagon-like peptide-1 receptor is a critical determinant of subtype specificity. Receptors Channels 1996, 4: 9–17.

    PubMed  CAS  Google Scholar 

  57. Wilmen A, Van Eyll B, Goke B, Goke R. Five out of sixtryp-tophan residues in the N-terminal extracellular domain of the rat GLP-1 receptor are essential for its ability to bind GLP-1. Peptides 1997, 18: 301–5.

    PubMed  CAS  Google Scholar 

  58. Takhar S, Gyomorey S, Su RC, Mahti SK, Li X, Wheeler MB. The thirs cytoplasmic domain of the GLP-1 [7–36]amide receptor is required for coupling to the adenylyl cyclase system. Endocrinology 1996, 137: 2175–8.

    PubMed  CAS  Google Scholar 

  59. Heller RS, Kieffer TJ, Habener JF. Point mutations in the first and thirs intracellular loop of the glucagon-like peptide-1 receptor after intracellular signaling. Biochem Biophys Res Commun 1996, 223: 624–32.

    PubMed  CAS  Google Scholar 

  60. Goke R, Oltmer B, Sheikh SP, Goke B. Solubilization of active GLP-1-(7–36) amide receptors from RINm5F plasma membranes. FEBS Lett 1992, 300: 232–6.

    PubMed  CAS  Google Scholar 

  61. Schmidtler J, Dehme K, Offermann S, Rosenthal W, Classen M, Schepp W. Stimulation of rat parietal cell function by histamine and GLP-1-(7–36) amide is mediated by Gs alpha. Am J Physiol 1994, 266: G775–82.

    PubMed  CAS  Google Scholar 

  62. Montrose-Rafizadeh C, Avdonin P, Garant MJ, et al. Pancreatic glucagons-like peptide-1 receptor couples to multiple G proteins and activates mitogen-activated protein kinase pathways in Chines hamster ovary cells. Endocrinology 1999, 140: 1132–40.

    PubMed  CAS  Google Scholar 

  63. Holz GG, Leech CA, Heller RS, Castonguay M, Habner JF. Camp-dependent mobilization of intracellular Ca2+ stores by activation of ryanodine receptors in pancreatic beta cells. A Ca2+ signaling system stimulated by the insulinotropic hormone glucagons-like peptide-1-(7–37). J Biol Chem 1999, 274: 14147–56.

    PubMed Central  PubMed  CAS  Google Scholar 

  64. Gromada J, Bokvist K, Knodsen LB, Wahl P. Glucagon-like peptide-1 receptor expression in Xenopus oocytes stimulates inositol triphosphate-dependent intracellular Ca2+ mobilization. FEBS Lett 1998, 425: 277–80.

    PubMed  CAS  Google Scholar 

  65. Flatt PR, Shiber O, Hampton SM, Marks V. Stimulatory effect of glucagon-like peptides on human insulinoma cells insulin-releasing clonal RINm5F cells. Diabetes Res 1990, 13: 55–9.

    PubMed  CAS  Google Scholar 

  66. Qualmann C, Nauck MA, Holst JJ, Orskov C, Creutzfeldt W. Insulinotropic actions of intravenous glucagon-like peptide-1 (GLP-1) [7–36 amide] in the fasting state in healthy subjects. Acta Diabetol 1995, 32: 13–6.

    PubMed  CAS  Google Scholar 

  67. Ritzel R, Orskov C, Holst JJ, Nauck MA. Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7–36 amide] aftersubcutaneous injection in healthy volunteers. Dose-response-relationships. Diabetologia 1995, 38: 720–5.

    PubMed  CAS  Google Scholar 

  68. Kreymann B, Williams G, Ghatei MA, Bloom SR.Glucagon-like peptide-17–36: a physiological incretin in man. Lancet 1987, 2: 1300–4

    PubMed  CAS  Google Scholar 

  69. Otonkoski T, Hayek A. Constitution of a biphasic insulin response to glucose in human fetal pancreatic beta cells with glucagon-like peptide-1. J Clin Endocrinol Metab 1995, 80: 3779–83.

    PubMed  CAS  Google Scholar 

  70. D’Alessio DA, Kahn SE, Leusner CR, Ensinck JW. Glucagon-like peptide-1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Invest 1994, 95: 2263–6.

    Google Scholar 

  71. Fieseler P, Bridenbaugh S, Nustede R, et al. Physiological augmentation of aminoacid-induced insulin secretion by GIP and GLP-1 but not CCK-8. Am J Physiol 1995, 268: E949–55.

    PubMed  CAS  Google Scholar 

  72. Parksen N, Grafte B, Nyholm B, et al. Glucagon-like peptide-1 increases mass but not frequency or orderliness of pulsatile insulin secretion. Diabetes 1998, 47: 45–9.

    Google Scholar 

  73. Gromada J, Bokvist K, Ding WG, Holst JJ, Nielsen JH, Rors-man P. Glucagon-like peptide-1 (7–36) amide stimulates exocytosis in human pancreatic beta cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes 1998, 47: 57–65.

    PubMed  CAS  Google Scholar 

  74. Tsuboi T, da Silva Xavier G, Holz GG, Jouaville LS, Thomas AP, Rutter GA. Glucagon-like peptide-1 mobilizes intracellular Ca++ and stimulates mithocondrial ATP syntesis in pancreatic MIN6 beta cells. Biochem J 2003, 369: 287–99.

    PubMed Central  PubMed  CAS  Google Scholar 

  75. McDonald PE, EL-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MB. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002, 51: S443–7.

    Google Scholar 

  76. Trapote MA, Clemente F, Galera C, et al. I.Inositolphosphoglycans are possible mediators of the glucagon-like peptide 1 (7–36)amide action in the liver. J Endocrinol Invest 1996, 19: 114–8.

    PubMed  CAS  Google Scholar 

  77. Dupre J, Behme MT, Hramiak IM, et al. Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM. Diabetes 1995, 44: 626–30.

    PubMed  CAS  Google Scholar 

  78. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999, 48: 2270–6.

    PubMed  CAS  Google Scholar 

  79. Hui H, Wright C, Perfetti R. Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells. Diabetes 2001, 50: 785–96.

    PubMed  CAS  Google Scholar 

  80. Shalev A, Ninnis R, Keller U. Effect of glucagon-like peptide-1 (7–36) amide on glucose kinetics during somatosta-tin-induced suppression of insulin secretion in healthy men. Horm Res 1998, 49: 221–5.

    PubMed  CAS  Google Scholar 

  81. Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S. Antidi-abetogenic effect of glucagon-like peptide-1 (7–36)amidein normal subjects and patients with diabetes mellitus. N Engl J Med 1992, 326: 1316–22.

    PubMed  CAS  Google Scholar 

  82. Toft-Nielson M, Madsbad S, Holst JJ. The effect of glucagon-like peptide-1 (glp-1) on glucose elimination in healthy subjects depends on the pancreatic glucoregolatory hormones. Diabetes 1996, 45: 552–6.

    PubMed  CAS  Google Scholar 

  83. Larsson H, Holst JJ, Ahren B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand 1997, 160: 413–22.

    PubMed  CAS  Google Scholar 

  84. Shalev A, Vosmeer S, Keller U. Absence of short-term effects of glucagon-like peptide-1 and of hyperglycemia on plasma leptin levels in man. Metabolism 1997, 46: 723–5.

    PubMed  CAS  Google Scholar 

  85. Ahren B, Larsson H, Holst JJ. Effects of glucagon-like pep-tide-1 on islet function and insulin sensitivity in non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997, 82: 473–8.

    PubMed  CAS  Google Scholar 

  86. Vella A, Shah P, Basu R, Basu A, Holst JJ, Rizza RA. Effect of glucagon-like peptide 1(7–36) amide on glucose effectiveness and insulin action in people with type 2 diabetes. Diabetes 2000, 49: 611–7.

    PubMed  CAS  Google Scholar 

  87. Qualmann C, Nauck MA, Holst JJ, Orskov C, Creutzfeldt W. Insulinotropic actions of intravenous glucagon-like pep-tide-1 (GLP-1) [7–36 amide] in the fasting state in healthy subjects. Acta Diabetol 1995, 32: 13–6.

    PubMed  CAS  Google Scholar 

  88. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-17–36: a physiological incretin in man. Lancet 1987, 2: 1300–4.

    PubMed  CAS  Google Scholar 

  89. Creutzfeldt WO, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide-1-(7–36) amide in type 1 diabetic patients. Diabetes Care 1996, 19: 580–6.

    PubMed  CAS  Google Scholar 

  90. Schirra J, Sturm K, Leicht P, Arnold R, Goke B, Katschinski M. Exendin (9–39) is an antagonist of glucagon-like peptide-1 (7–36) amide in humans. J Clin Invest 1998, 101: 1421–30.

    PubMed Central  PubMed  CAS  Google Scholar 

  91. Edwards CM, Todd JF, Mahmoud M. Glucagon-like peptide-1 has a physiological role in the control of post-prandial glucose in humans: studies with the antagonist exendin 9–39. Diabetes 1999, 48: 86–93.

    PubMed  CAS  Google Scholar 

  92. Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7–36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 1996, 81: 327–32.

    PubMed  CAS  Google Scholar 

  93. Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide-1 inibition of gatric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997, 273: E981–8.

    PubMed  CAS  Google Scholar 

  94. Nauck MA. Is glucagons-like peptide-1 an incretin hormone? Diabetologia 1999, 42: 373–9.

    PubMed  CAS  Google Scholar 

  95. Schirra J, Kuwert P, Wank U, et al. Differential effects of subcutaneous GLP-1 on gastric emptying, antroduodenal motility, and pancreatic function in men. Proc Assoc Am Physicians 1997, 109: 84–97.

    PubMed  CAS  Google Scholar 

  96. Merchenthaler I, Lane M, Shughrue P. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol 1999, 403: 261–80.

    PubMed  CAS  Google Scholar 

  97. Goke R, Larsen PJ, Mikkelsen JD, Sheikh SP. Identification of specific binding sites for glucagon-like peptide-1 on the posterior lobe of the rat pituitary. Neuroendocrinology 1995, 62: 130–4.

    PubMed  CAS  Google Scholar 

  98. Hwa JJ, Ghibaudi L, Williams P, Witten MB, Tedesco R, Strader CD. Differential effects of intracerebroventricular glucagon-like peptide-1 on feeding and energy expenditure regulation. Peptides 1998, 19: 869–75.

    PubMed  CAS  Google Scholar 

  99. Tang-Christensen M, Larsen PJ, Goke R. Central administration of GLP-1-(7–36) amide inhibits food and water intake in rats. Am J Physiol 1996, 271: R848–56.

    PubMed  CAS  Google Scholar 

  100. Tang-Christensen M, Vrang N, Larsen PJ. Glucagon-like peptide-1 (7–36) amide’s central inhibition of feeding and peripheral inhibition of drinking are abolished by neonatal monosodium glutamate treatment. Diabetes 1998, 47: 530–7.

    PubMed  CAS  Google Scholar 

  101. Wang T, Edwards GL, Baile CA. Glucagon-like peptide-1 (7–36) amide administered into the third cerebroventricle inhibits water intake in rats. Proc Soc Exp Biol Med 1998, 219: 85–91.

    PubMed  CAS  Google Scholar 

  102. Furuse M, Matsumoto M, Mori R, Sugahara K, Kano K, Hasegawa S. Influence of fasting and neuropeptideYonthe suppressive food intake induced by intracerebroventricular injection of glucagon-like peptide-1 in the neonatal chick. Brain Res 1997, 764: 289–92.

    PubMed  CAS  Google Scholar 

  103. Thiele TE, Van Dijk G, Campfield LA. Central infusion of GLP-1, but not leptin, produces conditioned taste aversion in rats. Am J Phsiol 1997, 272: R726–30.

    CAS  Google Scholar 

  104. Asarian L, Corp ES, Hrupka B, Geary N. I ntracerebroven-tricular glucagon-like peptide-1 (7–36) amide inhibits sham feeding in rats without eliciting satiety. Physiol Behav 1998, 64: 367–72.

    PubMed  CAS  Google Scholar 

  105. Orskov L, Holst JJ, Moller J, Orskov C, Moller N, Alberti KG, Schmitz O. GLP-1 does not not acutely affect insulin sensitivity in healthy man. Diabetologia 1996, 39: 1227–32.

    PubMed  CAS  Google Scholar 

  106. Chowen JA, de Fonseca FR, Alvarez E, Navarro M, Garcia-Segura LM, Blazquez E. Increased glucagon-like peptide-1 receptor expression in glia after mechanical lesion of the rat brain. Neuropeptides 1999, 33: 212–5.

    PubMed  CAS  Google Scholar 

  107. Naslund E, Bogefors J, Skogar S, et al. GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol 1999, 277: R910–6.

    PubMed  CAS  Google Scholar 

  108. Gutzwiller JP, Drewe J, Goke B, et al. Glucagon-like peptide-1 promotest satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 1999, 276: R1541–4.

    PubMed  CAS  Google Scholar 

  109. Wettergren A, Wjdemann M, Meisner S, Stadil F, Holst JJ. The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7–36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut 1997, 40: 597–601.

    PubMed Central  PubMed  CAS  Google Scholar 

  110. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentration of intact biologiccally active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001, 50: 609–13.

    PubMed  CAS  Google Scholar 

  111. Vaag AA, Holst JJ, Volund A, Beck-Nielsen HB. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM) — evidence for decreased glucagon-like peptide-1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol 1996, 135: 425–32.

    PubMed  CAS  Google Scholar 

  112. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001, 86: 3717–23.

    PubMed  CAS  Google Scholar 

  113. Berghofer P, Peterson RG, Schneider K, Fehmann HC, Goke B. Incretin hormone expression in the gut of diabetic mice and rats. Metabolism 1997, 46: 261–7.

    PubMed  CAS  Google Scholar 

  114. Vilsboll T, Agerso H, Krarup T, Holst JJ. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healty subjects. J Clin Endocrinol Metab 2003, 88: 220–4.

    PubMed  CAS  Google Scholar 

  115. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1-(7–36) amide, peptide histidine methionine, and is responsible for their degradation in human serum. Eur J Biochem 1993, 214: 829–35.

    PubMed  CAS  Google Scholar 

  116. Meneilly GS, Demuth HU, McIntosh CH, Pederson RA. Effect of ageing and diabetes on glucose-dependent insulinotropic polypeptide and dipeptidyl peptidase IV responses to oral glucose. Diabet Med 2000, 17: 346–50.

    PubMed  CAS  Google Scholar 

  117. Ahren B, Larsson H, Holst JJ. Reduced gastric inhibitory polypeptide but normal glucagon-like peptide 1 response to oral glucose in postmenopausal women with impaired glucose tolerance. EurJ Endocrinol 1997, 137: 127–31.

    CAS  Google Scholar 

  118. Deacon CF, Nauck MA, Meier J, Hucking K, Holst JJ. Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and type 2 diabetic subjects as revealed using a new assay for the intact peptide. J Clin Endocrinol Metab 2000, 85: 3575–81.

    PubMed  CAS  Google Scholar 

  119. Pala L, Mannucci E, Pezzatini A, et al. Dipeptidyl peptidase-IV expression and activity in human glomerular endothelial cells. Biochem Biophys Res Commun 2003, 310: 28–31.

    PubMed  CAS  Google Scholar 

  120. Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003, 52: 380–6.

    PubMed  CAS  Google Scholar 

  121. Vaxillaire M, Vionnet M, Vigoroux C, et al. Search for a third susceptibility gene for maturity-onset diabetes of the young. Studies with eleven candidate genes. Diabetes 1994, 43: 389–93.

    PubMed  CAS  Google Scholar 

  122. Zhang Y, Warren-Perry M, Saker PJ, et al. Candidate gene studies in pedigrees with maturity-onset diabetes of the young not linked with glucokinase. Diabetologia 1995, 38: 1055–60.

    PubMed  CAS  Google Scholar 

  123. Yagi T, Nishi S, Hinata S, Murakami M, Yoshimi T. A population association study of four candidate genes (hexokinase II, glucagon-like peptide-1 receptor, fatty acid binding protein-1, and apolipoprotein C-II) with type 2 diabetes and impaired glucose tolerance in Japanese subjects. Diabet Med 1996, 13: 902–7.

    PubMed  CAS  Google Scholar 

  124. Normann RA, Permana P, Tanizawa Y, Ravussin E. Absence of genetic variation in some obesity candidate genes (GLP1 R, ASIP, MC5R) among Pima indians. Int J Obes Relat Metab Disord 1999, 23:163–5.

    Google Scholar 

  125. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide-1 [7–36] amide in patients with type 2 diabetes mellitus. J Clin Invest 1993, 91: 301–7.

    PubMed Central  PubMed  CAS  Google Scholar 

  126. Quddusi S, Vahl TP, Hanson K, Prigeon RL, D’Alessio DA. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care 2003, 26: 791–8.

    PubMed  CAS  Google Scholar 

  127. Gutniak MK, Larsson H, Heiber SJ, Juneskans OT, Holst JJ, Ahren B. Potential therapeutic levels of glucagon-like peptide-1 achieved in humans by a buccal tablet. Diabetes Care 1996, 19: 843–8.

    PubMed  CAS  Google Scholar 

  128. Gutniak MK, Larsson H, Sanders SW, Juneskans O, Holst JJ, Ahren B. GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions. Diabetes Care 1997, 20: 1874–9.

    PubMed  CAS  Google Scholar 

  129. Deacon CF, Knudsen LB, Madsen K, Wiberg FC, Jacobsen O, Holst JJ. Dipeptidl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. Diabetologia 1998, 41: 271–8.

    PubMed  CAS  Google Scholar 

  130. Burcelin R, Dolci W, Thorens B. Long-lasting antidiabetic effect of a dipeptidyl-peptidase IV resistant analog of glu-cagons-like peptide-1. Metabolism 1999, 48: 252–82.

    PubMed  CAS  Google Scholar 

  131. Young AA, Gedulin BR, Bhavsar S. 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 monkey (Macaca mulatta). Diabetes 1999, 48: 1026–34.

    PubMed  CAS  Google Scholar 

  132. Wang Q and Brubaker PL. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia 2002, 45: 1263–73.

    PubMed  CAS  Google Scholar 

  133. Kolterman OG, Buse JB, Fineman MS, et al. Synteticexendi-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003, 88: 3082–9.

    PubMed  CAS  Google Scholar 

  134. Egan JM, Meneilly G, Elahi D. Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes. Am J Physiol Endocr Metab 2003, 284: E1072–9.

    CAS  Google Scholar 

  135. Fineman MS, Bicsak TA, Shen LZ, et al. Effect on glycemic control of exenatide (syntetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Daibetes Care 2003, 26: 2370–7.

    CAS  Google Scholar 

  136. Elbrond B, Jakobsen G, Larsen S, et al. Pharmacokinet-ics, pharmacodynamics, safety, and tolerability of a single dose of NN2211, a long-acting glucagon-like peptide-1 derivative, in healthy male subjects. Diabetes Care 2002, 25: 1398–404.

    PubMed  CAS  Google Scholar 

  137. Juhl CB, Hollingdal M, Sturis J, et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes 2002, 51: 424–9.

    PubMed  CAS  Google Scholar 

  138. Chou JZ, Place GD, Waters DG, Kirkwood JA, Bowsher RR. A radioimmunoassay for LY31 5902, an anaolog of glucagon-like insulinotropic peptide, and its application in the study of canine pharmacokinetics. J Pharm Sci 1997, 86: 768–73.

    PubMed  CAS  Google Scholar 

  139. Naslund E, Skogar S, Efendic S, Hellstrom PM. Glucagon-like peptide-1 analogue LY315902: effect on intestinal motility and release of insulin and somatostatin. Regul Pept 2002, 106: 89–95.

    PubMed  CAS  Google Scholar 

  140. Kim JG, Baggio LL, Bridon DP, et al. Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Diabetes 2003, 52: 751–9.

    PubMed  CAS  Google Scholar 

  141. Mooney MH, Abdel-Wahab YH, McKillop AM, O’Harte FP, Flatt PR. Evaluation of glycated glucagon-like peptide-1 (7–36)amide in intestinal tissue of normal and diabetic animal models. Biochem Biophys Acta 2002, 1569: 75–80.

    PubMed  CAS  Google Scholar 

  142. Joseph JW, Kalitsky J, St-Pierre S, Brubaker PL. Oral delivery of glucagon-like peptide-1 in a modified polymer preparation normalizes basal glycaemia in diabetic db/db mice. Diabetologia 2000, 43: 1319–28.

    PubMed  CAS  Google Scholar 

  143. Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 1998, 47: 1663–70.

    PubMed  CAS  Google Scholar 

  144. Deacon CF, Hughes TE, Holst JJ. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide-1 in the anesthetized pig. Diabetes 1998, 47: 764–9.

    PubMed  CAS  Google Scholar 

  145. Pederson RA, White HA, Schlenzig D, et al. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucinethiazolidide. Diabetes 1998, 47: 1253–8.

    PubMed  CAS  Google Scholar 

  146. Ahren B, Simonsson E, Larsson H, et al. Inhibition of dypeptidyl peptidase IV improves metabolic control over 4-week study period in type 2 diabetes. Diabetes Care 2002, 25: 869–75.

    PubMed  CAS  Google Scholar 

  147. Fukase N, Igarashi M, Takahashi H, et al. Hypersecretion of truncated glucagon-like peptide-1 and gastric inhibitory polypeptide in obese patients. Diabet Med 1993, 10: 44–9.

    PubMed  CAS  Google Scholar 

  148. Ranganath LR, Beety M, Mogan LM, Wright JW, Howland R, Marks V. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 1996, 38: 916–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  149. Naslund E, Gryback P, Backman L, et al. Distal small bowel hormones: correlation with fasting antroduodenal motility and gastric emptying. Dig Dis Sci 1998, 43: 945–52.

    PubMed  CAS  Google Scholar 

  150. Naslund E, Gryback P, Hellstrom PM, et al.Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity. Int J Obes Relat Metab Disord 1997, 21: 387–92.

    PubMed  CAS  Google Scholar 

  151. Naslund E, Backman L, Holst JJ, Theodorsson E, Hellstrom PM. Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg 1998, 8: 253–60.

    PubMed  CAS  Google Scholar 

  152. Gutzwiller JP, Goke B, Drewe J, et al. Glucagon-like peptide-1: a potent regulator of food intake in humans. Gut 1999, 44: 81–6.

    PubMed Central  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Sezione di Endocrinologia, Dipartimento di Fisiopatologia Clinica, Università di Firenze, Viale Pieraccini 6, 50139, Firenze, Italy

    C. M. Rotella & L. Pala

  2. Diabetology, Geriatric Unit, Department of Critical Care, University of Florence, Firenze, Italy

    E. Mannucci

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  1. C. M. Rotella
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  2. L. Pala
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  3. E. Mannucci
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Correspondence to C. M. Rotella.

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Rotella, C.M., Pala, L. & Mannucci, E. Glucagon-like peptide 1 (GLP-1) and metabolic diseases. J Endocrinol Invest 28, 746–758 (2005). https://doi.org/10.1007/BF03347560

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