Pancreatic islet dysfunction in type 2 diabetes: a rational target for incretin-based therapies

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Abstract
Insulin resistance alone does not result in the development of type 2 diabetes; progressive dysfunction of pancreatic islet alpha and beta cells, which results in inadequate control of hyperglycemia, must be present for the disease to develop. Because of these defects, meal-stimulated insulin secretion from beta cells is reduced and fails to meet the demands of the insulin-resistant state; in addition, glucagon production by alpha cells, which normally maintains hepatic glucose production during fasting periods, is not suppressed. This increased glucagon secretion leads to inappropriate levels of hepatic glucose output in the post-prandial state and consequently to hyperglycemia. This review will examine the pathophysiologic processes of type 2 diabetes and provide an overview of some of the new and emerging treatments targeting pancreatic islet dysfunction. A MEDLINE search was performed for literature published in the English language from 1966-August 2006. Abstracts and presentations from the American Diabetes Association Scientific Sessions (2002-2006) and the European Association for the Study of Diabetes Annual Meetings (1998-2006) were also searched for relevant studies. Key factors in maintaining the normal balance between insulin and glucagon levels are the incretins--glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Intestinal absorption of glucose stimulates secretion of these hormones, which act to increase insulin and decrease glucagon secretion. Studies demonstrating that incretin activity is impaired in type 2 diabetes have led to investigations into incretin-based therapies such as incretin mimetics (analogues of GLP-1) and inhibitors of the enzyme dipeptidyl peptidase-4 (DPP-4), which inactivates native incretins. Pancreatic islet dysfunction is a rational target for the treatment of type 2 diabetes. Incretin mimetics and DPP-4 inhibitors have been shown to improve glucose tolerance and may also hold the potential for improving overall pancreatic islet health. It should be noted, however, that the long-term effect of these agents on glycemic control has not yet been established, and their potential impact on beta-cell function in humans remains an area of active investigation.