Circadian disruption, the bane of modern lifestyle, has been strongly associated with diabetes and metabolic syndrome. Recent human studies also implicate b-cell dysfunction as a significant component of the metabolic abnormalities. It is, therefore, imperative to understand the interaction between the circadian clock and regulation of ?-cell function for the preservation of insulin secretion 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 ?-cell failure and diabetes, secondary to impaired glucose-stimulated ATP production, uncoupling of OXPHOS and impaired glucose-stimulated insulin secretion (GSIS). However, whether the intrinsic ?-cell clock is required for adaptive stress responses in ?-cells is unknown. In preliminary studies, we demonstrate that central clock disruption induced by shift work simulation, phenocopies genetic disruption of Bmal1 in ?-cells in inducing Unfolded Protein Response (UPR), upregulation of the pro-apoptotic gene CHOP, suggestive of irremediable ER stress in ?-cells, and is accompanied by impaired GSIS. Importantly, mice with a deletion of Bmal1 in ?-cells become diabetic due to ?-cell failure. Surprisingly, deletion of Rev-erb?, a negative regulator of clock function and a Bmal1 target gene, leads to similar induction of unfolded protein response (UPR) in ?-cells. We also show that ATF4, a key transcription factor involved in UPR, displays circadian rhythmicity in expression and is a direct transcriptional target of Bmal1. We, hence, hypothesized that intrinsic ?-cell clock regulators, Bmal1 and Rev-erb?, coordinate the adaptive UPR pathway, through transcriptional control of its key components, to mitigate ER stress. The broad goal is to delineate key circadian clock-regulated pathways in ER stress-induced ?-cell dysfunction through genetic, environmental and pharmacological modulation of the molecular clock. We will specifically 1. Test if circadian disruption is sufficient to induce ER stress and ?-cell failure b dissecting the differential role of the central and peripheral clocks on ER stress and ?-cell function. We will also determine the cell-autonomous role of the molecular clock in ER stress in ?-cells 2. Define the transcriptional targets of Bmal1 and Rev-erb? in UPR and ER stress in ?-cells and 3. Test if the circadian clock regulates ER stress adaptive responses and insulin secretory response in human islets. We will also test if pharmacological modulation of the molecular clock can rescue adaptive stress signaling in diabetic patient islets. Collectively, the proposed studies will critically address how the molecular clock regulates ER stress and ?-cell homeostasis and will lead to novel insights into circadian clock regulated adaptive stress pathways in ?-cells. We envision that the results from this study will lead to discovery of targeted therapies to modulate circadian clock function for the preservation of ?-cell function in combating diabetes.
Circadian rhythm perturbations in humans have been associated with metabolic syndrome and diabetes, with recent studies specifically implicating circadian genes in b- cell function and diabetes. With compelling data demonstrating that disruption of the intrinsic b-cell clock causes endoplasmic reticulum stress, b-cell failure and diabetes, we propose to identify and dissect molecular mechanisms that link circadian clock function with b-cell stress responses. Understanding the regulatory role of the circadian clock in regulation of adaptive responses to b-cell stress, will help develop novel therapies that prevent and reverse b-cell failure and diabetes.
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