Role of T-type calcium channels in basal [calcium(2+)](i) and insulin secretion in pancreatic beta-cells under hypergyclemia

Hyperinsulinemia is a commonly associated with type II diabetes, this hyperinsulinemia often precedes the clinical diagnosis of type II diabetes by several years. It is believed that hyperinsulinemia is the mechanism by which the pancreatic beta-cell compensates for deteriorating peripheral insulin sensitivity. It has been shown that hyperinsulinemia accompanies an increase in the basal intracellular concentration of calcium ([Ca2+ ]i) in the pancreatic beta-cell. This increase in basal [Ca2+]i is detrimental to the pancreatic beta-cell. If these two events are links and the exact mechanism of both is currently not understood. In the present study we investigated if these two events are linked by the T-type Ca2+ channel. Since there are no available selective T-type Ca2+ channel antagonists, we set forth to develop both a compound and utilizing a new technique small interfering RNA (siRNA) to complete this study. We found that T-type Ca2+ channels were upregulated in hyperglycemia both at the mRNA and current level. Next, we discovered that the increase in basal [Ca2+]i was linked to T-type Ca2+ channels and that antagonizing them basal [Ca2+]i could be reduced to control levels. By taking advantage of a dual patch clamp/calcium imaging technique, T-type Ca2+ channel mediated window current was the mechanism in which T-type Ca2+ channels increased basal [Ca2+ ]i. Additionally we found that antagonism of T-type Ca2+ channels decreased basal insulin secretion. Taken together this data suggest that T-type Ca2+ channels play a role in both basal insulin release and basal [Ca2+]i in rat pancreatic beta-cells under conditions of hyperglycemia.