Fadda G Z, Hajjar S M, Perna A F, Zhou X J, Lipson L G, Massry S G
Division of Nephrology and Geriatric Medicine, University of Southern California School of Medicine, Los Angeles 90033.
J Clin Invest. 1991 Jan;87(1):255-61. doi: 10.1172/JCI114979.
It has been suggested that a sustained rise in resting levels of cytosolic calcium [Ca2+]i of pancreatic islets is responsible for impaired insulin secretion in chronic renal failure (CRF). Evidence for such an event is lacking and the mechanisms through which it may affect insulin secretion are not known. Studies were conducted in normal, CRF, and normocalcemic, parathyroidectomized (PTX) CRF rats to answer these questions. Resting levels of [Ca2+]i of islets from CRF rats were higher (P less than 0.01) than in control of CRF-PTX rats. [3H]2-deoxyglucose uptake and cAMP production by islets were not different in the three groups. Insulin content of, and glucose-induced insulin secretion by islets from CRF rats was lower (P less than 0.01) than in control and CRF-PTX rats. In contrast, glyceraldehyde-induced insulin release by CRF islets was normal. Basal ATP content, both glucose-stimulated ATP content and ATP/ADP ratio, net lactic acid output, Vmax of phosphofructokinase-1, and Ca2+ ATPase of islets from CRF rats were lower (P less than 0.02-less than 0.01) than in normal or CRF-PTX animals. Data show that: (a) Glucose but not glyceraldehyde-induced insulin secretion is impaired in CRF; (b) the impairment in glucose-induced insulin release in CRF is due to a defect in the metabolism of glucose; (c) this latter defect is due to reduced ATP content induced partly by high [Ca2+]i of islets; and (d) the high [Ca2+]i in islets of CRF rats is due to augmented PTH-induced calcium entry into cells and decreased calcium extrusion from the islets secondary to reduced activity of the Ca2+ ATPase.
有人提出，胰腺胰岛细胞溶质钙[Ca2+]i的静息水平持续升高是慢性肾衰竭（CRF）中胰岛素分泌受损的原因。目前缺乏此类事件的证据，其影响胰岛素分泌的机制也尚不清楚。为回答这些问题，我们对正常大鼠、CRF大鼠以及血钙正常的甲状旁腺切除（PTX）CRF大鼠进行了研究。CRF大鼠胰岛的[Ca2+]i静息水平高于CRF - PTX大鼠对照组（P < 0.01）。三组中胰岛对[3H]2 - 脱氧葡萄糖的摄取和cAMP生成并无差异。CRF大鼠胰岛的胰岛素含量以及葡萄糖诱导的胰岛素分泌低于对照组和CRF - PTX大鼠（P < 0.01）。相比之下，CRF胰岛对甘油醛诱导的胰岛素释放正常。CRF大鼠胰岛的基础ATP含量、葡萄糖刺激后的ATP含量以及ATP/ADP比值、净乳酸产量、磷酸果糖激酶 - 1的Vmax以及Ca2+ ATP酶均低于正常或CRF - PTX动物（P < 0.02 - < 0.01）。数据表明：（a）CRF中葡萄糖而非甘油醛诱导的胰岛素分泌受损；（b）CRF中葡萄糖诱导的胰岛素释放受损是由于葡萄糖代谢缺陷；（c）后一种缺陷是由于胰岛[Ca2+]i升高部分导致的ATP含量降低；（d）CRF大鼠胰岛中[Ca2+]i升高是由于甲状旁腺激素诱导的钙进入细胞增加以及由于Ca2+ ATP酶活性降低导致胰岛钙外流减少。
