ABNORMAL LEUCINE-INDUCED INSULIN-SECRETION IN CHRONIC-RENAL-FAILURE

Chronic renal failure (CRF) is associated with a sundry of abnormaliti es in pancreatic islets including a rise in their cytosolic calcium, r educed ATP content, and impaired glucose-induced insulin secretion. Th e latter is also stimulated by amino acids (such as leucine), and the cellular processes involved in leucine-induced insulin secretion are d ifferent from those responsible for glucose-induced insulin release. T he present study examined whether leucine-induced insulin secretion is also impaired in CRF and investigated the cellular derangements for s uch a potential abnormality. The results showed that leucine-induced i nsulin secretion is markedly reduced by islets from CRF animals, and t his defect was prevented by parathyroidectomy (PTX) of the CRF animals or by their treatment with verapamil, an agent that blocks the action of parathyroid hormone (PTH) on the pancreatic islets. Both leucine u ptake and alpha-ketoisocaproic acid-induced insulin secretion by islet s from CRF rats are normal; however, both the activation of glutamate dehydrogenase (GLDH) by leucine or by 2-aminobicyclo-[2-2-1]-haptene a nd the utilization of ol-ketoglutarate are impaired, and the maximal r eaction rate (V-max) of glutaminase is reduced. These derangements are corrected by PTX of CRF rats or by their treatment with verapamil. Th e data demonstrate that 1) CRF is associated with impaired leucine-ind uced insulin secretion, 2) this defect is due to the state of secondar y hyperparathyroidism of CRF and 3) the cellular derangements responsi ble for this defect involve abnormalities in the metabolism of leucine and derangements in the leucine-GLDH-alpha-ketoglutarate-glutaminase pathway of the islets.