ASSESSING THE ROLE OF GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE TO MEDIATE IMPROVED BETA-CELL FUNCTION FOLLOWING BARIATRIC SURGERY
Bariatric surgery, in addition to promoting weight loss, has been demonstrated to improve hyperglycemia in diabetic patients. Improvements in glucose control following bariatric procedures like gastric bypass and vertical sleeve gastrectomy (VSG) occur prior to weight loss through mechanisms that are not yet described. A potential mechanism for alleviating diabetes following surgery is that of increased signaling by enteric peptides that act on the islet, known as incretins, given observations that patients receiving VSG display stimulated insulin secretion following oral glucose administration. A mouse model of VSG has been developed that mimics the clinical effects of surgery on glucose homeostasis, βcell function, and remarkably, shows stimulation of the β cell receptor for glucose-dependent insulinotropic polypeptide (GIP), a prominent incretin. It is unknown how GIP action in the β cell is regulated following VSG, or whether GIPR mediates the glucose lowering effects of bariatric surgery. Thus, the goal of this proposal is to test the hypothesis that improved glucose tolerance and β cell function after bariatric surgery are mediated by increased GIP action in the β cell. This hypothesis will be addressed through two related aims. The first aim is to assess VSG driven changes to GIP sensitivity in the β-cell by measuring post-VSG insulin secretion in response to exogenous GIP. It is predicted that GIPR signaling will be augmented following VSG. The second aim is to characterize the role of β cell GIPR in improving islet function after VSG by measuring glucose tolerance and insulin secretion in mice with β cell specific deletion of the GIP receptor following surgery. It is predicted that GIPR deletion will mute the VSG effects on glucose control and β cell function. This project employs the robust effects of VSG in mice as a model not only to understand metabolic disease in humans, but also to identify mechanisms necessary for restoring proper islet physiology.
This research is funded by the National Institutes of Health (NIH), National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship Parent F32 (1F32DK115031-01).
Discovering circulating factors responsible for diabetes alleviation after bariatric surgery.
While bariatric surgeries have been developed primarily as a means to treat morbid obesity, there is an emerging consensus that these procedures have an almost wholly unique effect to alleviate diabetes, a disease of impaired glucose control. We have developed a mouse model of vertical sleeve gastrectomy (VSG) that closely mimics this procedure now in high clinical usage. Our studies demonstrate a novel finding that VSG enhances the function of specialized, glucose-sensing β-cellsin the pancreas to secrete insulin, the primary hormone regulating blood glucose. This finding provides a mechanism explaining a large number of clinical observations. In this context it is now clear that bariatric modifications to the gastrointestinal anatomy profoundly modulate β-cellfunction and, subsequently, diabetic status. However, the connection between the gut and the b-cells is not understood. It seems very likely that changes in nutrient flux following surgery are central to this process. This project will employ our validated preclinical model of VSG, the most widely used bariatric surgery in the clinic today. Our primary aim is to characterize global changes in circulating peptides and metabolites during the first week after surgery, a time we have determined is critical to shape b-cell function and glucose control. As a secondary aim we will adapt a cost-effective, clinical, continuous glucose monitoring system (CGSM) to mice to generate real-time measures of substrate flux. The overall goal is to develop new therapeutic approaches to diabetes using the physiologic processes co-opted by bariatric surgery. Secondarily we will establish a novel technical means of studying glucose metabolism in rodent models.