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Enhancing Incretin Action for the Treatment of Type 2 Diabetes

Banting and Best Diabetes Centre, Department of Medicine, Toronto General Hospital, University of Toronto, Ontario, Canada

Address correspondence and reprint requests to Daniel J. Drucker, MD, Banting and Best Diabetes Centre, University of Toronto, Toronto General Hospital, 200 Elizabeth St., MBRW 4R-402, Toronto, Ontario, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca

OBJECTIVE—To examine the mechanisms of action, therapeutic potential, and challenges inherent in the use of incretin peptides and dipeptidyl peptidase-IV (DPP-IV) inhibitors for the treatment of type 2 diabetes.

RESEARCH DESIGN AND METHODS—The scientific literature describing the biological importance of incretin peptides and DPP-IV inhibitors in the control of glucose homeostasis has been reviewed, with an emphasis on mechanisms of action, experimental diabetes, human physiological experiments, and short-term clinical studies in normal and diabetic human subjects.

RESULTS—Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) exert important effects on ß-cells to stimulate glucose-dependent insulin secretion. Both peptides also regulate ß-cell proliferation and cytoprotection. GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of GLP-1, but not GIP, are preserved in subjects with type 2 diabetes. However, native GLP-1 is rapidly degraded by DPP-IV after parenteral administration; hence, degradation-resistant, long-acting GLP-1 receptor (GLP-1R) agonists are preferable agents for the chronic treatment of human diabetes. Alternatively, inhibition of DPP-IV–mediated incretin degradation represents a complementary therapeutic approach, as orally available DPP-IV inhibitors have been shown to lower glucose in experimental diabetic models and human subjects with type 2 diabetes.

CONCLUSIONS—GLP-1R agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes. The need for daily injections of potentially immunogenic GLP-1–derived peptides and the potential for unanticipated side effects with chronic use of DPP-IV inhibitors will require ongoing scrutiny of the risk-benefit ratio for these new therapies as they are evaluated in the clinic.

Abbreviations: DPP, dipeptidyl peptidase IV • GI, gastrointestinal • GIP, glucose-dependent insulinotropic peptide • GIPR, GIP receptor • GLP, glucagon-like peptide • GLP-1R, GLP-1 receptor

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