#61 Investigating the role of the circadian clock in control of daily cycles of insulin secretion.
Nivedita Seshadri, Child Health research institute, University of Manitoba; Tianna Flett, Child Health reseach institute; Youstina Soliman, University of Manitoba; Yilin Tian, University of manitoba; Michael E. Jonnason, Child Health Research Institute; Kristin Hunt, Child Health research instute Manitoba; Bo Xiang, Child Health Institute research Manitoba; Vernon Dolinsky, University of Manitoba; Christine Doucette, University of Manitoba
Manitoban Indigenous youth are disproportionately affected by Type 2 Diabetes (T2D). Pancreatic β cell failure is central to T2D, therefore it is critical that we understand how the β cell works so that we can appropriately restore β cell function in those affected by T2D. Our recent study shows that daily cycles of insulin secretion are needed to maintain glucose tolerance over 24hrs and that a mitochondrial protein, called uncoupling protein 2 (UCP2), is an important regulator of daily insulin secretion cycles. We now aim to test the hypothesis that the circadian clock machinery ultimately drives Ucp2 expression and controls daily cycles of insulin secretion.
BMAL1, a core component of the circadian clock machinery, was silenced in MIN6 clonal β cells by Bmal1siRNA and used to determine the impact of circadian dysfunction on temporal Ucp2 mRNA expression, glucose-stimulated insulin secretion (GSIS) and ATP production (an important triggering molecule of GSIS).
Bmal1 knockdown impaired rhythmic GSIS by increasing Ucp2 expression 2.4-fold 4 hours post-synchronization, which was the same expression level observed at 16 hours (i.e. chronically upregulated Ucp2). Upregulation of Ucp2 was associated with reduced ATP production over 24hrs, indicative of chronically increased mitochondrial uncoupling.
The circadian clock regulates daily cycles of Ucp2 expression in MIN6 cells, which is a part of an important metabolic switch needed to align time-of-day insulin secretion capacity with 24hr glucose tolerance. T2D treatments must account for daily cycles of insulin secretion to fully restore pancreatic function in the diabetes state. In future, we will generate β cell-specific Bmal1 knockout mice to examine the impact of these cycles in whole animals.