DeFronzo R A, Bonadonna R C, Ferrannini E
Division of Diabetes, University of Texas Health Science Center, San Antonio 78284-7886.
Diabetes Care. 1992 Mar;15(3):318-68. doi: 10.2337/diacare.15.3.318.
Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.
非胰岛素依赖型糖尿病（NIDDM）是由胰岛素敏感性和胰岛素分泌之间的失衡引起的。纵向和横断面研究均表明，NIDDM最早可检测到的异常是机体对胰岛素反应能力的损害。由于胰腺能够适当增加胰岛素分泌以抵消胰岛素抵抗，葡萄糖耐量仍保持正常。然而，随着时间的推移，β细胞无法维持其高胰岛素分泌率，相对胰岛素缺乏（即相对于胰岛素抵抗程度）导致葡萄糖耐量受损，最终发展为显性糖尿病。胰腺“耗竭”的原因尚不清楚，但可能与遗传易感性β细胞中葡萄糖毒性的作用有关。本文讨论了与NIDDM中β细胞功能改变相关的关于第一相胰岛素分泌丧失、胰岛素释放脉冲性改变以及胰岛素原-胰岛素分泌比例增加的信息。NIDDM中的胰岛素抵抗涉及肝脏和外周肌肉组织。在吸收后状态下，尽管存在空腹高胰岛素血症，但肝脏葡萄糖输出正常或增加，而组织葡萄糖摄取效率降低。对内源性分泌或外源性给予的胰岛素，肝脏葡萄糖生成均不能正常抑制，肌肉葡萄糖摄取减少。肝脏葡萄糖输出加速完全归因于糖异生增加。在肌肉中，已描述了许多胰岛素作用的细胞缺陷，包括胰岛素受体酪氨酸激酶活性受损、葡萄糖转运减少以及糖原合酶和丙酮酸脱氢酶减少。这些异常导致了葡萄糖处置的两个主要细胞内途径，糖原合成和葡萄糖氧化的紊乱。在NIDDM的最早阶段，主要缺陷是胰岛素无法促进葡萄糖摄取并储存为糖原。为解释胰岛素抵抗而提出的其他潜在机制包括脂质氧化增加、骨骼肌毛细血管密度/纤维类型/血流改变、胰岛素跨血管内皮转运受损、胰淀素增加、降钙素基因相关肽水平升高以及葡萄糖毒性。
