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Review

Treatment of Type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors

Jens Juul Holst JDepartment of Medical Physiology, The Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark. [email protected]
Pages 155-166 | Published online: 02 Mar 2005

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  • •Demonstrates the impressive effect of a GLP-1 receptor agonist on 13-cell proliferation and neogenesis.
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  • ••In this important study it wasdemonstrated for the first time that administration of GLP-1 can completely normalise plasma glucose concentrations In patients with Type 2 diabetes.
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  • •This experimental study demonstrates that glucagon antagonism can dramatically reduce the hyperglycaemia of diabetic animals.
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  • ••This study demonstrated for the first timethe full clinical effect of prolonged treatment of Type 2 diabetic subjects with GLP–1.
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  • •This study established exendin-4 as a full GLP-1 receptor agonist.
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  • •Bernard Thorens was the first to clone the GLP-1 receptor and here describes cloning of the human receptor.
  • EDWARDS CM, STANLEY SA, DAVIS Ret al: Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am. I Physiol. Endocrinol. Metab. (2001) 281(1):E155–E161.
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  • •This study provides proof-of-concept for the use of exendin-4 for diabetes treatment.
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  • STURIS J, GOTFREDSEN CE ROMER J et al.: GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics. Br. J. Pharmacol. (2003) 140(1):123–132.
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  • 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(11):2530–2539.
  • BREGENHOLT S, MOLDRUP A, KNUDSEN LB, PETERSEN JS: The GLP-1 derivative NN2211 inhibits cytokine-induced apoptosis in primary rat beta cells. Diabetes (2001) 50\(Suppl. 2):A31 (Abstract).
  • BREGENHOLT S, MOLDRUP A, BLUME N, KNUDSEN LB, PETERSEN JS: The GLP-1 analogue, NN2211, inhibits free fatty acid induced apoptosis in primary rat beta cells. Diabetologia (2001) a44\(Suppl. 1):A19 (Abstract).
  • MATTHEWS D, MADSBAD S, SCHMITZ O, LANGENDORF KW, JAKOBSEN G: The long-acting GLP-1 derivative, NN2211, a new agent for the treatment of Type 2 diabetes. Diabetes (2002) 51\(Suppl. 2):A84 (Abstract).
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  • LAWRENCE B, DREYFUS J, WEN S, GUICARC'H P, DRUCKER D, CASTAIGNE JP: CJC-1131, a long acting GLP-1 derivative, exhibits an extended pharmacokinetic profile in healthy human volunteers. Diabetes (2003) 52\(Suppl. 1):A125.
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  • DEACON CE HUGHES TE, HOLST JJ: Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes (1998) 47(5):764–769.
  • AHREN B, HOLST JJ, MARTENSSON H, BALKAN B: Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur. I Pharmacol. (2000) 404(1-2):239–245.
  • 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 beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes (2002) 51(4):943–950.
  • •The study demonstrates the remarkable effects of long-term treatment of diabetic animals with a DPP-IV inhibitor.
  • 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(5):1461–1469.
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  • CONARELLO SL, LI Z, RONAN J et al: Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc. Nati Acad. Sri. USA (2003) 100(11):6825–6830.
  • 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(5):869–875.
  • •This study provides proof-of-concept for the use of DPP-IV inhibitors for the treatment of diabetes.
  • AHREN B, LANDIN-OLSSON M, JANSSON PA et al.: The DPPIV inhibitor, LAF237, reduces fasting and postprandial glucose in subjects with Type 2 diabetes over a 4 week period by increasing active GLP-1, sustaining insulin and reducing glucagon. Diabetes (2003) 52\(Suppl. 1):A15.
  • •This study demonstrates that GLP-1 is capable of completely restoring 13-cell sensitivity to glucose in patients with diabetes, but also that their sensitivity to GLP-1 is nevertheless reduced compared with that of healthy subjects.
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Websites

  • http://www.amylin.comidefaulf.cfm Amylin pharmaceuticals homepage.
  • http://www.novertis.comi Novartis homepage.

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