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, ?-cell function, and remarkably, shows stimulation of the ?-cell receptor for glucose-dependent insulinotropic polypeptide (GIP), a prominent incretin. It is unknown how GIP action in the ?-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 ?-cell function after bariatric surgery are mediated by increased GIP action in the ?-cell. This hypothesis will be addressed through two related aims.
The first aim i s to assess VSG driven changes to GIP sensitivity in the ?-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 i s to characterize the role of ?-cell GIPR in improving islet function after VSG by measuring glucose tolerance and insulin secretion in mice with ?-cell specific deletion of the GIP receptor following surgery. It is predicted that GIPR deletion will mute the VSG effects on glucose control and ?-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. Finally, the project will provide a rich training experience that merges cell biology and translational systems, laying a foundation for future, independent research.
This research is focused on understanding diabetic alleviation following the bariatric surgery vertical sleeve gastrectomy, while preparing the trainee for an autonomous research career in metabolic disease. Interventions like vertical sleeve gastrectomy have been demonstrated to consistently improve glycemic control in patients prior to significant weight loss, making these procedures an excellent model for understanding and enhancing the functionality of insulin secreting ?-cells. Ultimately these studies will characterize the regulation and improvement of ?-cell function following vertical sleeve gastrectomy, while potentially identifying therapeutic or pharmacological targets to improve glucose control in diabetic patients without invasive surgical intervention.
| Douros, Jonathan D; Lewis, Alfor G; Smith, Eric P et al. (2018) Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a ?-Cell Glucagon-Like Peptide 1 Receptor. Diabetes 67:1504-1511 |
| Douros, Jonathan D; Baltzegar, David A; Reading, Benjamin J et al. (2018) Leptin Stimulates Cellular Glycolysis Through a STAT3 Dependent Mechanism in Tilapia. Front Endocrinol (Lausanne) 9:465 |
| Douros, Jonathan D; Baltzegar, David A; Mankiewicz, Jamie et al. (2017) Control of leptin by metabolic state and its regulatory interactions with pituitary growth hormone and hepatic growth hormone receptors and insulin like growth factors in the tilapia (Oreochromis mossambicus). Gen Comp Endocrinol 240:227-237 |
