Sex dependent function of the orphan nuclear receptor Nr4a1 in the pancreatic beta cell during Type 2 Diabetes disease progression

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A central aspect of type 2 diabetes disease progression is impaired functional beta cell mass. The hyperglycemic and hyperlipidemic environment present in type 2 diabetes corresponds with impaired beta cell function. The orphan nuclear receptor Nr4a1 is critical for fuel utilization in various tissues, however little is known regarding its function in the beta cell. Nr4a1 expression is decreased in the beta cell of rodent models of type 2 diabetes, as well as in primary human islets from type 2 diabetic patients. Our preliminary data demonstrate that beta cell specific Nr4a1 deletion in the context of high fat feeding results in impaired glucose tolerance in female mice. While there is a clear connection between Nr4a1 and type 2 diabetes disease progression in female mice, there is a fundamental gap in our understanding of Nr4a1 in the beta cell in terms of 1) the effect of estrogen signaling on Nr4a1 in female beta cells, 2) the transcriptional changes dependent on Nr4a1 loss in the context of high fat feeding that lead to glucose intolerance, and 3) how these observed phenotypes apply to beta cell function in gestational diabetes. These gaps hinder the rationale design of targeted therapies to improve functional beta cell mass as a treatment for type 2 diabetes in women. The long-term goal is to develop strategies to improve beta cell function, proliferation and survival to improve patient outcomes. The overall objective of this proposal is to determine the mechanism by which beta cell Nr4a1 loss results in high fat diet mediated impaired glucose tolerance in females. Our central hypothesis is that Nr4a1 is a key downstream target of estrogen signaling in the beta cell, and that Nr4a1 loss under high fat feeding predisposes the animal to beta cell failure and ultimately impaired glucose tolerance and diabetes. Guided by our preliminary data, this hypothesis will be tested in the following specific aims: Aim 1: Determine the effect of estrogen signaling on Nr4a1 expression in the beta cell. Aim 2: Determine the Nr4a1 mediated transcriptional changes in the beta cell that impair glucose tolerance in high fat fed females. Aim 3: Determine the effect of Nr4a1 beta cell deletion in a mouse model of gestational diabetes. The proposal is innovative because it elucidates novel functions of Nr4a1 regulation by estrogen in the female beta cell. The proposed research is significant because it fills fundamental gaps in our understanding of an understudied beta cell regulator, Nr4a1, its regulation by the estrogen signaling pathway, and the link to increased type 2 diabetes in postmenopausal women and gestational diabetes in pregnant women.