Enhancing the Action of Incretin Hormones: A New Whey Forward?

The gastrointestinal tract is an often overlooked but complex endocrine organ, home to dozens of regulatory peptides produced in specialized endocrine cells and enteric neurons. These hormones subserve complex roles as signals regulating appetite, gastrointestinal motility, control of secretion from the exocrine and endocrine pancreas, and nutrient absorption (1). The majority of gut peptides are secreted within minutes of nutrient ingestion and rise transiently in the circulation, with levels rapidly falling back to basal levels after termination of feeding. Because complex disorders such as obesity and diabetes involve imbalances in the control of energy ingestion and disposal, there is considerable interest in understanding the physiological role and therapeutic potential of gut peptides in the control of nutrient assimilation. Two enteroendocrine-derived peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play important roles in preparing the pancreas to handle an incoming nutrient load. Both GIP and GLP-1 function as incretin hormones, gut-derived peptides that potentiate insulin secretion from the islet β-cell in a glucose-dependent manner (2, 3). Considerable recent evidence suggests that incretin-based therapies may be useful for the treatment of type 2 diabetes because continuous administration of GLP-1 produces substantial improvements in glucose control and β-cell function in subjects with type 2 diabetes (4). However, the rapid degradation of both GIP and GLP-1 by the aminopeptidase, dipeptidyl peptidase-4 (DPP-4), has fostered the development of degradation-resistant GLP-1R agonists such as exendin-4 (Exenatide), now employed as a twice daily injectable agent for the treatment of type 2 diabetes (5). Complementary efforts to prolong incretin action include the use of chemical inhibitors of DPP-4 activity, and several DPP-4 inhibitors have completed extensive clinical testing in subjects with type 2 diabetes.