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Coming of Age for the Incretins

  • Chapter
Controversies in Treating Diabetes

Part of the book series: Contemporary Endocrinology ((COE))

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Summary

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may be responsible for up to 70% of postprandial insulin secretion. In type 2 diabetes (2DM), the incretin effect is severely reduced. Secretion of GIP is normal, but its effect on insulin is lost. GLP-1 secretion may be impaired, but its actions may restore insulin secretion to near normal levels. Substitution therapy with GLP-1 might therefore be possible. GLP-1 actions include potentiation of glucose-induced insulin secretion, up-regulation of insulin and other β-cell genes, stimulation of β-cell proliferation and neogenesis and inhibition of β-cell apoptosis, inhibition of glucagon secretion, inhibition of gastric emptying, and inhibition of appetite and food intake. It may also have cardioprotective and neuroprotective actions. These actions make GLP-1 particularly attractive as a therapeutic agent for 2DM, but GLP-1 is rapidly destroyed in the body by the enzyme, dipeptidyl peptidase IV (DPP-IV). Clinical strategies therefore include (i) the development of metabolically stable activators of the GLP-1 receptor and (ii) inhibition of DPP-IV. Orally active DPP-IV inhibitors are currently undergoing clinical trials, and recent clinical studies have provided long-term proof of concept. Metabolically stable analogs/activators include the structurally related lizard peptide, exendin-4, or analogs thereof, as well as GLP-1-derived molecules that bind to albumin and thereby assume the pharmacokinetics of albumin. These molecules are effective in animal experimental models of 2DM and have been employed successfully in clinical studies of up to 82 weeks’ duration, and exendin-4 has just been approved for add-on therapy of 2DM.

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Authors
  1. Jens Juul Holst MD
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  2. Carolyn F. Deacon DR MED SCI
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Editors and Affiliations

  1. Division of Endocrinology, Diabetes, and Bone Disease, Department of Medicine, Mount Sinai School of Medicine, New York, NY

    Derek LeRoith MD PhD

  2. Diabetes Research Institute Department of Medicine, Eastern Virginia Medical School The Leonard Strelitz Diabetes Institutes, Norfolk, VA

    Aaron I. Vinik MD PhD FCP FACP

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Holst, J.J., Deacon, C.F. (2008). Coming of Age for the Incretins. In: LeRoith, D., Vinik, A.I. (eds) Controversies in Treating Diabetes. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-59745-572-5_14

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  • DOI: https://doi.org/10.1007/978-1-59745-572-5_14

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