Mechanisms of impaired insulin secretion after chronic excess of parathyroid hormone

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Abstract
Excess parathyroid hormone (PTH) in presence or absence of chronic renal failure impairs insulin release from pancreatic islets. This abnormality has been attributed to PTH-induced accumulation of Ca in the cytosol of the islets. Direct evidence for the latter phenomenon is lacking. This study examined the effect of chronic administration of PTH to rats with normal renal function on resting cytosolic Ca of the islets and evaluated the mechanisms through which a rise in resting cytosolic Ca may inhibit insulin secretion. After 42 days of PTH administration, glucose-induced insulin secretion was impaired, and this defect was corrected by the use of D-glyceraldehyde as secretagogue for insulin. Resting cytosolic Ca of islets from PTH-treated rats was markedly increased compared with that of islets from normal animals (288 .+-. 27.1 vs. 135 .+-. 3.7 nM, P < 0.01), and their content of ATP in the presence of both 2.8 and 16.7 mM D-glucose was reduced (2.8 mM D-glucose, 4.6 .+-. 0.17 vs 6.0 .+-. 0.42 pmol/islet, P < 0.01; and 16.7 mM D-glucose, 6.9 .+-. 0.25 vs. 11.1 .+-. 0.95 pmol/islet, P < 0.01). D-Glyceraldehyde increased ATP content in islets of PTH-treated rats from 4.6 .+-. 0.17 to 8.8 .+-. 0.71 pmol/islet. Glucose uptake by the islets, their insulin content, and both the Vmax and the apparent Km for fructose 6-phosphate of phosphofructokinase 1 (EC 2.7.1.11) in PTH-treated rats were not different from normal. The two major cellular derangements in the islets of PTH-treated rats were a reduction in ATP content and a rise in resting cytosolic Ca. These two abnormalities may interfere with glucose metabolism by the islet and lead to impaired insulin secretion. Also, a reduced ATP content may cause impaired insulin release through its effect on ATP-dependent K channels.