Glucose-Dependent Insulinotropic Polypeptide in Incretin Physiology: Role in Health and Disease

Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid hormone that is synthesized and released from upper intestinal enteroendocrine K cells in response to the ingestion of glucose or fat. The structure of GIP places it in the secretin/vasoactive intestinal polypeptide family of gastrointestinal regulatory peptides. Although originally named "gastric inhibitory polypeptide" on the basis of its ability to inhibit gastric acid secretion, GIP accounts for 60% to 80% of the postprandial insulin response, consistent with the notion that this regulatory peptide constitutes the principal physiological incretin. Under normal conditions, GIP plays a major role in nutrient deposition and storage, both directly through its insulin-mimetic properties and indirectly by enhancing insulin release. GIP is overexpressed in obese individuals, which may exacerbate insulin resistance manifested by many patients with type 2 diabetes mellitus. Enhanced postprandial secretion of GIP also initiates a vicious cycle characterized by increased nutrient uptake and storage in adipocytes, leading to insulin resistance and hyperinsulinemia, which then further increases adipocyte nutrient uptake and storage. Despite the deleterious consequences of GIP overexpression, when combined with glucagon-like peptide-1 analogues, GIP agonism has been demonstrated to provide benefit in treating obesity by mechanisms currently not fully elucidated. In contrast, consistent with the etiologic role of GIP overexpression in the pathogenesis of obesity, both genetic abrogation and immunoneutralization of GIP signaling have been shown to reduce the development of obesity in preclinical models. Whether these beneficial effects of GIP antagonism will be extended to humans needs to be determined.