Orexin regulates glucose homeodynamics with daily rhythm

Daily rhythm of glucose metabolism is tightly controlled by circadian systems, and entrained to sleep/wake cycles. Chronic sleep disturbance causes insulin resistance and increased risk of type 2 diabetes. Thus, synchronizing the daily rhythm of glucose metabolism with biological clock, sleep/wake cycle, and feeding cycle is required for maintaining glucose homeostasis, although the coordination mechanism remains unclear. A hypothalamic neuropeptide, orexin, contributes to maintenance of glucose and energy homeostasis, in addition to stabilization of sleep/wake cycle. Here we summarized current knowledge about the role of hypothalamic orexin system in dynamic regulation of glucose homeostasis, namely, glucose homeodynamics at physiological and pathophysiological states. Importantly, the levels of orexin per se oscillate with a daily rhythm in the central nervous system under the control of biological clock. Based on this rhythm, orexin promotes to generate daily blood glucose oscillation through bidirectional regulation of hepatic glucose production, as well as sleep/wake cycle. The glucose oscillation not only helps adequate supply of energy at the time of awakening but also effectively prevents insulin resistance caused by aging, obesity, and depression. Therefore, we would like to propose a novel concept of chronotherapy to treat type 2 diabetes by targeting hypothalamic orexin system.