Phosphate depletion (PD) is associated with resistance to the peripheral action of insulin and with glucose intolerance. However, data on the effect of PD on insulin secretion are not consistent, and were derived indirectly by measurements of blood levels of insulin during intravenous glucose tolerance test (IVGTT) or with hyperglycemic clamp technique. Direct evidence for an effect of PD on insulin secretion by pancreatic islets is not available, and the potential mechanisms through which PD may affect insulin secretion are not known. We performed IVGTT, examined in vitro insulin secretion by pancreatic islets, and evaluated various factors involved in insulin secretion in PD and pair weighed (PW) rats. PD animals had fasting hyperglycemia and normal plasma insulin levels, and displayed abnormal IVGTT as compared to PW rats. Both initial and late phases of D-glucose-induced insulin secretion from islets were markedly and significantly (P < 0.01) lower than from islets of PW rats. In contrast, D-glyceraldehyde-induced insulin release in PD rats was similar to that of PW rats. [H3]2-deoxyglucose uptake by islets and their cyclic AMP content after exposure to D-glucose, D-glyceraldehyde or forskolin were not different among the two groups of animals. Insulin content in PD islets was modestly but significantly (P < 0.01) higher than PW islets. In PD islets, ATP content and the ATP/ADP ratio at basal state and after incubation with 16.7 mM D-glucose were significantly (P < 0.01) lower and resting cytosolic calcium was significantly (P < 0.01) higher than in PW islets. Lactic acid output by islets from PD rats was significantly (P < 0.01) less than that from islets of PW rats. The data show that: 1) PD rats have glucose intolerance and marked reduction in insulin secretion; 2) resting cytosolic calcium of pancreatic islets of PD rats is elevated; 3) the defect in insulin secretion is not due to abnormal glucose uptake or cAMP production by or insulin content of the islets but due to a reduced ATP content, elevated resting cytosolic calcium and/or defective glucose metabolism by the islets. This latter defect is most likely due to reduced ATP content which is required for phosphorylation of glucose to fructose bisphosphate. 4) The decrease in ATP content of islets is most likely due to both PD per se and the associated high resting cytosolic calcium, since chronic rise in the latter is known to inhibit ATP production.
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