Pathophysiology of type 2 diabetes and the role of incretin hormones and beta-cell dysfunction.
Type 2 diabetes is a heterogeneous, polygenic disorder in which dysfunction in a number of important metabolic pathways appears to play roles. Although it remains unclear exactly which event triggers the disorder, beta-cell dysfunction is a key element in the underlyingpathophysiology. Both impaired insulin secretion and insulin resistance contribute to the hyperglycemic state that causes the devastating cardiovascular, neurologic, and renal effects characteristic of type 2 diabetes. To prevent these complications, the American Diabetes Association recommends maintaining A1C levels below 7%. A1C has long been the target of diabetes therapy, and while this remains true in those with A1C levels above 8.4%, it is now apparent that in those with mild to moderate diabetes, postprandial glucose excursions may be of greater importance. Postprandial hyperglycemia occurs in 74% of those diagnosed with diabetes and 39% of those with optimal A1C levels. Involvement of impaired alpha-cell function has recently been recognized in the pathophysiology of type 2 diabetes. As a result of this dysfunction, glucagon and hepatic glucose levels that rise during fasting are not suppressed with a meal. Given inadequate levels of insulin and increased insulin resistance, hyperglycemia results. The incretins are important gut mediators of insulin release, and in the case of GLP-1, of glucagon suppression. Although GIP activity is impaired in those with type 2 diabetes, GLP-1 insulinotropic effects are preserved, and thus GLP-1 represents a potentially beneficial therapeutic option. However, like GIP, GLP-1 is rapidly inactivated by DPP-IV in vivo. Two therapeutic approaches to this problem have been developed: GLP-1 analogs with increased half-lives, and DPP-IV inhibitors, which prevent the breakdown of endogenous GLP-1 as well as GIP. Both classes of agent have shown promise, with potential not only to normalize fasting and postprandial glucose levels but also to improve beta-cell functioning and mass.
Fujioka
Ken
K
Center for Weight Management, Scripps Clinic, Department of Endocrinology and Diabetes, San Diego, CA, USA.
D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D018450:Disease Progression; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D054795:Incretins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D010182:Pancreatic Diseases / Q000378:metabolism / Q000503:physiopathology*; D019518:Postprandial Period
D054795:Incretins; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1