Uncoupling Protein 2 Regulates Daily Rhythms of Insulin Secretion Capacity in MIN6 Cells and Isolated Islets from Male Mice

Objective: Upregulation of uncoupling protein 2 (UCP2) is associated with impaired glucose-stimulated insulin secretion (GSIS), which is thought to be an important contributor to pathological β cell failure in obesity and type 2 diabetes (T2D); however, the physiological function of UCP2 in the β cell remains undefined. It has been suggested, but not yet tested, that UCP2 plays a physiological role in β cells by coordinating insulin secretion capacity with anticipated fluctuating nutrient supply, such that upregulation of UCP2 in the inactive/fasted state inhibits GSIS as a mechanism to prevent hypoglycemia. Therefore, we hypothesized that daily cycles of GSIS capacity are dependent on rhythmic and predictable patterns of gene expression such that low in the active/fed phase promotes maximal GSIS capacity, whereas elevated expression in the inactive/fasted phase supresses GSIS capacity. We further hypothesized that rhythmic expression is required for the maintenance of glucose tolerance over the 24 h cycle.

Methods: We used synchronized MIN6 clonal β cells and isolated mouse islets from wild type (C57BL6) and mice with β cell knockout of (βKO; and respective -cre controls) to determine the endogenous expression pattern of over 24 h and its impact on GSIS capacity and glucose tolerance over 24 h.

Results: A dynamic pattern of mRNA expression was observed in synchronized MIN6 cells, which showed a reciprocal relationship with GSIS capacity in a time-of-day-specific manner. GSIS capacity was suppressed in islets isolated from wild type and control mice during the light/inactive phase of the daily cycle; a suppression that was dependent on in the β cell and was lost in islets isolated from βKO mice or wild type islets treated with a UCP2 inhibitor. Finally, suppression of GSIS capacity by UCP2 in the light phase was required for the maintenance of normal patterns of glucose tolerance.

Conclusions: Our study suggests that /UCP2 in the β cell is part of an important, endogenous, metabolic regulator that controls the temporal capacity of GSIS over the course of the day/night cycle, which, in turn, regulates time-of-day glucose tolerance. Targeting /UCP2 as a therapeutic in type 2 diabetes or any other metabolic condition must take into account the rhythmic nature of its expression and its impact on glucose tolerance over 24 h, specifically during the inactive/fasted phase.