Gut peptides in the treatment of diabetes mellitus

Expert Opinion on Investigational Drugs

Volumn 13, Issue 3, 2004, Pages 177-188

  Vahl, Torsten P ^a   D'Alessio, David A ^a  

^a UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

Author keywords

DPP IV; GIP; GLP 1; Incretins

Indexed keywords

ANTIDIABETIC AGENT; CARBOHYDRATE; CJC 1131; CYCLIC AMP DEPENDENT PROTEIN KINASE; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; ENZYME INHIBITOR; EXENDIN 4; G PROTEIN COUPLED RECEPTOR; GASTRIC INHIBITORY POLYPEPTIDE; GASTRIC INHIBITORY POLYPEPTIDE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 DERIVATIVE; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCOSE; HEMOGLOBIN A1C; HYPOPHYSIS ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE RECEPTOR; INSULIN; LIRAGLUTIDE; METFORMIN; SULFONYLUREA; UNCLASSIFIED DRUG; VASOACTIVE INTESTINAL POLYPEPTIDE; VASOACTIVE INTESTINAL POLYPEPTIDE RECEPTOR;

CARBOHYDRATE ABSORPTION; CIRCULATION; CLINICAL PRACTICE; CLINICAL TRIAL; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG METABOLISM; DRUG RECEPTOR BINDING; ENZYME ACTIVATION; ENZYME INHIBITION; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; GLUCOSE TOLERANCE; HUMAN; INSULIN RELEASE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; POSTPRANDIAL STATE; PROTEIN BLOOD LEVEL; PROTEIN DEGRADATION; PROTEIN SECRETION; REVIEW; SIDE EFFECT;

ANIMALS; ANTIGENS, CD26; DIABETES MELLITUS; DIABETES MELLITUS, TYPE 2; GASTRIC INHIBITORY POLYPEPTIDE; GASTROINTESTINAL HORMONES; GLUCAGON; GLUCAGON-LIKE PEPTIDE 1; HUMANS; HYPOGLYCEMIC AGENTS; PEPTIDE FRAGMENTS; PEPTIDE HORMONES; PROTEASE INHIBITORS; PROTEIN PRECURSORS; RECEPTORS, GASTROINTESTINAL HORMONE; RECEPTORS, GLUCAGON;

EID: 1542708286     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.13.3.177     Document Type: Review

References (177)

1. ELRICK H, STIMMRLER L, HLAD CJ Jr, ARAI Y: Plasma insulin response to oral and intravenous glucose administration. J. Clin. Endocrinol. Metab. (1964) 24:1076-1082.
2. McINTYRE N, HOLDSWORTH CD, TURNER DS: New interpretation of oral glucose tolerance. Lancet (1964) 41:20-21.
3. NAUCK MA, HOMBERGER 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) 63:492-498.
4. CREUTZFELDT W, NAUCK M: Gut hormones and diabetes mellitus. Diabetes Metab. Rev. (1992) 8:149-177.
5. KOLLIGS F, FEHMANN HC, GOKE R, GOKE B: Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide. Diabetes (1995) 44:16-19.
6. WANG Z, WANG RM, OWJI AA et al.: Glucagon-like peptide-1 is a physiological incretin in rat. J. Clin. Invest. (1995) 95:417-421.
7. D'ALESSIO DA, VOGEL R, PRIGEON R et al.: Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J. Clin. Invest. (1996) 97:133-138.
8. EDWARDS CM, TODD JF, MAHMOUDI M et al.: Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: Studies with the antagonist exendin 9-39. Diabetes (1999) 48:86-93.
9. SCHIRRA J, STURM K, LEICHT P et al.: Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J. Clin. Invest. (1998) 101:1421-1430.
10. SCROCCHI LA, MARSHALL BA, COOK SM, BRUBAKER PL, DRUCKER DJ: Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling. Diabetes (1998) 47:632-639.
11. TSENG CC, KIEFFER TJ, JARBOE LA, USDIN TB, WOLFE MM: Postprandial stimulation of insulin release by glucose-dependent insulinotropic polypeptide (GIP). J. Clin. Invest. (1996) 98:2440-2445.
12. TSENG CC, ZHANG XY, WOLFE MM: Effect of GIP and GLP-1 antagonists on insulin release in the rat. Am. J. Physiol. (1999) 276:E1049-E1054.
13. 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. USA (1999) 96:14843-14847.
14. LEWIS JT, DAYANANDAN B, HABENER JF, KIEFFER TJ: Glucose-dependent insulinotropic polypeptide confers early phase insulin release to oral glucose in rats: Demonstration by a receptor antagonist. Endocrinology (2000) 141:3710-3716.
15. BAGGIO L, KIEFFER TJ, DRUCKER DJ: Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, regulates fasting glycemia and nonenteral glucose clearance in mice. Endocrinology (2000) 141:3703-3709.
16. GAULT VA, O'HARTE FP, HARRIOTT P et al.: Effects of the novel (Pro3)GIP antagonist and exendin(9-39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: Evidence that GIP is the major physiological incretin. Diabetologia (2003) 46:222-230.
17. CAVAGHAN MK, EHRMANN DA, POLONSKY KS: Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J. Clin. Invest. (2000) 106:329-333.
18. KULKARNI RN, BRUNING JC, WINNAY JN et al.: Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in Type 2 diabetes. Cell (1999) 96:329-339.
19. NAUCK M, STOCKMANN F, EBERT R, CREUTZFELDT W: Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes. Diabetologia (1986) 29:46-52.
20. VILSBOLL T, KRARUP T, DEACON CF, MADSBAD S, HOLST JJ: Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in Type 2 diabetic patients. Diabetes (2001) 50:609-613.
21. VAAG AA, HOLST JJ, VOLUND A, BECK-NIELSEN H: 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) 135:425-432.
22. 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) 86:3717-3723.
23. RANGANATH LR, BEETY JM, MORGAN LM et al.: Attenuated GLP-1 secretion in obesity: Cause or consequence? Gut (1996) 38:916-919.
24. VILSBOLL T, AGERSO H, KRARUP T, HOLST JJ: Similar elimination rates of glucagon-like peptide-1 in obese Type 2 diabetic patients and healthy subjects. J. Clin. Endocrinol. Metab. (2003) 88:220-224.
25. NAUCK MA, HEIMESAAT MM, ORSKOV 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) 91:301-307.
26. ELAHI D, McALOON-DYKE M, FUKAGAWA NK et al.: The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul. Pept. (1994) 51:63-74.
27. VILSBOLL T, KRARUP T, MADSBAD S, HOLST JJ: Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia (2002) 45:1111-1119.
28. VILSBOLL T, KNOP FK, KRARUP T et al.: The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. J. Clin. Endocrinol. Metab. (2003) 88:4897-4903.
29. LYNN FC, PAMIR N, NG EH et al.: Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes (2001) 50:1004-1011.
30. BELL GI, SANTERRE RF, MULLENBACH GT: Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature (1983) 302:716-718.
31. MOJSOV S, HEINRICH G, WILSON IB et al.: Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J. Biol. Chem. (1986) 261:11880-11889.
32. ORSKOV C, RABENHOJ L, WETTERGREN A, KOFOD H, HOLST JJ: Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide in humans. Diabetes (1994) 43:535-539.
33. WEIR GC, MOJSOV S, HENDRICK GK, HABENER JF: Glucagonlike peptide I (7-37) actions on endocrine pancreas. Diabetes (1989) 38:338-342.
34. KREYMANN B, GHATEI MA, WILLIAMS G, BLOOM SR: Glucagon-like peptide-1 7-36: A physiological incretin in man. Lancet (1987) 2:1300-1303.
35. ELLIOTT RM, MORGAN LM, TREDGER JA et al.: Glucagon-like peptide-1(7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: Acute post-prandial and 24-h secretion patterns. J. Endocrinol. (1993) 138:159-166.
36. HERMANN C, GOKE R, RICHTER G et al.: Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion (1995) 56:117-126.
37. EISSELE R, GOKE R, WILLEMER S et al.: Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur. J. Clin. Invest. (1992) 22:283-291.
38. ROCCA AS, BRUBAKER PL: Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology (1999) 140:1687-1694.
39. MORTENSEN K, PETERSEN LL, ORSKOV C: Colocalization of GLP-1 and GIP in human and porcine intestine. Ann. NY Acad. Sci. (2000) 921:469-472.
40. 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) 214:829-835.
41. KIEFFER TJ, McINTOSH CHS, PEDERSON RA: Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology (1995) 136:3585-3596.
42. PAULY RP, ROSCHE F, WERMANN M et al.: Investigation of glucose-dependent insulinotropic polypeptide-(1-42) and glucagon-like peptide-1-(7-36) degradation in vitro by dipeptidyl peptidase IV using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. A novel kinetic approach. J. Biol. Chem. (1996) 271:23222-23229.
43. 2-terminus in Type II diabetic patients and in healthy subjects. Diabetes (1995) 44:1126-1131.
44. 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) 318:429-435.
45. VAHL TP, PATY BW, FULLER BD, PRIGEON RL, D'ALESSIO DA: Effects of GLP-1-(7-36)NH2, 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.
46. DEACON CF, PLAMBOECK A, MOLLER S, HOLST JJ: GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion. Am. J. Physiol. Endocrinol. Metab. (2002) 282:E873-E879.
47. BROWN JC: A gastric inhibitory polypeptide. I. The amino acid composition and the tryptic peptides. Can. J. Biochem. (1971) 49:255-261.
48. BROWN JC, DRYBURGH JR: A gastric inhibitory polypeptide. II. The complete amino acid sequence. Can. J. Biochem. (1971) 49:867-872.
49. BUCHAN AM, POLAK JM, CAPELLA C, SOLCIA E, PEARSE AG: Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) in man. Histochemistry (1978) 56:37-44.
50. CATALAND S, CROCKETT SE, BROWN JC, MAZZAFERRI EL: Gastric inhibitory polypeptide (GIP) stimulation by oral glucose in man. J. Clin. Endocrinol. Metab. (1974) 39:223-228.
51. FALKO JM, CROCKETT SE, CATALAND S, MAZZAFERRI EL: Gastric inhibitory polypeptide (GIP) stimulated by fat ingestion in man. J. Clin. Endocrinol. Metab. (1975) 41:260-265.
52. CROCKETT SE, CATALAND S, FALKO JM, MAZZAFERRI EL: The insulinotropic effect of endogenous gastric inhibitory polypeptide in normal subjects. J. Clin. Endocrinol. Metab. (1976) 42:1098-1103.
53. BUFFA R, POLAK JM, PEARSE AG et al.: Identification of the intestinal cell storing gastric inhibitory peptide. Histochemistry (1975) 43:249-255.
54. THOMAS FB, SHOOK DF, O'DORISIO TM et al.: Localization of gastric inhibitory polypeptide release by intestinal glucose perfusion in man. Gastroenterology (1977) 72:49-54.
55. INAGAKI N, SEINO Y, TAKEDA J et al.: Gastric inhibitory polypeptide: Structure and chromosomal localization of the human gene. Mol. Endocrinol. (1989) 3:1014-1021.
56. DEACON CF, NAUCK MA, MEIER J, HUCKING K, HOLST JJ: Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in Type 2 diabetic subjects as revealed using a new assay for the intact peptide. J. Clin. Endocrinol. Metab. (2000) 85:3575-3581.
57. JORNVALL H, CARLQUIST M, KWAUK S et al.: Amino acid sequence and heterogeneity of gastric inhibitory polypeptide (GIP). FEBS Lett. (1981) 123:205-210.
58. SCHMIDT WE, SIEGEL EG, KUMMEL H, GALLWITZ B, CREUTZFELDT W: Commercially available preparations of porcine glucose-dependent insulinotropic polypeptide (GIP) contain a biologically inactive GIP-fragment and cholecystokinin-33/-39. Endocrinology (1987) 120:835-837.
59. DEACON CF, PLAMBOECK A, HOLST JJ: Effect of the N-terminally truncated metabolite, GIP(3-42) on the insulinotropic activity of GIP(1-42) in anaesthetized pigs. ADA Abstract Book (2002) (Abstract 579).
60. THORENS B: Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc. Natl. Acad. Sci. USA (1992) 89:8641-8645.
61. 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) 42:1678-1682.
62. DILLON JS, TANIZAWA Y, WHEELER MB et al.: Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor. Endocrinology (1993) 133:1907-1910.
63. 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.
64. GOKE R, LARSEN PJ, MIKKELSEN JD, SKEIKH SP: Distribution of GLP-1 binding sites in the rat brain: Evidence that exendin is a ligand of brain GLP-1 sites. Eur. J. Neurosci. (1995) 7:2294-2300.
65. VAN EYLL B, LANKAT-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.
66. DRUCKER D, PHILLIPPE J, MOJSOV S, CHICK W, HABENER J: Glucagon-like peptide 1 stimulates insulin gene expression and increases cyclic AMP levels in rat islet cell line. Proc. Nat. Acad. Sci. USA (1987) 94:3434-3438.
67. FEHMANN HC, STROWSKI M, GOKE B: Interaction of glucagon-like peptide-I (7-37) and somatostatin-14 on signal transduction and proinsulin gene expression in beta TC-1 cells. Metabolism (1994) 43:787-792.
68. GROMADA J, HOLST JJ, RORSMAN P: Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflugers Arch. (1998) 435:583-594.
69. WHEELER MB, LU M, DILLON JS et al.: Functional expression of the rat glucagon-like peptide-1 receptor, evidence for coupling to both adenyl cyclase and phospholipase-C. Endocrinology (1993) 133:57-62.
70. LU M, WHEELER MB, LENG XH, BOYD AED: The role of the free cytosolic calcium level in β-cell signal transduction by gastric inhibitory polypeptide and glucagon-like peptide I(7-37). Endocrinology (1993) 132:94-100.
71. 2+ channel activity. Endocrinology (1993) 133:1685-1692.
72. HOLZ GGT, KUHTREIBER WM, HABENER JF: Pancreatic β-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature (1993) 361:362-365.
73. MOJSOV S, GEIR GC, HABENER J: Insulinotropin: glucagon-like peptide 1 (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Invest. (1987) 79:616-619.
74. FEHMANN H-C, HABENER J: Insulinotropic hormone glucagon-like peptide-1 (7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma bTC-1 cells. Endocrinology (1992) 130:159-166.
75. SHIMA K, HIROTA M, OHBOSHI C: Effect of glucagon-like peptide-1 on insulin secretion. Regul. Pept. (1988) 22:245-252.
76. WEIR GC, MOJSOV S, HENDRICK GK, HABENER JF: Glucagon like peptide 1 (7-37) actions on endocrine pancreas. Diabetes (1989) 38:338-342.
77. GOKE R, WAGNER B, FEHMANN HC, GOKE B: Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 (7-36) amide on the rat pancreas. Res. Exp. Med. (Berl.) (1993) 193:97-103.
78. NAUCK MA, KLEINE N, ORSKOV C et al.: Normalization of fasting hyperglycemia by endogenous glucagon-like peptide 1 (7-36 amide) in Type 2 (non-insulin-dependent) diabetic patients. Diabetologia (1993) 36:741-744.
79. 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) 32:13-16.
80. KNOP FK, VILSBOLL T, LARSEN S et al.: No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean Type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis. Diabetes Care (2003) 26:2581-2587.
81. HVIDBERG A, NIELSEN MT, HILSTED J, ORSKOV C, HOLST JJ: Effect of glucagon-like peptide-1(proglucagon 78-107 amide) on hepatic glucose production in healthy man. Metabolism (1994) 43:104-108.
82. 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) 5:281-284.
83. HELLER RS, KIEFFER TJ, HABENER JF: Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing α-cells of the rat endocrine pancreas. Diabetes (1997) 46:785-791.
84. FEHMANN H-C, GOKE R, GOKE B: Cell and molecular biology of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulin releasing polypeptide. Endocr. Rev. (1995) 16:390-410.
85. 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) 87:1239-1246.
86. CREUTZFELDT W, ORSKOV C, KLEINE N 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) 19:580-586.
87. WETTERGREN A, SCHJOLDAGER B, MORTENSEN PE et al.: Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig. Dis. Sci. (1993) 38:665-673.
88. 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) 81:327-332.
89. 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.
90. MEIER JJ, GALLWITZ B, SALMEN S et al.: Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with Type 2 diabetes. J. Clin. Endocrinol. Metab. (2003) 88:2719-2725.
91. 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-G927.
92. DUPRE J, BEHME MT, HRAMIAK IM, McDONALD TJ: Subcutaneous glucagon-like peptide I combined with insulin normalizes postcibal glycemic excursions in IDDM. Diabetes Care (1997) 20:381-384.
93. XU G, STOFFERS DA, HABENER JF, BONNER-WEIR S: Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes (1999) 48:2270-2276.
94. STOFFERS DA, KIEFFER TJ, HUSSAIN MA et al.: Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes (2000) 49:741-748.
95. PERFETTI R, ZHOU J, DOYLE ME, EGAN JM: Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology (2000) 141:4600-4605.
96. ZHOU J, WANG X, PINEYRO MA, EGAN JM: Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes (1999) 48:2358-2366.
97. ZULEWSKI H, ABRAHAM EJ, GERLACH MJ et al.: Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes (2001) 50:521-533.
98. HARDIKAR AA, WANG XY, WILLIAMS LJ et al.: Functional maturation of fetal porcine β-cells by glucagon-like peptide 1 and cholecystokinin. Endocrinology (2002) 143:3505-3514.
99. MOVASSAT J, BEATTIE GM, LOPEZ AD, HAYEK A: Exendin 4 up-regulates expression of PDX 1 and hastens differentiation and maturation of human fetal pancreatic cells. J. Clin. Endocrinol. Metab. (2002) 87:4775-4781.
100. ABRAHAM EJ, LEECH CA, LIN JC, ZULEWSKI H, HABENER JF: Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology (2002) 143:3152-3161.
101. LI Y, HANSOTIA T, YUSTA B et al.: Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J. Biol. Chem. (2003) 278:471-478.
102. FARILLA L, HUI H, BERTOLOTTO C et al.: Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology (2002) 143:4397-4408.
103. WANG Q, BRUBAKER PL: Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia (2002) 45:1263-1273.
104. JIN SL, HAN VK, SIMMONS JG et al.: Distribution of glucagonlike peptide 1, glucagon, and glicentin in the rat brain: An immunocytochemical study. J. Comp. Neurol. (1988) 271:519-532.
105. 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) 403:261-280.
106. TURTON MD, O'SHEA D, GUNN I et al.: A role for glucagon-like peptide-1 in the central regulation of feeding. Nature (1996) 379:69-72.
107. TANG-CHRISTENSEN M, LARSEN PJ, GOKE R et al.: Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. Am. J. Physiol. (1996) 271:R848-R856.
108. DAVIS HR Jr, MULLINS DE, PINES JM et al.: Effect of chronic central administration of glucagon-like peptide-1 (7-36) amide on food consumption and body weight in normal and obese rats. Obes. Res. (1998) 6:147-156.
109. MEERAN K, O'SHEA D, EDWARDS CM et al.: Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. Endocrinology (1999) 140:244-250.
110. LARSEN PJ, FLEDELIUS C, KNUDSEN LB, TANG-CHRISTENSEN M: Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes (2001) 50:2530-2539.
111. DONAHEY JCK, VAN DIJK G, WOODS SC, SEELEY RJ: Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats. Brain Res. (1998) 779(1-2):75-83.
112. THIELE TE, VAN DIJK G, CAMPFIELD LA et al.: Central administration of GLP-1, but not leptin, produce conditioned taste aversions in the rat. Am. J. Physiol. (1997) 272:R726-R730.
113. KINZIG KP, D'ALESSIO DA, SEELEY RJ: The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J. Neurosci. (2002) 22:10470-10476.
114. RINAMAN L: A functional role for central glucagon-like peptide-1 receptors in lithium chloride-induced anorexia. Am. J. Physiol. (1999) 277:R1537-R1540.
115. SEELEY RJ, BLAKE K, RUSHING PA et al.: The role of CNS glucagon-like peptide-1 (7-36) amide receptors in mediating the visceral illness effects of lithium chloride. J. Neurosci. (2000) 20:1616-1621.
116. FLINT A, RABEN A, ASTRUP A, HOLST JJ: Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Invest. (1998) 101:515-520.
117. GUTZWILLER JP, GOKE B, DREWE J et al.: Glucagon-like peptide-1: A potent regulator of food intake in humans. Gut (1999) 44:81-86.
118. GUTZWILLER JP, DREWE J, GOKE 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-R1544.
119. NASLUND E, GUTNIAK M, SKOGAR S, ROSSNER S, HELLSTROM PM: Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am. J. Clin. Nutr. (1998) 68:525-530.
120. USDIN TB, MEZEY E, BUTTON DC, BROWNSTEIN MJ, BONNER TI: 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) 133:2861-2870.
121. AMIRANOFF B, VAUCLIN-JACQUES N, LABURTHE M: Functional GIP receptors in a hamster pancreatic β-cell line, In 111: Specific binding and biological effects. Biochem. Biophys. Res. Commun. (1984) 123:671-676.
122. AMIRANOFF B, VAUCLIN-JACQUES N, LABURTHE M: Interaction of gastric inhibitory polypeptide (GIP) with the insulin-secreting pancreatic beta cell line, In III: Characteristics of GIP binding sites. Life Sci. (1985) 36:807-813.
123. MALETTI M, PORTHA B, CARLQUIST M et al.: Evidence for and characterization of specific high affinity binding sites for the gastric inhibitory polypeptide in pancreatic β-cells. Endocrinology (1984) 115:1324-1331.
124. ANDERSEN DK, ELAHI D, BROWN JC, TOBIN JD, ANDRES R: Oral glucose augmentation of insulin secretion. Interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels. J. Clin. Invest. (1978) 62:152-161.
125. ELAHI D, ANDERSEN DK, BROWN JC et al.: Pancreatic α- and β-cell responses to GIP infusion in normal man. Am. J. Physiol. (1979) 237:E185-191.
126. MEIER JJ, GALLWITZ B, SIEPMANN N et al.: Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia (2003) 46:798-801.
127. BROWN JC, PEDERSON RA, JORPES E, MUTT V: Preparation of highly active enterogastrone. Can. J. Physiol. Pharmacol. (1969) 47:113-114.
128. BROWN JC, PEDERSON RA: Cleavage of a gastric inhibitory polypeptide with cyanogen bromide and the physiological action of the C-terminal fragment. J. Physiol. (1970) 210:52P-53P.
129. NAUCK MA, BARTELS E, ORSKOV C, EBERT R, CREUTZFELDT W: 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) 52:214-221.
130. MEIER JJ, GOETZE O, ANSTIPP J et al.: Gastric inhibitory polypeptide (GIP) Does not inhibit gastric emptying in man. Am. J. Physiol. Endocrinol. Metab. (2003) (In Press).
131. TRUMPER A, TRUMPER K, HORSCH D: Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in β-(INS-1)-cells. J. Endocrinol. (2002) 174:233-246.
132. EHSES JA, CASILLA VR, DOTY T et al.: Glucose-dependent insulinotropic polypeptide promotes β-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase. Endocrinology (2003) 144:4433-4445.
133. ECKEL RH, FUJIMOTO WY, BRUNZELL JD: Gastric inhibitory polypeptide enhanced lipoprotein lipase activity in cultured preadipocytes. Diabetes (1979) 28:1141-1142.
134. OBEN J, MORGAN L, FLETCHER J, MARKS V: Effect of the entero-pancreatic hormones, gastric inhibitory polypeptide and glucagon-like polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue. J. Endocrinol. (1991) 130:267-272.
135. 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.
136. YIP RG, WOLFE MM: GIP biology and fat metabolism. Life Sci. (2000) 66:91-103.
137. MIYAWAKI K, YAMADA Y, BAN N et al.: Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. (2002) 8:738-742.
138. GUTNIAK M, ORSKOV C, HOLST J, AHREN B, EFENDIC S: Antidiabetogenic effect of glucagon-like peptide-1(7-36) amide in normal subjects and patients with diabetes mellitus. N. Engl. J. Med. (1992) 326:1316-1322.
139. NATHAN DM, SCHREIBER E, FOGEL H, MOJSOV S, HABENER JF: Insulinotropic action of glucagonlike peptide-1-(7-37) in diabetic and nondiabetic subjects. Diabetes Care (1992) 15:270-276.
140. 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) 38:720-725.
141. GUTNIAK MK, LINDE B, HOLST JJ, EFENDIC S: Subcutaneous injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM. Diabetes Care (1994) 17:1039-1044.
142. GUTNIAK MK, JUNTTI-BERGGREN L, HELLSTROM PM et al.: Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas. Diabetes Care (1996) 19:857-863.
143. NAUCK MA, HOLST JJ, WILLMS B: Glucagon-like peptide 1 and its potential in the treatment of non-insulin-dependent diabetes mellitus. Horm. Metab. Res. (1997) 29:411-416.
144. NAUCK MA, SAUERWALD A, RITZEL R, HOLST JJ, SCHMIEGEL W: Influence of glucagon-like peptide 1 on fasting glycemia in Type 2 diabetic patients treated with insulin after sulfonylurea. secondary failure. Diabetes Care (1998) 21:1925-1931.
145. TOFT-NIELSEN MB, MADSBAD S, HOLST JJ: Determinants of the effectiveness of glucagon-like peptide-1 in Type 2 diabetes. J. Clin. Endocrinol. Metab. (2001) 86:3853-3860.
146. RACHMAN J, GRIBBLE FM, BARTOW BA et al.: Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM. Diabetes (1996) 45:1524-1530.
147. 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) 26:791-798.
148. RACHMAN J, BARROW BA, LEVY JC, TURNER RC: Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia (1997) 40:205-211.
149. LARSEN J, HYLLEBERG B, NG K, DAMSBO P: Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in Type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Diabetes Care (2001) 24:1416-1421.
150. ZANDER M, MADSBAD S, MADSEN JL, HOLST JJ: Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in Type 2 diabetes: A parallel-group study. Lancet (2002) 359:824-830.
151. MENEILLY GS, GREIG N, TILDESLEY H et al.: Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with Type 2 diabetes. Diabetes Care (2003) 26:2835-2841.
152. LAMBEIR AM, DURINX C, PROOST P et al.: Kinetic study of the processing by dipeptidyl-peptidase IV/CD26 of neuropeptides involved in pancreatic insulin secretion. FEBS Lett. (2001) 507:327-330.
153. GOKE 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 β-cells. J. Biol. Chem. (1993) 268:19650-19655.
154. 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.
155. YOUNG AA, GEDULIN BR, BHAVSAR S et al.: 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.
156. KOLTERMAN OG, BUSE JB, FINEMAN MS et al.: Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with Type 2 diabetes. J. Clin. Endocrinol. Metab. (2003) 88:3082-3089.
157. FINEMAN MS, BICSAK TA, SHEN LZ et al.: Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with Type 2 diabetes. Diabetes Care (2003) 26:2370-2377.
158. ROLIN B, LARSEN MO, GOTFREDSEN CF et al.: The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases β-cell mass in diabetic mice. Am. J. Physiol. Endocrinol Metab (2002) 283:E745-E752.
159. RIAEL U, LARSEN MO, ROLIN B et al.: NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs. Eur. J. Pharmacol. (2002) 451:217-225.
160. JUHL CB, HOLLINGDAL M, STURIS J et al.: Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially
161. AGERSO H, JENSEN LB, ELBROND B, ROLAN P, ZDRAVKOVIC M: The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia (2002) 45:195-202.
162. ELBROND B, JAKOBSEN G, LARSEN S et al.: Pharmacokinetics, 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) 25:1398-1404.
163. CHANG AM, JAKOBSEN G, STURIS J et al.: The GLP-1 derivative NN2211 restores β-cell sensitivity to glucose in Type 2 diabetic patients after a single dose. Diabetes (2003) 52:1786-1791.
164. 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) 52:751-759.
165. MARGUET D, BAGGIO L, KOBAYASHI T et al.: Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc. Natl. Acad. Sci. USA (2000) 97:6874-6879.
166. NAGAKURA T, YASUDA N, YAMAZAKI K et al.: Improved glucose tolerance via enhanced glucose-dependent insulin secretion in dipeptidyl peptidase IV-deficient Fischer rats. Biochem. Biophys. Res. Commun. (2001) 284:501-506.
167. AHREN B, HOLST JJ, MARTENSSON H, BALKAN B: Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur. J. Pharmacol. (2000) 404:239-245.
168. 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) 51:1461-1469.
169. POSPISILIK JA, STAFFORD SG, DEMUTH HU et al.: Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and β-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes (2002) 51:943-950.
170. CONARELLO SL, LI Z, RONANJ et al.: Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc. Natl. Acad. Sci. USA (2003) 100:6825-6830.
171. POSPISILIK JA, STAFFORD SG, DEMUTH HU, McINTOSH CH, PEDERSON RA: Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: A euglycemic-hyperinsulinemic clamp study. Diabetes (2002) 51:2677-2683.
172. POSPISILIK JA, MARTIN J, DOTY T et al.: Dipeptidyl peptidase TV inhibitor treatment stimulates β-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes (2003) 52:741-750.
173. AHREN 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) 25:869-875.
174. LAMBEIR AM, DURINX C, SCHARPE, S, DE MEESTER I: Dipeptidyl-peptidase IV from bench to bedside: An update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit. Rev. Clin. Lab. Sci. (2003) 40:209-294.
175. O'HARTE FP, ABDEL-WAHAB YH, CONLON JM, FLATT PR: Amino terminal glycation of gastric inhibitory polypeptide enhances its insulinotropic action on clonal pancreatic B-cells. Biochim. Biophys. Acta (1998) 1425:319-327.
176. O'HARTE FP, MOONEY MH, KELLY CM, FLATT PR: Improved glycaemic control in obese diabetic ob/ob mice using N-terminally modified gastric inhibitory polypeptide. J. Endocrinol. (2000) 165:639-648.
177. O'HARTE FP, GAULT VA, PARKER JC et al.: Improved stability, insulin-releasing activity and antidiabetic potential of two novel N-terminal analogues of gastric inhibitory polypeptide: N-acetyl-GIP and pGlu-GIP. Diabetologia (2002) 45:1281-1291.