Molecular Physiology and Biophysics, Vanderbilt University, 2215 Garland Avenue, Nashville, TN 37232, USA.
Diabetologia. 2011 May;54(5):1087-97. doi: 10.1007/s00125-010-2039-7. Epub 2011 Jan 27.
AIMS/HYPOTHESIS: Mutations that render ATP-sensitive potassium (K(ATP)) channels insensitive to ATP inhibition cause neonatal diabetes mellitus. In mice, these mutations cause insulin secretion to be lost initially and, as the disease progresses, beta cell mass and insulin content also disappear. We investigated whether defects in calcium signalling alone are sufficient to explain short-term and long-term islet dysfunction.
We examined the metabolic, electrical and insulin secretion response in islets from mice that become diabetic after induction of ATP-insensitive Kir6.2 expression. To separate direct effects of K(ATP) overactivity on beta cell function from indirect effects of prolonged hyperglycaemia, normal glycaemia was maintained by protective exogenous islet transplantation.
In endogenous islets from protected animals, glucose-dependent elevations of intracellular free-calcium activity (Ca(2+)) were severely blunted. Insulin content of these islets was normal, and sulfonylureas and KCl stimulated increased Ca(2+). In the absence of transplant protection, Ca(2+) responses were similar, but glucose metabolism and redox state were dramatically altered; sulfonylurea- and KCl-stimulated insulin secretion was also lost, because of systemic effects induced by long-term hyperglycaemia and/or hypoinsulinaemia. In both cases, Ca(2+) dynamics were synchronous across the islet. After reduction of gap-junction coupling, glucose-dependent Ca(2+) and insulin secretion was partially restored, indicating that excitability of weakly expressing cells is suppressed by cells expressing mutants, via gap-junctions.
CONCLUSIONS/INTERPRETATION: The primary defect in K(ATP)-induced neonatal diabetes mellitus is failure of glucose metabolism to elevate Ca(2+), which suppresses insulin secretion and mildly alters islet glucose metabolism. Loss of insulin content and mitochondrial dysfunction are secondary to the long-term hyperglycaemia and/or hypoinsulinaemia that result from the absence of glucose-dependent insulin secretion.
目的/假设：使 ATP 敏感性钾 (K(ATP)) 通道对 ATP 抑制作用不敏感的突变导致新生儿糖尿病。在小鼠中，这些突变导致胰岛素分泌最初丧失，随着疾病的进展，β细胞质量和胰岛素含量也消失。我们研究了钙信号传导的缺陷是否足以解释胰岛的短期和长期功能障碍。
我们检查了诱导 ATP 不敏感 Kir6.2 表达后发生糖尿病的小鼠胰岛的代谢、电和胰岛素分泌反应。为了将 K(ATP) 过度活跃对β细胞功能的直接影响与长期高血糖的间接影响分开，通过保护性的胰岛外植体移植来维持正常的血糖。
在受保护动物的内源性胰岛中，葡萄糖依赖性细胞内游离钙活性 (Ca(2+)) 的升高严重受损。这些胰岛的胰岛素含量正常，磺酰脲类药物和 KCl 刺激增加了 Ca(2+)。在没有移植保护的情况下，Ca(2+) 反应相似，但葡萄糖代谢和氧化还原状态发生了巨大变化；由于长期高血糖和/或低胰岛素血症引起的全身效应，磺酰脲类药物和 KCl 刺激的胰岛素分泌也丧失。在这两种情况下，Ca(2+) 动力学在整个胰岛中都是同步的。在缝隙连接偶联减少后，葡萄糖依赖性 Ca(2+) 和胰岛素分泌部分恢复，表明通过缝隙连接，弱表达细胞的兴奋性被表达突变体的细胞抑制。
结论/解释：K(ATP) 诱导的新生儿糖尿病的主要缺陷是葡萄糖代谢不能升高 Ca(2+)，这抑制了胰岛素分泌并轻微改变了胰岛的葡萄糖代谢。胰岛素含量的丧失和线粒体功能障碍是由于缺乏葡萄糖依赖性胰岛素分泌而导致的长期高血糖和/或低胰岛素血症的继发结果。
