The body circadian system governs our physiology to anticipate daily changes in geophysical time. There is accumulating evidence attributing a critical role to the cell-autonomous oscillators operative in different metabolic organs in regulation of glucose homeostasis. This work proposes a functional link between the molecular clocks of the endocrine pancreas and the pancreatic islet gene transcription and hormone secretion under physiological conditions, and in the pathogenesis of type 2 diabetes (T2D) in humans and mouse models. We provide detailed characterisation of core-clock and clock-related genes in mouse and human glucagon- producing α-cells and insulin-producing β-cells. Our experiments demonstrate that clock disruption in human islet α- and β-cells impairs the accumulation and exocytosis of insulin and glucagon granules. Furthermore, we observed that circadian oscillators operative in the islets from donors suffering from T2D bear reduced circadian amplitude and compromised synchronization capacity in vitro. Noteworthy, the clock modulator Nobiletin partly restores the amplitude of circadian oscillations concomitant with secretion of insulin by these T2D islets. Moreover, we provide evidence on circadian regulation of lipid metabolism and membrane fluidity in human pancreatic islets that are perturbed upon T2D, highlighting that circadian orchestration of sphingolipid metabolites in human pancreatic islets contributes to regulation of insulin secretion and membrane fluidity. Finally, we report that β-cell regeneration in diabetic mice exhibits daily rhythms, with the core-clock protein BMAL1 playing essential role in this conjunction.

Within the frame of circadian endocrinology, new perspectives are discussed aimed at studying of inter-organ circadian desynchrony following solid organ transplantation and its role in development of T2D, as well as at characterisation of human parathyroid cell clocks and its role in function and dysfunction of the parathyroid glands.