Insulin secretion, myo-inositol transport, and Na⁺-K⁺-ATPase in glucose-desensitized rat islets

Glucose-induced insulin secretion is desensitized during long-term exposure of pancreatic islet β-cells to elevated glucose levels. This study characterizes an in vitro model of glucose-induced desensitization in cultured isolated islets of the rat. Insulin secretion in desensitized islets cultured with 11 mM glucose for 4-7 days was progressively reduced compared with the normal freshly isolated (fresh) islets. When desensitized islets were returned to a basal concentration of glucose (5.5 mM) for up to 2 h, the glucose sensitivity of insulin secretion was restored to normal (recovered islets). Carbachol and L-arginine also reversed the effects of desensitization. However, basal insulin release was elevated in desensitized and recovered islets. Sodium-dependent myo-inositol uptake was reduced during desensitization by up to 49% within 4 days, myo-Inositol uptake was restored to normal in a time-dependent manner during recovery of islets at 5.5 mM glucose. The recovery of myo-Inositol uptake paralleled that of insulin release. The apparent transport constant for myo-inositol uptake was significantly increased during desensitization, whereas the maximum uptake was not changed, myo-Inositol supplementation (35 or 250 μM) during islet culture did not alter myo-inositol uptake or insulin secretion in desensitized islets. Na⁺-K⁺-ATPase activity, but not 5′-nucleotidase activity, in desensitized islets was also inhibited by 65 and 47% when compared with fresh islet and recovered islet Na⁺-K⁺-ATPase activity, respectively. Thus, cultured islets represent an appropriate model to study biochemical parameters associated with the onset and reversibility of glucose desensitization of insulin secretion. Alterations in Na⁺-K⁺-ATPase activity and coupled myo-inositol uptake during desensitization may contribute to the defective pattern of insulin release in this model.