Review

The Alpha-Cell as Target for Type 2 Diabetes Therapy

Mikkel Christensen, Jonatan I. Bagger, Tina Vilsboll, Filip K. Knop

Manuscript submitted September 21, 2011; resubmitted October 21, 2011; accepted November 4, 2011.

Keywords: alpha-cell, DPP-4, GLP-1, glucagon receptor antagonist, glucagon-like peptide 1, incretin-based therapy, LY-2409021, MK-0893, pramlintide, type 2 diabetes

Abstract

Glucagon is the main secretory product of the pancreatic alpha-cells. The main function of this peptide hormone is to provide sustained glucose supply to the brain and other vital organs during fasting conditions. This is exerted by stimulation of hepatic glucose production via specific G protein-coupled receptors in the hepatocytes. Type 2 diabetic patients are characterized by elevated glucagon levels contributing decisively to hyperglycemia in these patients. Accumulating evidence demonstrates that targeting the pancreatic alpha-cell and its main secretory product glucagon is a possible treatment for type 2 diabetes. Several lines of preclinical evidence have paved the way for the development of drugs, which suppress glucagon secretion or antagonize the glucagon receptor. In this review, the physiological actions of glucagon and the role of glucagon in type 2 diabetic pathophysiology are outlined. Furthermore, potential advantages and limitations of antagonizing the glucagon receptor or suppressing glucagon secretion in the treatment of type 2 diabetes are discussed with a focus on already marketed drugs and drugs in clinical development. It is concluded that the development of novel glucagon receptor antagonists are confronted with several safety issues. At present, available pharmacological agents based on the glucose-dependent glucagonostatic effects of GLP-1 represent the most favorable way to apply constraints to the alpha-cell in type 2 diabetes.

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