All-encomPASsing regulation of ß-cells: PAS domain proteins in ß-cell dysfunction and diabetes.

ABSTRACT

As a sensory micro-organ, pancreatic ß-cells continually respond to nutritional signals and neuroendocrine input from other glucoregulatory organs. This sensory ability is essential for normal ß-cell function and systemic glucose homeostasis. Period circadian protein (Per)-aryl hydrocarbon receptor nuclear translocator protein (Arnt)-single-minded protein (Sim) (PAS) domain proteins have a conserved role as sensory proteins, critical in adaptation to changes in voltage, oxygen potential, and xenobiotics. Within ß-cells, PAS domain proteins such as hypoxia inducible factor 1α (Hif1α), Arnt, PAS kinase, Bmal1, and Clock respond to disparate stimuli, but act in concert to maintain proper ß-cell function. Elucidating the function of these factors in islets offers a unique insight into the sensing capacity of ß-cells, the consequences of impaired sensory function, and the potential to develop novel therapeutic targets for preserving ß-cell function in diabetes.