Gastrointestinal regulatory peptides have long been known to play an important role in postprandial release of insulin, and glucose-dependent insulinotropic polypeptide is one of two incretins that has been thoroughly investigated. Within the last few years, great progress has been made in understanding the physiologic properties of glucose-dependent insulinotropic polypeptide and its potential use as a therapeutic modality for type 2 diabetes mellitus and obesity. Although glucose-dependent insulinotropic polypeptide possesses insulinotropic properties, its insulin-stimulatory effect is diminished in type 2 diabetic patients, but the mechanisms for this observation remain unclear. Recent studies have suggested a possible genetic defect in meal-stimulated glucose-dependent insulinotropic polypeptide release in diabetic patients and their first-degree relatives, but other mechanisms, including a decrease in glucose-dependent insulinotropic polypeptide receptor number on the pancreatic islet &bgr; cells, shorter glucose-dependent insulinotropic polypeptide half-life, and chronic desensitization of the glucose-dependent insulinotropic polypeptide receptor because of elevated serum glucose-dependent insulinotropic polypeptide levels, may also contribute to this phenomenon. Moreover, the glucose-dependent insulinotropic polypeptide receptor is expressed in adipose tissue, and glucose-dependent insulinotropic polypeptide stimulates lipoprotein lipase activityin vitro, suggesting a potent role of glucose-dependent insulinotropic polypeptide in modulating fat metabolism. In glucose-dependent insulinotropic polypeptide receptor knockout mice, triglyceride synthesis in the adipocyte was found to be significantly impaired. Furthermore, glucose-dependent insulinotropic polypeptide receptor knockout mice did not develop obesity or insulin resistance when fed a high-fat diet. These data indicate that glucose-dependent insulinotropic polypeptide may govern the disposition of fat in the adipose tissue, and they suggest that a glucose-dependent insulinotropic polypeptide antagonist may be useful in preventing obesity.