Oh H Y, Fadda G Z, Smogorzewski M, Liou H H, Massry S G
Division of Nephrology, University of Southern California, School of Medicine, Los Angeles 90033.
Am J Physiol. 1994 Nov;267(5 Pt 2):F853-60. doi: 10.1152/ajprenal.1994.267.5.F853.
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.
慢性肾衰竭（CRF）与胰岛的多种异常有关，包括胞质钙升高、ATP含量降低以及葡萄糖诱导的胰岛素分泌受损。后者也受到氨基酸（如亮氨酸）的刺激，亮氨酸诱导胰岛素分泌所涉及的细胞过程与葡萄糖诱导胰岛素释放所涉及的过程不同。本研究检测了CRF中亮氨酸诱导的胰岛素分泌是否也受损，并研究了这种潜在异常的细胞紊乱情况。结果表明，CRF动物的胰岛显著降低了亮氨酸诱导的胰岛素分泌，而CRF动物的甲状旁腺切除术（PTX）或用维拉帕米（一种阻断甲状旁腺激素（PTH）对胰岛作用的药物）治疗可预防这种缺陷。CRF大鼠胰岛对亮氨酸的摄取以及α-酮异己酸诱导的胰岛素分泌均正常；然而，亮氨酸或2-氨基双环-[2-2-1]-庚烯对谷氨酸脱氢酶（GLDH）的激活以及α-酮戊二酸的利用均受损，谷氨酰胺酶的最大反应速率（Vmax）降低。CRF大鼠的PTX或用维拉帕米治疗可纠正这些紊乱。数据表明：1）CRF与亮氨酸诱导的胰岛素分泌受损有关；2）这种缺陷是由于CRF的继发性甲状旁腺功能亢进状态；3）导致这种缺陷的细胞紊乱涉及亮氨酸代谢异常以及胰岛中亮氨酸-GLDH-α-酮戊二酸-谷氨酰胺酶途径的紊乱。
