Abnormal leucine-induced insulin secretion in chronic renal failure

Chronic renal failure (CRF) is associated with a sundry of abnormalities in pancreatic islets including a rise in their cytosolic calcium, reduced ATP content, and impaired glucose-induced insulin secretion. The latter is also stimulated by amino acids (such as leucine), and the cellular processes involved in leucine-induced insulin secretion are different from those responsible for glucose-induced insulin release. The present study examined whether leucine-induced insulin secretion is also impaired in CRF and investigated the cellular derangements for such a potential abnormality. The results showed that leucine-induced insulin secretion is markedly reduced by islets from CRF animals, and this 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 uptake and alpha-ketoisocaproic acid-induced insulin secretion by islets from CRF rats are normal; however, both the activation of glutamate dehydrogenase (GLDH) by leucine or by 2-aminobicyclo-[2-2-1]-haptene and the utilization of alpha-ketoglutarate are impaired, and the maximal reaction rate (Vmax) of glutaminase is reduced. These derangements are corrected by PTX of CRF rats or by their treatment with verapamil. The data demonstrate that 1) CRF is associated with impaired leucine-induced insulin secretion, 2) this defect is due to the state of secondary hyperparathyroidism of CRF, and 3) the cellular derangements responsible for this defect involve abnormalities in the metabolism of leucine and derangements in the leucine-GLDH-alpha-ketoglutarate-glutaminase pathway of the islets.