Unravelling the regulatory mechanisms of rhythmic insulin secretion: A physiological role for UCP2?

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Glucose tolerance over a 24hr cycle displays daily variations due to robust and predictable fluctuations in the capacity of the ß cell to secrete insulin. Currently, very little is known about the regulation of rhythmic insulin secretory capacity over 24hr cycles. The LONG-TERM OBJECTIVES OF MY RESEARCH PROGRAM are define the mechanistic pathways that regulate daily fluctuations in insulin secretion and ultimately glucose homeostasis over 24hrs, with a particular focus on the factors that couple metabolism to the control of insulin. Uncoupling protein 2 (UCP2) expression in the ß cell is associated with reduced glucose-stimulated insulin secretion (GSIS) and elevated basal insulin secretion (BIS). While some hypotheses have emerged regarding the function of UCP2 in the ß cell, the majority of these studies have used either stressed/diseased states or supra-physiological conditions to assess UCP2 function in the ß cell. A physiologically relevant function for UCP2 in the healthy ß cells remains to be elucidated. The SHORT-TERM OBJECTIVES OF THIS DISCOVERY GRANT are to define a physiological function for UCP2 in healthy ß cells by examining its role in the regulation of daily rhythms of insulin secretion, to define a mechanism by which UCP2 contributes to the control of daily rhythms of insulin secretion, and to explore the biological rhythms that drive daily rhythms of UCP2 expression. GENERAL SCIENTIFIC APPROACH: Our overall HYPOTHESIS is that UCP2 in the ß cell is dynamic and is an important regulator of rhythmic insulin secretion and ultimately glucose homeostasis over 24hrs. Studies utilizing well-established cell-based and mouse model systems (MIN6 cells and a ß cell-specific UCP2 knockout mouse, respectively) will be performed to determine 24hr rhythms of insulin secretion capacities, mitochondrial bioenergetics, gene expression analyses, glucose tolerance, plasma hormone levels and reactive oxygen species signalling profiles. The mechanistic contribution of UCP2 to daily cycles of GSIS and BIS will be explored using these techniques. The impact of the circadian clock and feeding rhythms on rhythmic UCP2 will also be explored to determine the driving force behind daily rhythms of UCP2. EXPECTED SIGNIFICANCE: This study will allow us to define, for the first time, a relevant physiological function for UCP2 in the ß cell, while also creating excellent training opportunities for HQP. It is anticipated that the knowledge gained from this study will pave the way for future studies to define other novel regulators of rhythmic insulin secretion and ultimately broaden our understanding of the fundamental mechanisms of insulin secretion regulation and glucose homeostasis, and importantly, allowing pursuit of the long-term objectives of my research program.