Abstract

Glucose metabolism is closely regulated by the opposing actions of two islet hormones insulin and glucagon.  In health, increased glucose concentrations in blood stimulates insulin and suppresses glucagon secretion, both responses of which are lost early in both type 1 and 2 diabetes. These differential responses to glucose are mediated by glucose metabolism which is perturbed in both beta and alpha cells in diabetes.  We will use Fluorescence lifetime imaging microscopy (FLIM) to measure beta and alpha cell metabolism in living islet cells in vitro and in vivo in islets transplanted into the anterior chamber of the mouse eye. This has the advantage that the islets are not only living, but have a blood supply, and that the same islets can be evaluated after weeks of an intervention. To exploit this option, we will first study islet metabolism (human and mouse islets) transplanted in diabetic compared to nondiabetic mice to determine the role of glucotoxicity on beta and alpha cell metabolism in diabetes. We will then treat the diabetic mice with a glucose lowering therapy that does not have a direct effect on islets (SGLT2 inhibitor) and repeat the measured islet metabolism to establish the extent to which metabolic remodeling induced by glucose toxicity is reversible. Collectively these studies will bring a new state of the art technology to the diabetes field while providing an excellent platform for the applicant to train in a wide range of aspects of islet biology.