ER stress increases store-operated Ca2+entry (SOCE) and augments basal insulin secretion in pancreatic β cells

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting ER stress can lead to b-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on b-cell function remain incompletely understood. To determine the interrelationship between ER stress and b-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response (UPR). b Cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca(2+) oscillations. As ER stress is known to reduce ER Ca(2+) levels, we tested the hypothesis that the observed increase in Ca(2+) oscillations occurred because of reduced ER Ca(2+) levels and, in turn, increased store-operated Ca(2+) entry (or SOCE). TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca(2+) channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mM glucose, YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca(2+) depletion-activated Ca(2+) current in mediating Ca(2+)-induced insulin secretion in response to ER stress.