New insights into glucose regulation.

This review article describes the regulation of glucose homeostasis in subjects with and without diabetes based on the emergence of new information and discusses modes of action, attributes, and limitations of current diabetes therapies. In normal physiology, glucose homeostasis is tightly controlled by the interaction of pancreatic and gut hormones. Since the 1920s, diabetes has been viewed as a disease caused by deficient secretion of insulin, resulting in reduced glucose uptake and subsequent hyperglycemia. The discovery in the 1950s of the pancreatic hormone glucagon, which opposes insulin by increasing glucose appearance in the circulation, resulted in a bihormonal model of glucose homeostasis. More recently, with the discovery of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) in the 1970s and the pancreatic hormone amylin in the 1980s, it is now understood that several organs and hormones play roles in maintaining glucose homeostasis. Therapies for diabetes have focused on compensation for deficient insulin action through stimulation of insulin secretion, administration of insulin itself, reduction of peripheral insulin resistance, or decreased glucose absorption from the intestine. The discoveries of amylin and GLP-1 have furthered our understanding of the abnormalities involved in diabetes, enabling the development of additional therapeutic options.