Weir G C, Sharma A, Zangen D H, Bonner-Weir S
Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Acta Diabetol. 1997 Oct;34(3):177-84. doi: 10.1007/s005920050071.
Well-characterized defects in insulin secretion, most notably a loss of glucose-induced insulin secretion, are found in virtually all forms of NIDDM, as well as in early IDDM. Similar abnormalities have been found in all animal models of diabetes in which they have been studied. A novel hypothesis is being proposed to explain the mechanisms responsible for these alterations. Many abnormalities in the various steps of glucose-induced insulin secretion have been identified in rodent models of diabetes, but none by itself seems sufficient to explain the defects. These include a loss of GLUT2, glycogen accumulation, glucose recycling, abnormal glucokinase or hexokinase, altered mitochondrial glycerol phosphate dehydrogenase (mGPDH) activity, abnormal ion channel function and beta cell degranulation. We propose that optimal secretory function is dependent upon the unique differentiation of beta cells that is maintained by a set of transcription factors and that this control is disrupted by the diabetic state. Therefore, we propose that key transcription factors are affected even when beta cells are stressed by insulin resistance in very earliest stages of diabetes and that the abnormality becomes more severe as full-blown diabetes develops, which leads to loss of beta cell differentiation and a resultant derangement of insulin secretion.
在几乎所有类型的非胰岛素依赖型糖尿病（NIDDM）以及早期胰岛素依赖型糖尿病（IDDM）中，均发现了胰岛素分泌方面特征明确的缺陷，最显著的是葡萄糖诱导的胰岛素分泌丧失。在所有已研究的糖尿病动物模型中也发现了类似的异常情况。目前正在提出一种新的假说来解释导致这些改变的机制。在糖尿病啮齿动物模型中，已确定了葡萄糖诱导的胰岛素分泌各个步骤中的许多异常情况，但单独来看，似乎没有一种足以解释这些缺陷。这些异常包括葡萄糖转运蛋白2（GLUT2）缺失、糖原积累、葡萄糖循环、葡萄糖激酶或己糖激酶异常、线粒体甘油磷酸脱氢酶（mGPDH）活性改变、离子通道功能异常以及β细胞脱颗粒。我们提出，最佳分泌功能依赖于由一组转录因子维持的β细胞独特分化，而这种控制在糖尿病状态下会被破坏。因此，我们提出，即使在糖尿病最早期β细胞受到胰岛素抵抗应激时，关键转录因子也会受到影响，并且随着糖尿病的全面发展，这种异常会变得更加严重，从而导致β细胞分化丧失以及胰岛素分泌紊乱。
