Quin 2 and Manganese Define Multiple Alterations in Cellular Calcium Homeostasis in Diabetic Rat Pancreas

The effects of streptozocin-induced diabetes on Ca²⁺ fluxes and intracellular free-Ca2+ ([ Ca²⁺]_i) levels were studied in isolated rat pancreatic acini. The basal rates of ⁴⁵Ca influx in acini and of ⁴⁵Ca efflux from acini that were preloaded with ⁴⁵Ca were similar in normal and diabetic rats. The gastrointestinal hormone cholecystokinin octapeptide (CCK-8, 0.1 nM) and the Ca²⁺ ionophore A23187 (2 μM) increased ⁴⁵Ca influx to the same extent in both groups of acini. CCK-8 and the divalent cation manganese exerted marked stimulatory effects on ⁴⁵Ca efflux. In contrast to the rapid effect of CCK-8 on ⁴⁵Ca efflux, the effect of manganese was slow in onset and was greater in diabetic rat acini. The diabetic state was also associated with a significant decrease in resting [Ca²⁺]_i levels, as determined with the Ca²⁺ indicator quin 2. Furthermore, the ability of CCK-8 to raise [Ca²⁺]_i levels was significantly attenuated in these cells. Insulin did not alter either basal or CCK-8–mediated increases in [Ca²⁺]_i levels. Our findings suggest that insulin deficiency is associated with multiple alterations in Ca²⁺ homeostasis in the pancreatic acinar cell. These include a decrease in basal [Ca²⁺]_i levels, perturbations in the signal transduction system that mediates the rapid mobilization of [Ca2+]_i after CCK-8–receptor binding, and enhanced sensitivity to the actions of manganese on intracellular Ca²⁺ pools.