Circadian disruption-induced mitochondrial dysfunction in diabetes

昼夜节律紊乱与糖尿病和代谢综合征密切相关。最近的人体研究

Circadian disruption has been strongly associated with diabetes and metabolic syndrome. Recent human studies implicate β-cell dysfunction as a potential mechanism underlying the increased risk for diabetes with circadian disruption. It is, therefore, imperative to understand the interaction between the circadian clock and regulation of β-cell function to prevent diabetes. We have shown previously that genetic disruption of the circadian clock, by deletion of Bmal1, a non-redundant core clock gene, in mice, leads to β-cell failure and diabetes, secondary to impaired glucose-stimulated ATP production, uncoupling and impaired glucose-stimulated insulin secretion (GSIS). β-cells, normally, need to be “metabolically flexible” in being able to switch between substrates for energy production. However, it is unknown if circadian clock regulates this metabolic flexibility in β-cells. Our preliminary data suggests that circadian disruption, even for short periods, via an upregulation of Pdk (pyruvate dehydrogenase kinase), restricts pyruvate entry into mitochondria for oxidation and induces metabolic inflexibility, and impairment in glucose utilization by the pancreatic β-cells leading to diabetes. The overarching hypothesis for this proposal is that the circadian clock orchestrates the metabolic pathways in β-cells to ensure efficient stimulus-secretion coupling. New data from our lab indicates that circadian disruption leads to metabolic inflexibility in the β-cell wherein it is unable to utilize glucose effectively. We hence hypothesize that circadian disruption leads to impaired mitochondrial function resulting in impaired substrate utilization, metabolic inflexibility leading to β-cell failure and diabetes. We will use environmental means to induce circadian disruption in mice, complemented by inducible and β-cell specific genetic deletion and overexpression models of molecular clock (Bmal1 and Rev-erb alpha) along with pharmacological and genetic modulation of the molecular clock and the proposed target pathways including Pdk in human and mouse islets, to test mechanisms underlying the β- cell failure seen with circadian disruption, especially as it relates to substrate oxidation. We will use pharmacological interventions to target specific disrupted pathways to restore metabolic flexibility in circadian disrupted β-cells. The specific aims of the proposal are: (1) To test if circadian disruption leads to mitochondrial dysfunction and metabolic inflexibility in β-cells, using environmental and genetic circadian disruption models and investigate if Rev-erb alpha-Pdk axis mediate the circadian regulation of substrate utilization in β-cells. (2) To delineate circadian clock regulation of mitochondrial function in normal human β-cells and alteration in diabetic state using loss-of and gain-of-function studies of the molecular clock in normal and diabetic human islets. (3) Test targeted pharmacological interventions to reverse circadian disruption-induced β-cell mitochondrial dysfunction. This proposal will decipher the underlying mechanisms of β-cell failure with circadian disruption in mouse models, test their applicability in human islets and look at targeting specific pathways to improve β-cell function that lead to therapies to prevent and treat diabetes.