GLP-1: Target for a New Class of Antidiabetic Agents?

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53

UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65

Emslie-Smith A.M. , Boyle D.I. , Evans J.M. , Sullivan F. , Morris A.D. , for the DARTS/MEMO collaboration. Contraindications to metformin therapy in patients with type 2 diabetes—a population-based study of adherence to prescribing guidelines. Diabetic Med 2001; 18: 483–8

Edwards C.M. , Barton M.A. , Snook J. , David M. , Mak V.H. , Chowdhury T.A. Metformin-associated lactic acidosis in a patient with liver disease. Quart J Med 2003; 96: 315–16

Bailey C.J. , Turner R.C. Metformin. N Engl J Med 1996; 334: 574–9

Lebovitz H.E. , Melander A. Sulphonylureas: basic aspects and clinical uses. In: Alberti KGMM , Defronzo R.A. , Keen H. , Zimmet P. , eds. International Textbook of Diabetes Mellitus, 1st edn. Oxford: Alden Press, 1992: 745–72

Nathan D.M. Some answers, more controversy, from UKPDS. United Kingdom Prospective Diabetes Study. Lancet 1998; 352: 832–3

Dornhorst A. Insulinotropic meglitinide analogues. Lancet 2001; 358: 1709–16

Saloranta C. , Hershon K. , Ball M. , Dickinson S. , Holmes D. Efficacy and safety of nateglinide in type 2 diabetic patients with modest fasting hyperglycemia. J Clin Endocrinol Metab 2002; 87: 4171–6

Coniff R.F. , Shapiro J.A. , Seaton T.B. , Bray G.A. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med 1995; 98: 443–51

Nolan J.J. , Ludvik B. , Beerdsen P. , Joyce M. , Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331: 1188–93

Lebovitz H.E. , Dole J.F. , Patwardhan R. , Rappaport E.B. , Freed M.I. , Rosiglitazone Clinical Trials Study Group. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 280–8

Aronoff S. , Rosenblatt S. , Braithwaite S. , Egan J.W. , Mathisen A.L. , Schneider R.L. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose–response study. The Pioglitazone 001 Study Group. Diabetes Care 2000; 23: 1605–11

Yale J.F. , Valiquett T.R. , Ghazzi M.N. , Owens-Grillo J.K. , Whitcomb R.W. , Foyt H.L. The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin. A multicenter, randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001; 134: 737–45

Creutzfeldt W. , Ebert R. New developments in the incretin concept. Diabetologia 1985; 28: 565–73

Nauck M.A. , Bartels E. , Orskov C. , Ebert R. , Creutzfeldt W. 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: 912–17

Scrocchi L.A. , Brown T.J. , MaClusky N. . Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med 1996; 2: 1254–8

Edwards C.M. , Todd J.F. , Mahmoudi M. . 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

Edwards C.M. , Edwards A.V. , Bloom S.R. Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7-36) amide in the conscious calf. Exp Physiol 1997; 82: 709–16

Nauck M.A. , Heimesaat M.M. , Orskov C. , Holst J.J. , Ebert R. , Creutzfeldt W. 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

Gutniak M. , Orskov C. , Holst J.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: 1316–22

Drucker D.J. Minireview: the glucagon-like peptides. Endocrinology 2001; 142: 521–7

Farilla L. , Bulotta A. , Hirshberg B. . Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003; 144: 5149–58

Nathan D.M. , Schreiber E. , Fogel H. , Mojsov S. , Habener J.F. Insulinotropic action of glucagonlike peptide-I-(7-37) in diabetic and nondiabetic subjects. Diabetes Care 1992; 15: 270–6

Edwards C.M. , Todd J.F. , Ghatei M.A. , Bloom S.R. Subcutaneous glucagon-like peptide-1 (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects. Clin Sci (Lond) 1998; 95: 719–24

Todd J.F. , Edwards C.M. , Ghatei M.A. , Mather H.M. , Bloom S.R. Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early type 2 diabetes. Clin Sci (Lond) 1998; 95: 325–9

Rachman J. , Barrow B.A. , Levy J.C. , Turner R.C. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 1997; 40: 205–11

Zander M. , Madsbad S. , Madsen J.L. , Holst J.J. 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

Meneilly G.S. , Greig N. , Tildesley H. , Habener J.F. , Egan J.M. , 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

Deacon C.F. , Pridal L. , Klarskov L. , Olesen M. , Holst J.J. Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am J Physiol Endocrinol Metab 1996; 271: E458–64

Mentlein R. , Gallwitz B. , Schmidt W.E. 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

Deacon C.F. , Johnsen A.H. , Holst J.J. 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

Marguet D. , Baggio L. , Kobayashi T. . Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA 2000; 97: 6874–9

Conarello S.L. , Li Z. , Ronan J. . Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci USA 2003; 100: 6825–30

Pospisilik J.A. , Stafford S.G. , Demuth H.U. . Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes 2002; 51: 943–50

Reimer M.K. , Holst J.J. , Ahren B. Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur J Endocrinol 2002; 146: 717–27

Pospisilik J.A. , Martin J. , Doty T. . Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 2003; 52: 741–50

Sudre B. , Broqua P. , White R.B. . 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

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

Villhauer E.B. , Brinkman J.A. , Naderi G.B. . J-[[3-hydroxy-l-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2003; 46: 2774–89

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

Thorens B. , Porret A. , Buhler L. , Deng S.P. , Morel P. , Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes 1993; 42: 1678–82

Young A.A. , Gedulin B.R. , 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 monkeys (Macaca mulatta). Diabetes 1999; 48: 1026–34

Szayna M. , Doyle M.E. , Betkey J.A. . Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology 2000; 141: 1936–41

Xu G. , Stoffers D.A. , Habener J.F. , 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

Zhou J. , Wang X. , Pineyro M.A. , Egan J.M. Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes 1999; 48: 2358–66

Stoffers D.A. , Kieffer T.J. , Hussain M.A. . Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 2000; 49: 741–8

Jonsson J. , Carlsson L. , Edlund T. , Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 1994; 371: 606–9

Baggio L. , Adatia F. , Bock T. , Brubaker P.L. , Drucker D.J. Sustained expression of exendin-4 does not perturb glucose homeostasis, beta-cell mass, or food intake in metallothionein–preproexendin transgenic mice. J Biol Chem 2000; 275: 34471–7

Tourrel C. , Bailbe D. , Meile M.J. , Kergoat M. , Portha B. Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 2001; 50: 1562–70

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

Stoffers D.A. , Desai B.M. , DeLeon D.D. , Simmons R.A. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes 2003; 52: 734–40

Edwards C.M. , Stanley S.A. , Davis R. . Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 2001; 281: E155–61

Vella A. , Shah P. , Reed A.S. , Adkins A.S. , Basu R. , Rizza R.A. Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans. Diabetologia 2002; 45: 1410–15

Egan J.M. , Clocquet A.R. , 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

Kolterman O.G. , Buse J.B. , Fineman M.S. . Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 3082–9

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

Fineman M.S. , Bicsak T.A. , Shen L.Z. . 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: 2370–7

Gedulin B. , Smith P. , Prickett K. . Dose-response for 2-day glycemic improvement following a single injection of long-acting-release exenatide (synthetic exendin-4) in diabetic fatty zucker (ZDF) rats. Diabetes 2003; 52(suppl. 1): A109

Knudsen L.B. , Nielsen P.F. , Huusfeldt P. . Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 2000; 43: 1664–9

Larsen P.J. , Fledelius C. , Knudsen L.B. , 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: 2530–9

Rolin B. , Larsen M.O. , Gotfredsen C.F. . The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrinol Metab 2002; 283: E745–52

Bock T. , Pakkenberg B. , Buschard K. The endocrine pancreas in non-diabetic rats after short-term and long-term treatment with the long-acting GLP-1 derivative NN2211. APMIS 2003; 111: 1117–24

Elbrond B. , Jakobsen G. , Larsen S. . 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: 1398–404

Juhl C.B. , Hollingdal M. , Sturis J. . 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

Chang A.M. , Jakobsen G. , Sturis J. . The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 2003; 52: 1786–91

Kim J.G. , Baggio L.L. , Bridon D.P. . 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

Deacon C.F. , Knudsen L.B. , Madsen K. , Wiberg F.C. , Jacobsen O. , Holst J.J. Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. Diabetologia 1998; 41: 271–8

Burcelin R. , Dolci W. , Thorens B. Long-lasting antidiabetic effect of a dipeptidyl peptidase IV-resistant analog of glucagon-like peptide-1. Metabolism 1999; 48: 252–8

Doyle M.E. , Greig N.H. , Holloway H.W. , Betkey J.A. , Bernier M. , Egan J.M. Insertion of an N-terminal 6-aminohexanoic acid after the 7 amino acid position of glucagon-like peptide-1 produces a long-acting hypoglycemic agent. Endocrinology 2001; 142: 4462–8

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

Green B.D. , Gault V.A. , Mooney M.H. . Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo. J Mol Endocrinol 2003; 31: 529–40