The Incretin Approach for Diabetes Treatment

Modulation of Islet Hormone Release by GLP-1 Agonism

  1. Jens Juul Holst and
  2. Cathrine Ørskov
  1. From the Departments of Medical Physiology and Medical Anatomy, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
  1. Address correspondence and reprint requests to Jens Juul Holst, MD, Departments of Medical Physiology and Medical Anatomy, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark. E-mail: holst{at}mfi.ku.dk

Abstract

Glucagon-like peptide (GLP)-1 is a gut hormone that stimulates insulin secretion, gene expression, and β-cell growth. Together with the related hormone glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect, the augmentation of insulin secretion after oral as opposed to intravenous administration of glucose. Type 2 diabetic patients typically have little or no incretin-mediated augmentation of insulin secretion. This is due to decreased secretion of GLP-1 and loss of the insulinotropic effects of GIP. GLP-1, however, retains insulinotropic effects, and the hormone effectively improves metabolism in patients with type 2 diabetes. Continuous subcutaneous administration greatly improved glucose profiles and lowered body weight and HbA1c levels. Further, free fatty acid levels were lowered, insulin resistance was improved, and β-cell performance was greatly improved. The natural peptide is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV), but resistant analogs as well as inhibitors of DPP IV are now under development, and both approaches have shown remarkable efficacy in experimental and clinical studies.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    J.J.H. has received honoraria from Novartis and is a paid consultant for Novo Nordisk and Amylin.

    • Accepted May 24, 2004.
    • Received March 12, 2004.
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