UCLA

The circadian system plays an essential role in regulation of glucose homeostasis, and the disruption of this system leads to deleterious health consequences, such as Type 2 Diabetes Mellitus (T2DM). Disruption of circadian organization in humans is strongly associated with development of metabolic dysfunction and increases the propensity for development of T2DM. Importantly, the correlation between circadian disruption and T2DM is partly attributed to loss of beta-cell function and mass, called beta-cell failure. To address this association, we first hypothesized that exposure to environmental conditions associated with disruption of circadian rhythms and susceptibility to T2DM in humans disrupts islet clock and beta-cell function. We reported that prolonged exposure to LL disrupts islet circadian clock function through impairment in the amplitude, phase, and interislet synchrony of clock transcriptional oscillations. We also reported that exposure to LL leads to diminished glucose-stimulated insulin secretion due to a decrease in insulin secretory pulse mass. Second, obesity-mediated insulin resistance is an important contributory factor to induction and progression of T2DM. We, therefore, hypothesized that disruption of circadian rhythms compromises pancreatic beta cell functional and morphological adaption to diet-induced obesity leading to development of T2DM. We found that concomitant exposure to LL and HFD resulted in development of hyperglycemia characterized by loss of circadian rhythms in insulin secretion, compromised beta cell function, and induction of beta cell apoptosis, suggesting that circadian disruption and diet-induced obesity synergize to promote development of beta cell failure, likely mediated as a consequence of impaired beta cell clock function. Third, as accumulating evidence pointed out that metabolic signals can feed back into the circadian system, we tested whether the impaired glucose homeostasis disturbs the circadian system in return. We examined the expression of circadian rhythms in the human islet amyloid polypeptide transgenic (HIP) rats: a validated non-obese, beta-cell dysfuntion model of T2DM. Diurnal and circadian rhythms of locomotor activity, circadian entrainment, and clock gene oscillation in SCN, pancreatic islets and aorta all remains intact in the HIP rats. In summary, these studies examined mechanisms by which circadian disruption predisposes to beta-cell failure in the development of T2DM. We also showed that glucose intolerance caused by beta-cell dysfunction might not be sufficient to cause circadian deficits, which emphasized the causal role of circadian disruption in the development of T2DM.