Fellowship for Nathan Vanderford: Regulation of the Glucose-Dependent Expression of MafA in Pancreatic Beta Cells

Maintaining a correctly balanced level of blood glucose, or maintaining glucose homeostasis, is crucial to ensure proper metabolism and energy balance within the body. Defects in the regulation of glucose homeostasis can lead to the development of diabetes and to the secondary complications associated with this disease such as cardiovascular disease and stroke. The hormone insulin is a major regulator of glucose homeostasis. Insulin stimulates glucose uptake into tissues such as muscle and fat. Insulin stimulated glucose uptake lowers blood glucose levels, which maintains glucose homeostasis in nondiabetics. Insulin production and secretion is achieved through several molecular mechanisms within pancreatic beta cells including cellular signaling and transcriptional events. Inasmuch, the beta cell-enriched transcription factor MafA is a key regulator of insulin production and insulin secretion. Interestingly, the synthesis of MafA itself is known to be up-regulated in response to high glucose concentrations, but the mechanism controlling this event is not fully understood. Therefore, this proposal aims to characterize the cellular mechanisms which ultimately regulate the expression of MafA. Our preliminary data suggest that MafA expression is mediated by both transcriptional and post-translational mechanisms. Moreover, our data suggest that distinct signaling events are mediating both the up-regulation of MafA under high glucose conditions as well as its down-regulation under low glucose conditions. Thus, we hypothesize that high glucose levels activate/inactivate specific signaling cascades that enhance the production of MafA while concurrently shutting off post-translational mechanisms that normally lead to the degradation of MafA protein under low glucose conditions. We will address this hypothesis through two Specific Aims: 1) To delineate the signaling events regulating MafA expression in beta cells and 2) To analyze the mechanisms regulating the degradation of MafA protein under low glucose conditions. Understanding the mechanisms responsible for the glucose-dependent expression of MafA will provide greater insight into how glucose homeostasis is maintained considering the role MafA plays in insulin synthesis and insulin secretion. As such, our study may lead to the elucidation of proteins and/or signaling pathways that can act as targets for the development of novel diabetes therapies.