Skip to main content
Log in

Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide

Potential Applications in Type 2 Diabetes Mellitus

  • Peptide Therapy
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Although the insulinotropic actions of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been known for almost 2 decades, the incretin hormones have not yet become available for clinical application. This can be explained by their unfavourable pharmacological properties. Both hormones are rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP IV), yielding biologically inactive fragments. There have been several attempts to make use of the antidiabetogenic potential of the incretin hormones. Various analogues of GLP-1 and GIP have been generated in order to achieve resistance to DPP IV degradation. The natural GLP-1 receptor agonist exendin-4, found in the saliva of the Gila monster, has a longer biological half-life after subcutaneous injection than GLP-1, and inhibition of DPP IV using, for example, pyrrolidine derivatives provides elevated concentrations of intact, biologically active GIP and GLP-1 endogenously released from the gut. A continuous intravenous infusion of native GLP-1 for a limited time may be suitable in certain clinical situations. Numerous clinical studies are currently underway to evaluate these approaches. Therefore, an anti-diabetic treatment based on incretin hormones may become available within the next 5 years.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Fig. 1

Similar content being viewed by others

References

  1. Moore B, Edie ES, Abram JH. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J 1906; 1: 28–38

    PubMed  CAS  Google Scholar 

  2. Elrick H, Stimmler L, Hlad CJ, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964; 24: 1076–82

    Article  PubMed  CAS  Google Scholar 

  3. Shuster LT, Go VLW, Rizza RA, et al. Incretin effect due to increased secretion and decreased clearance of insulin in normal humans. Diabetes 1988; 37: 200–3

    Article  PubMed  CAS  Google Scholar 

  4. Creutzfeldt W. The incretin concept today. Diabetologia 1979; 16: 75–85

    Article  PubMed  CAS  Google Scholar 

  5. Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabetologia1985; 28: 565–73

    Article  PubMed  CAS  Google Scholar 

  6. Creutzfeldt W, Nauck M. Gut hormones and diabetes mellitus. Diabetes Metab Rev 1992; 8: 149–77

    Article  PubMed  CAS  Google Scholar 

  7. Nauck MA, Hornberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 1986; 63: 492–8

    Article  PubMed  CAS  Google Scholar 

  8. Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia 2001; 44: 929–45

    Article  PubMed  CAS  Google Scholar 

  9. Nauck M, Stöckmann F, Ebert R, et al. Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes. Diabetologia 1986; 29: 46–54

    Article  PubMed  CAS  Google Scholar 

  10. Jorde R, Burhol PG. The insulinotropic effect of gastric inhibitory polypeptide in non-insulin dependent diabetes. Ital J Gastroenterol 1987; 19: 76–8

    Google Scholar 

  11. Amland PF, Jorde R, Aanderup S, et al. Effects of intravenously infused porcine GIP on serum insulin, plasma C-peptide, and pancreatic polypeptide in non-insulin-dependent diabetes in the fasting state. Scand J Gastroenterol 1985; 20: 315–20

    Article  PubMed  CAS  Google Scholar 

  12. Nauck MA, Heimesaat MM, Ørskov C, et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993; 91: 301–7

    Article  PubMed  CAS  Google Scholar 

  13. Meier JJ, Hücking K, Holst JJ, et al. Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes. Diabetes 2001; 50: 2497–504

    Article  PubMed  CAS  Google Scholar 

  14. Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 [7-36]: a physiological incretin in man. Lancet 1987; II: 1300–4

    Article  Google Scholar 

  15. Nathan DM, Schreiber E, Fogel H, et al. Insulinotropic action of glucagon-like peptide 1 (7-37) in diabetic and non-diabetic subjects. Diabetes Care 1992; 15: 270–6

    Article  PubMed  CAS  Google Scholar 

  16. Nauck MA, Kleine N, Ørskov C, et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36: 741–4

    Article  PubMed  CAS  Google Scholar 

  17. Nauck MA, Wollschläger D, Werner J, et al. Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia 1996; 39: 1546–53

    Article  PubMed  CAS  Google Scholar 

  18. Nauck MA, Holst JJ, Willms B, et al. Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for Type 2-diabetes. Exp Clin Endocrinol Diabetes 1997; 105:187–95

    Article  PubMed  CAS  Google Scholar 

  19. Brown JC, Dryburgh JR. A gastric inhibitory polypeptide: II. the complete amino acid sequence. Can J Biochem 1971; 49: 867–72

    PubMed  CAS  Google Scholar 

  20. Ørskov C, Bersani M, Johnsen AH, et al. Complete sequences of glucagon-like peptide-1 from human and pig small intestine. J Biol Chem 1989; 264: 12826–9

    PubMed  Google Scholar 

  21. Buffa B, Polak JM, Pearse AGE, et al. Identification of the intestinal cell storing gastric inhibitory polypeptide. Histochemistry 1975; 43: 249–55

    Article  PubMed  CAS  Google Scholar 

  22. Cleator IG, Gourlay RH. Release of immunoreactive gastric inhibitory polypeptide (IR-GIP) by oral ingestion of food substances. Am J Surg 1975; 130: 128–35

    Article  PubMed  CAS  Google Scholar 

  23. Ørskov C, Jeppesen J, Madsbad S, et al. Proglucagon products in plasma of non-insulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. J Clin Invest 1991; 87: 415–23

    Article  PubMed  Google Scholar 

  24. Vilsbøll T, Krarup T, Deacon CF, et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001; 50: 609–13

    Article  PubMed  Google Scholar 

  25. Dupré J, Ross SA, Watson D, et al. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 1973; 37: 826–8

    Article  PubMed  Google Scholar 

  26. Ørskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like peptide-1 [proglucagon-(78–107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 1988; 123: 2009–13

    Article  PubMed  Google Scholar 

  27. Xu G, Stoffers DA, Habener JF, et al. Exendin-4 stimulates both b-cell replication and neogenesis, resulting in increased b-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48: 2270–6

    Article  PubMed  CAS  Google Scholar 

  28. Trumper A, Trumper K, Trusheim H, et al. Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. Mol Endocrinol 2001; 15: 1559–70

    Article  PubMed  CAS  Google Scholar 

  29. Eckel RH, Fujimoto WY, Brunzell JD. Gastric inhibitory polypeptide enhances lipoprotein lipase activity in cultured preadipocytes. Diabetes 1979; 28:1141–2

    Article  PubMed  CAS  Google Scholar 

  30. Wasada T, McCorkle K, Harris V, et al. Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs. J Clin Invest 1981; 68: 1106–7

    Article  PubMed  CAS  Google Scholar 

  31. Juntti-Berggren L, Pigon J, Karpe F, et al. The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dislipoproteinemia in NIDDM patients. Diabetes Care 1996; 19: 1200–6

    Article  PubMed  CAS  Google Scholar 

  32. Schjoldager BT, Mortensen PE, Christiansen J, et al. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig Dis Sci 1989; 34: 703–8

    Article  PubMed  CAS  Google Scholar 

  33. Flint A, Raben A, Astrup A, et al. Glucagon-like peptide-1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998; 101: 515–20

    Article  PubMed  CAS  Google Scholar 

  34. Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon-like peptide 1 but not glucagon-like peptide 2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 1985; 28: 704–7

    Article  PubMed  CAS  Google Scholar 

  35. 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  37. Knudsen LB, Pridal L. Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur J Pharmacol 1996; 318(2-3): 429–35

    Article  PubMed  CAS  Google Scholar 

  38. Wettergren A, Wojdemann M, Holst JJ. The inhibitory effect of glucagon-like peptide-1 (7-36) amide on antral motility is antagonized by its N-terminally truncated primary metabolite GLP-1 (9-36) amide. Peptides 1998; 19(5): 877–82

    Article  PubMed  CAS  Google Scholar 

  39. Groop LC. Sulfonylureas in NIDDM. Diabetes Care 1992; 15: 737–54

    Article  PubMed  CAS  Google Scholar 

  40. Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 2002; 87: 1239–46

    Article  PubMed  CAS  Google Scholar 

  41. Nauck MA, Bartels E, Ørskov C, et al. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 1993; 76: 912–7

    Article  PubMed  CAS  Google Scholar 

  42. Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon gene contains the sequence of glucagon and two related peptides. Nature 1983; 302: 716–8

    Article  PubMed  CAS  Google Scholar 

  43. Lopez LC, Frazier ML, Su C-J, et al. Mammalian pancreatic proglucagon contains three glucagon-related peptides. Proc Natl Acad Sci U S A 1983; 80: 5485–9

    Article  PubMed  CAS  Google Scholar 

  44. Drucker DJ, Philippe J, Mojsov S, et al. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci U S A 1987; 84(10): 3434–8

    Article  PubMed  CAS  Google Scholar 

  45. Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 1987; 79: 616–9

    Article  PubMed  CAS  Google Scholar 

  46. Holst JJ, Ørskov C, Vagn-Nielsen O, et al. Truncated glucagon-like peptide 1, an insulin-releasing hormone from the distal gut. FEBS Lett 1987; 211: 169–74

    Article  PubMed  CAS  Google Scholar 

  47. Ørskov C, Holst JJ, Seier-Poulsen S, et al. Pancreatic and intestinal processing of proglucagon in man. Diabetologia 1987; 30: 874–81

    PubMed  Google Scholar 

  48. Kreymann B, Yiangou Y, Kanse S, et al. Isolation and characterisation of GLP-1 7-36 amide from rat intestine: elevated levels in diabetic rats. FEBS Lett 1988; 242: 167–70

    Article  PubMed  CAS  Google Scholar 

  49. Nauck MA, Sauerwald A, Ritzel R, et al. Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea failure. Diabetes Care 1998; 21: 1925–31

    Article  PubMed  CAS  Google Scholar 

  50. Komatsu R, Matsuyama T, Namba M, et al. Glucagonostatic and insulinotropic action of glucagonlike peptide I — (7-36)-amide. Diabetes 1989; 38: 902–5

    Article  PubMed  CAS  Google Scholar 

  51. Matsuyama T, Komatsu R, Namba M, et al. Glucagon-like peptide-1 (7-36 amide): a potent glucagonostatic and insulinotropic hormone. Diabetes Res Clin Pract 1988; 5: 281–4

    Article  PubMed  CAS  Google Scholar 

  52. Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature1996; 379: 69–72

    Article  PubMed  CAS  Google Scholar 

  53. Gutzwiller J-P, Drewe J, Göke B, et al. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 1999; 276: R1541–4

    PubMed  CAS  Google Scholar 

  54. Young AA, Gedulin BR, Rink TJ. Dose-responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7-36) NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake. Metabolism 1996; 45: 1–3

    Article  PubMed  CAS  Google Scholar 

  55. Wettergren A, Schjoldager B, Mortensen PE, etal. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993; 38: 665–73

    Article  PubMed  CAS  Google Scholar 

  56. Willms B, Werner J, Holst JJ, et al. 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

    Article  PubMed  CAS  Google Scholar 

  57. Schmidtler J, Schepp W, Janczewska I, et al. GLP-1-(7-36) amide, — (1-37), and - (1-36) amide: potent cAMP-dependent stimuli of rat parietal cell function. Am J Physiol 1991; 260: G940–50

    PubMed  CAS  Google Scholar 

  58. Nauck MA, Bartels E, Ørskov C, et al. Lack of effect of synthetic human gastric inhibitory polypeptide and glucagon-like peptide 1 [7-36 amide] infused at near-physiological concentrations on pentagastrin-stimulated gastric acid secretion in normal human subjects. Digestion 1992; 52: 214–21

    Article  PubMed  CAS  Google Scholar 

  59. Valverde I, Villanueva Penacarrillo ML. In vitro insulinomimetic effects of GLP-1 in liver, muscle and fat. Acta Physiol Scand 1996; 157: 359–60

    Article  PubMed  CAS  Google Scholar 

  60. Valverde I, Morales M, Clemente F, et al. Glucagon-like peptide 1: a potent glycogenic hormone. FEBS Lett 1994; 349: 313–6

    Article  PubMed  CAS  Google Scholar 

  61. Villanueva Penacarrillo ML, Alcantara AI, Clemente F, et al. Potent glycogenic effect of GLP-1 (7-36) amide in rat skeletal muscle. Diabetologia 1994; 37: 1163–6

    Article  PubMed  CAS  Google Scholar 

  62. Morales M, Lopez-Delgado MI, Alcantara A, et al. Preserved GLP-I effects on glycogen synthase a activity and glucose metabolism in isolated hepatocytes and skeletal muscle from diabetic rats. Diabetes 1997; 46(8): 1264–9

    Article  PubMed  CAS  Google Scholar 

  63. Kawai K, Suzuki S, Ohashi S, et al. Comparison of the effects of glucagon-like peptide-1-(1-37) and — (7-37) and glucagon on islet hormone release from isolated perfused canine and rat pancreases. Endocrinology 1989; 124:1768–73

    Article  PubMed  CAS  Google Scholar 

  64. Creutzfeldt WO, Kleine N, Willms B, et al. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I (7-36) amide in type I diabetic patients. Diabetes Care 1996; 19: 580–6

    Article  PubMed  CAS  Google Scholar 

  65. Nauck MA, Busing M, Ørskov C, et al. Basal and nutrient-stimulated pancreatic and gastrointestinal hormone concentrations in type-1-diabetic patients after successful combined pancreas and kidney transplantation. Clin Invest 1992; 70: 40–8

    Article  CAS  Google Scholar 

  66. Willms B, Idowu K, Holst JJ, et al. Overnight GLP-1 normalizes fasting but not daytime plasma glucose values in NIDDM patients. Exp Clin Endocrinol Diabetes 1998; 106: 103–7

    Article  PubMed  CAS  Google Scholar 

  67. Groop LC, Pelkonen R, Koskimies S, et al. Secondary failure to treatment with oral antidiabetic agents in non-insulin-dependent diabetes. Diabetes Care 1986; 9: 129–33

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  70. Imeryuz N, Yegen BC, Bozkurt A, et al. Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol 1997; 273: G920–7

    PubMed  CAS  Google Scholar 

  71. 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 

  72. Schirra J, Houk P, Wank U, et al. Effects of glucagon-like peptide-1 (7-36) amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans. Gut 2000; 56: 622–31

    Article  Google Scholar 

  73. Kassander P. Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum). Ann Intern Med 1958; 48: 797–812

    PubMed  CAS  Google Scholar 

  74. De Block CE, De Leeuw IH, Pelckmans PA, et al. Delayed gastric emptying and gastric autoimmunity in type 1 diabetes. Diabetes Care 2002; 25: 912–7

    Article  PubMed  Google Scholar 

  75. Ritzel R, Ørskov C, Holst JJ, et al. 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

    Article  PubMed  CAS  Google Scholar 

  76. Zander M, Madsbad S, Madsen JL, et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359: 824–30

    Article  PubMed  CAS  Google Scholar 

  77. Conlon JM, Samson WK, Dobbs RE, et al. Glucagon-like polypeptides in canine brain. Diabetes 1979; 28: 700–2

    Article  PubMed  CAS  Google Scholar 

  78. Tager H, Hohenboken M, Markese J, et al. Identification and localisation of glucagon-related peptides in rat brain. Proc Natl Acad Sci U S A 1980; 77: 6229–33

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  80. Schick RR, Zimmermann JP, vorm Walde T, et al. Glucagon-like-peptide (GLP)-1-(7-36)-amide: a central suppressor of food intake in rats. Gastroenterology 1992; 102 Suppl. 1

  81. Gutzwiller JP, Göke B, Drewe J, et al. Glucagon-like peptide-1 is a physiologic regulator of food intake in humans [abstract]. Gastroenterology 1997; 112: A1153

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  83. Zander M, Madsbad S, Holst JJ. GLP-1 for six weeks reduces body weight and improves insulin sensitivity and glycemic control in patients with Type 2 diabetes. Diabetes 2001; 50Suppl. 2: A31

    Google Scholar 

  84. Meier JJ, Gallwitz B, Schmidt WE, et al. Glucagon-like peptide 1 (GLP-1) as a regulator of food intake and body weight: therapeutic perspectives. Eur J Pharmacol 2002; 440: 269–79

    Article  PubMed  CAS  Google Scholar 

  85. Brown JC, Pederson RA, Jorpes E, et al. Preparation of highly active enterogastrone. Can J Physiol Pharmacol 1969; 47: 113–4

    Article  PubMed  CAS  Google Scholar 

  86. Brown JC, Mutt V, Pederson RA. Further purification of a polypeptide demonstrating enterogastrone activity. J Physiol 1970; 209: 57–64

    PubMed  CAS  Google Scholar 

  87. Brown JC. A gastric inhibitory polypeptide: I. the amino acid composition and the tryptic peptides. Can J Biochem 1971; 49: 255–61

    PubMed  CAS  Google Scholar 

  88. May JM, Williams RH. The effect of endogenous gastric inhibitory polypeptide on glucose-induced insulin secretion in mild diabetes. Diabetes 1978; 27: 849–55

    PubMed  CAS  Google Scholar 

  89. Siegel EG, Creutzfeldt W. Stimulation of insulin release in isolated rat islets by GIP in physiological concentrations and its relation to cyclic AMP content. Diabetologia 1985; 28: 857–61

    Article  PubMed  CAS  Google Scholar 

  90. Pederson RA, Brown JC. Interaction of gastric inhibitory polypeptide, glucose, and arginine on insulin and glucagon secretion from the perfused rat pancreas. Endocrinology 1978; 103: 610–5

    Article  PubMed  CAS  Google Scholar 

  91. Andersen DK, Elahi D, Brown JC, et al. Oral glucose augmentation of insulin secretion: interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels. J Clin Invest 1978; 62: 152–61

    Article  PubMed  CAS  Google Scholar 

  92. Jones IR, Owens DR, Moody AJ, et al. The effects of glucose-dependent insulinotropic polypeptide infused at physiological concentrations in normal subjects and Type 2 (non-insulin-dependent) diabetic patients on glucose tolerance and B-cell secretion. Diabetologia 1987; 30: 707–12

    Article  PubMed  CAS  Google Scholar 

  93. Krarup T, Saurbrey N, Moody AJ, et al. Effect of porcine gastric inhibitory polypeptide on β-cell function in Type 1 and Type II diabetes mellitus. Metabolism 1988; 36: 677–82

    Article  Google Scholar 

  94. Nauck M, Schmidt WE, Ebert R, et al. Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man; interactions with glucose, phenylalanine, and cholecystokinin-8. J Clin Endocrinol Metab 1989; 69: 654–62

    Article  PubMed  CAS  Google Scholar 

  95. Elahi D, Andersen DK, Brown JC, et al. Pancreatic a- and β-cell responses to GIP infusion in normal man. Am J Physiol 1979; 237: E185–91

    PubMed  CAS  Google Scholar 

  96. Meier JJ, Nauck MA, Siepmann N, et al. Insulin secretion following a bolus injection of gastric inhibitory polypeptide (GIP) in first-degree relatives of type 2 diabetic patients and healthy control subjects [abstract]. Diabetes 2002; 51Suppl. 2: A580

    Google Scholar 

  97. Meier JJ, Nauck MA, Schmidt WE, et al. Gastric inhibitory polypeptide (GIP): the neglected incretin revisited. Regul Pept 2002; 107: 1–13

    Article  PubMed  CAS  Google Scholar 

  98. Miyawaki K, Yamada Y, Yano H, et al. Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci U S A 1999; 96: 14843–7

    Article  PubMed  CAS  Google Scholar 

  99. Dupré J, Caissignac Y, McDonald TJ, et al. Stimulation of glucagon secretion by gastric inhibitory polypeptide in patients with hepatic cirrhosis and hyper-glucagonemia. J Clin Endocrinol Metab 1991; 72: 125–9

    Article  PubMed  Google Scholar 

  100. Usdin TB, Mesey É, Button DC, et al. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 1993; 133: 2861–70

    Article  PubMed  CAS  Google Scholar 

  101. Yip RGC, Boylan MO, Kieffer TJ, et al. Functional GIP receptors are present on adipocytes. Endocrinology 1998; 139: 4004–7

    Article  PubMed  CAS  Google Scholar 

  102. Oben J, Morgan L, Fletcher J, et al. Effect of the entero-pancreatic hormones, gastric inhibitory polypeptide and glucagon-like polypeptide-1 (7-36) amide, on fatty acid synthesis in expiants of rat adipose tissue. J Endocrinol 1991; 130: 267–72

    Article  PubMed  CAS  Google Scholar 

  103. Beck B, Max JP. Gastric inhibitory polypeptide enhancement of the insulin effect on fatty acid incorporation into adipose tissue in the rat. Regul Pept 1983; 7: 3–8

    Article  PubMed  CAS  Google Scholar 

  104. Beck B, Max JP. Hypersensitivity of adipose tissue to gastric inhibitory polypeptide action in the obese Zucker rat. Cell Mol Biol 1987; 33: 555–62

    PubMed  CAS  Google Scholar 

  105. Ebert R, Nauck M, Creutzfeldt W. Effect of exogenous or endogenous gastric inhibitory polypeptide (GIP) on plasma triglyceride response in rats. Horm Metab Res 1991; 23: 517–21

    Article  PubMed  CAS  Google Scholar 

  106. Miyawaki K, Yamada Y, Ban N, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 2002; 8: 738–42

    Article  PubMed  CAS  Google Scholar 

  107. Lauritsen KB, Holst JJ, Moody AJ. Depression of insulin release by Anti-GIP serum after oral glucose in rats. Scand J Gastroenterol 1981; 16: 417–20

    Article  PubMed  CAS  Google Scholar 

  108. Tseng C-C, Kieffer TJ, Jarboe LA, et al. Postprandial stimulation of insulin release by glucose-dependent insulinotropic peptide (GIP): effect of a specific glucose-dependent insulinotropic polypeptide receptor antagonist in the rat. J Clin Invest 1996; 98: 2440–5

    Article  PubMed  CAS  Google Scholar 

  109. Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intrave-nously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type 2-diabetic patients and in healthy subjects. Diabetes 1995; 44: 1126–31

    Article  PubMed  CAS  Google Scholar 

  110. Deacon CF, Nauck MA, Meier JJ, et al. Degradation of endogenous and exogenous gastric inhibitory polypeptide (GIP) in healthy and in Type 2 diabetic subjects as revealed using a new assay for the intact peptide. J Clin Endocrinol Metab 2000; 85: 3575–81

    Article  PubMed  CAS  Google Scholar 

  111. Gelling RW, Coy DH, Pederson RA, et al. GIP (6-30 amide) contains the high affinity binding region of GIP and is a potent inhibitor of GIP1-42 action in vitro. Regul Pept 1997; 69(3): 151–4

    Article  PubMed  CAS  Google Scholar 

  112. Mentlein R. Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regul Pept 1999; 85: 9–24

    Article  PubMed  CAS  Google Scholar 

  113. Hanks JB, Andersen DK, Wise JE, et al. The hepatic extraction of gastric inhibitory polypeptide and insulin. Endocrinology 1984; 115: 1011–8

    Article  PubMed  CAS  Google Scholar 

  114. Chap Z, O’Doriso TM, Cataland S, et al. Absence of hepatic extraction of gastric inhibitory polypeptide in conscious dogs. Dig Dis Sci 1987; 32: 280–4

    Article  PubMed  CAS  Google Scholar 

  115. Deacon C, Danielsen P, Klarskov L, et al. Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic effects in anesthetized pigs. Diabetes 2001; 50: 1588–97

    Article  PubMed  CAS  Google Scholar 

  116. Deacon CF, Knudsen LB, Madsen K, et al. Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. Diabetologia 1998; 41: 271–8

    Article  PubMed  CAS  Google Scholar 

  117. Deacon CF, Highes 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

    Article  PubMed  CAS  Google Scholar 

  118. Siegel EG, Gallwitz B, Scharf G, etal. Biological activity of GLP-1-analogues with N-terminal modifications. Regul Pept 1999; 79: 93–102

    Article  PubMed  CAS  Google Scholar 

  119. O’Harte FP, Abdel-Wahab YH, Conlon JM, et al. Amino terminal glycation of gastric inhibitory polypeptide enhances its insulinotropic action on clonal pancreatic B-cells. Biochem Biophys Acta 1998; 1425: 319–27

    Article  PubMed  Google Scholar 

  120. O’Harte FPM, Mooney MH, Flatt PR. NH2-terminally modified gastric inhibitory polypeptide exhibits amino-peptidase resistance and enhanced antihyperglycemic activity. Diabetes 1999; 48: 758–65

    Article  PubMed  Google Scholar 

  121. O’Harte FP, Mooney MH, Kelly CM, et al. Improved glycaemic control in obese diabetic ob/ob mice using N-terminally modified gastric inhibitory polypepide. J Endocrinol 2000; 165: 639–48

    Article  PubMed  Google Scholar 

  122. Gallwitz B, Ropeter T, Morys-Wortmann C, et al. GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro. Regul Pept 2000; 86: 103–11

    Article  PubMed  CAS  Google Scholar 

  123. Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 2000; 43: 1664–9

    Article  PubMed  CAS  Google Scholar 

  124. Bridon DP, Robitaille MF, Lawrence B, et al. The long-acting GLP-1 agonist CJC-1131 exhibits high potency and extended pharmacokinetics in vivo [abstract]. Diabetes 2002; 51Suppl. 2: A93

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  127. Åhren B, Holst JJ, Martensso H, et al. Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur J Pharmacol 2000; 404: 239–45

    Article  PubMed  Google Scholar 

  128. Hinke SA, Gelling RW, Pederson RA, et al. Dipeptidyl peptidase IV-resistant [D-Ala (2)] glucose-dependent insulinotropic polypeptide (GIP) improves glucose tolerance in normal and obese diabetic rats. Diabetes 2002; 51: 652–61

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  130. Agersø H, Jensen LB, Elbrond B, et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 2002; 45: 195–202

    Article  PubMed  Google Scholar 

  131. 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

    Article  PubMed  CAS  Google Scholar 

  132. Kapitza C, Trautmann ME, Heise T, et al. Daily administration of LY307161SR (GLP-1 Analog) normalizes blood glucose in type 2 diabetes [abstract]. Diabetes 2002; 51Suppl. 2: A84

    Google Scholar 

  133. Lawrence B, Wen SY, Jette L, et al. CJC-1131, the novel acting GLP-1 analogue, delays gastric emptying and demonstrates safety and tolerability in preclinical testing [abstract]. Diabetes 2002; 51Suppl. 2: A84

    Google Scholar 

  134. Kim J-G, Baggio LL, Drucker DJ. The GLP-1-DAC analogue CJC-1131 upregulates insulin gene expression and exerts a memory effect on glycemic control in db/db mice [abstract]. Diabetes 2002; 51 Suppl. 2: A340

    Google Scholar 

  135. Thorens B, Porret A, Buhler L, et al. 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

    Article  PubMed  CAS  Google Scholar 

  136. Göke R, Fehmann HC, Linn T, et al. 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: 19650–5

    PubMed  Google Scholar 

  137. Young AA, Gedulin BR, Bhavsar S, et al. Glucose lowering and insulin-sensitizing actions of exendin-4. Diabetes 1999; 48: 1026–34

    Article  PubMed  CAS  Google Scholar 

  138. Greig NH, Holloway HW, De Ore KA, et al. Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. Diabetologia 1999; 42: 45–50

    Article  PubMed  CAS  Google Scholar 

  139. Parkes DG, Pittner R, Jodka C, et al. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism 2001; 50: 583–9

    Article  PubMed  CAS  Google Scholar 

  140. Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab 2002; 87: 1282–90

    Article  PubMed  CAS  Google Scholar 

  141. Taylor K, Tim D, Biscak T, et al. Continuous subcutaneous infusion of AC2993 (synthetic exendin-4) provides sustained day-long glycemic control to patients with type 2 diabetes [abstract]. Diabetes 2002; 51Suppl. 2: A85

    Google Scholar 

  142. Lindsay JR, Au STB, Kelly CM, et al. A novel amino-terminally glycated analogue of glucose-dependent insulinotropic polypeptide (GIP), with prolonged insulinotropic activity in type 2 diabetes mellitus [abstract]. Diabetes 2002; 51Suppl. 2: A341

    Google Scholar 

  143. Balkan B, Kwasnik L, Miserendino R, et al. Inhibition of dipeptidyl peptidase IV with NVP-DPP728 increases plasma GLP-1 (7-36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats. Diabetologia 1999; 42: 1324–31

    Article  PubMed  CAS  Google Scholar 

  144. Deacon CF, Wamberg S, Bie P, et al. Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs. J Endocrinol 2002; 172: 355–62

    Article  PubMed  CAS  Google Scholar 

  145. Sudre B, Broqua P, White RB, et al. Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male Zucker diabetic fatty rats. Diabetes 2002; 51: 1461–9

    Article  PubMed  CAS  Google Scholar 

  146. Burkey BF, Li X, Bolognese L, et al. Combination treatment of a DPP-IV inhibitor NVP-LAF237 with pioglitazone completely normalized glucose concentrations in adult obese Zucker rats [abstract]. Diabetes 2002; 51Suppl. 2: A338

    Google Scholar 

  147. Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY (3-36) physiologically inhibits food intake. Nature 2002; 418(6898): 650–4

    Article  PubMed  CAS  Google Scholar 

  148. Malmberg K, Ryden L, Hamsten A, et al. Mortality prediction in diabetic patients with myocardial infarction: experiences from the DIGAMI study. Cardiovasc Res 1997; 34: 248–53

    Article  PubMed  CAS  Google Scholar 

  149. Norhammer A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359: 2127–8

    Article  Google Scholar 

  150. Nauck MA, Deifuss S, Klamann A, et al. Influence of glycémie control on size of myocardial infarction and long-term survival of type 2 diabetic patients [abstract]. Diabetes Res Clin Pract 2000; 50Suppl. 1: 300–1

    Article  Google Scholar 

  151. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 1359–67

    Article  PubMed  Google Scholar 

  152. Malmberg K. Prospective randomised study of intensive treatment on long term survival after myocardial infarction in patients with diabetes mellitus: DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997; 314: 1512–5

    Article  PubMed  CAS  Google Scholar 

  153. Gutniak MK, Kavianipour M, Nystroem T, et al. Glucagon-like peptide-1 (7-36) amide improves glucose utilisation and prevents the accumulation of pyruvate and lactate in ischemie myocardium [abstract]. Diabetes 2002; 51Suppl. 1: A339

    Google Scholar 

  154. Plamboeck A, Holst JJ, Carr R, et al. Augmentation of glucagon-like Peptide-1 mediated insulin release by neutral Endopeptidease 24.11 and Dipeptidyl Peptidase IV inhibition in dogs [abstract]. Diabetes 2002; 51Suppl. 2: A343

    Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge support of their work by the Deutsche Forschungsgemeinschaft (grant No 203/6-1), by the Deutsche Diabetes-Gesellschaft, and by the Ruhr-University Bochum (FoRUM programm). We also thank Professor W. Schmidt, Bochum and Professor J. Holst, Copenhagen, for critical and helpful discussion. Michael Nauck has received grant support for clinical research involving GLP-1 or derivatives from NovoNordisk, Copenhagen, Denmark, from Eli Lilly & Co., Indianapolis, Indiana, USA, from Novartis Pharma GmbH, Basel, Switzerland, from probiodrug GmbH, Halle, Germany, and from Restoragen Inc., Lincoln, Nebraska, USA. He has also received honoraria as a consultant or speaker from these companies as well as Amylin Pharmaceuticals, San Diego, California, USA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael A. Nauck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meier, J.J., Gallwitz, B. & Nauck, M.A. Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide. BioDrugs 17, 93–102 (2003). https://doi.org/10.2165/00063030-200317020-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00063030-200317020-00002

Keywords

Navigation