The Effect of Chloroquine on the Binding, Intracellular Distribution, and Action of Insulin on Isolated Mouse Pancreatic Acini

The effects of chloroquine on the binding, intracellular distribution, and action of insulin were studied in isolated pancreatic acini prepared from diabetic mice. Chloroquine had three effects on these cells. First, chloroquine altered cellular morphology by inducing an increase in the number and size of autophagic vacuoles and vesicles in the Golgilysosomal region. Second, chloroquine, in a dose-dependent fashion, increased the amount of ¹²⁵I-insulin associated with acini. A detectable effect of chloroquine was seen at 10 μM, and a maximal effect was seen at 30–100 μM where cell-associated insulin was more than doubled. Employing electron microscope autoradiographs, this accumulation of hormone was observed in the Golgilysosome area of the pancreatic acinar cell. Third, chloroquine had selective effects on the action of insulin. Preincubation with chloroquine had no effect on basal [³H]2-deoxy-D-glucose uptake, but in a dose-dependent fashion it decreased the stimulatory effect of insulin on this function; at 100 μM chloroquine, the effect of insulin was abolished. In contrast, chloroquine had negligible effects on the stimulation of 2-deoxy-D-glucose uptake into acini by cholecystokinin. Chloroquine in dose-dependent fashion partially inhibited basal [³H]leucine incorporation into acinar cell protein, but in contrast to its effects on 2-deoxy-D-glucose uptake, the drug had no effects on the stimulation of this function by insulin. These data indicate, therefore, that: (1) chloroquine alters the morphology of pancreatic acini by increasing the size and number of autophagic vesicles and vacuoles in the Golgilysosomal area; (2) chloroquine increases the accumulation of insulin into these structures; and (3) chloroquine selectively blocks the action of insulin on 2-deoxy-D-glucose uptake.