Bergman R N, Mittelman S D
Department of Physiology and Biophysics, University of Southern California, Los Angeles 90033, USA.
J Basic Clin Physiol Pharmacol. 1998;9(2-4):205-21. doi: 10.1515/jbcpp.1998.9.2-4.205.
Mechanisms of insulin resistance in subjects at risk for type 2 diabetes remain to be elucidated. Insulin acts slowly in vivo, but rapidly in vitro, suggesting that the pathway insulin traverses from B-cell to insulin sensitive tissue may be altered in diabetes. An important component of that pathway is transport of insulin across the capillary endothelium. Several groups have demonstrated that insulin resistance may result from reduced capillary permeability to insulin--it remains to be determined whether reduced permeability contributes to insulin resistance in any stage leading to type 2 diabetes. Interestingly, the transport of insulin across the endothelial barrier not only limits the rate of insulin to stimulate glucose uptake by skeletal muscle, but appears also to determine the rate at which insulin suppresses liver glucose output. Because the liver circulation is fenestrated, it is not possible that insulin transport into the liver is the rate determining step for suppression of liver glucose output. An alternative hypothesis was considered--that insulin is transported into an extrahepatic tissue. A "second signal" is generated by the extrahepatic tissue, the signal is released into the blood, and the signal in turn controls hepatic glucose output. Several lines of evidence suggest that the second signal is free fatty acids (FFA): 1) There is a strong correlation between FFA and liver glucose output under a variety of experimental conditions. 2) If FFA are maintained at basal concentrations during insulin administration, glucose output fails to decline. 3) If FFA are reduced independent of insulin administration, glucose output is reduced. These three points support the concept that insulin, by regulating adipocyte lipolysis, controls liver glucose production. Thus, the adipocyte is a critical mediator between insulin and liver glucose output. Evidence that FFA also suppress skeletal muscle glucose uptake and insulin secretion from the B-cell supports the overall central role of the adipocyte in the regulation of glycemia. Insulin resistance at the fat cell may be an important component of the overall regulation of glycemia because of the relationships between FFA and glucose production, glucose uptake, and insulin release. It is possible that insulin resistance at the adipocyte itself can be a major cause of the dysregulation of carbohydrate metabolism in the prediabetic state.
2型糖尿病高危人群胰岛素抵抗的机制仍有待阐明。胰岛素在体内作用缓慢，但在体外作用迅速，这表明胰岛素从B细胞到胰岛素敏感组织的途径在糖尿病中可能发生改变。该途径的一个重要组成部分是胰岛素跨毛细血管内皮的转运。几个研究小组已经证明，胰岛素抵抗可能是由于毛细血管对胰岛素的通透性降低所致——在导致2型糖尿病的任何阶段，通透性降低是否导致胰岛素抵抗仍有待确定。有趣的是，胰岛素跨内皮屏障的转运不仅限制了胰岛素刺激骨骼肌摄取葡萄糖的速率，而且似乎还决定了胰岛素抑制肝脏葡萄糖输出的速率。由于肝脏循环有窗孔，胰岛素转运入肝脏不可能是抑制肝脏葡萄糖输出的速率决定步骤。于是考虑了另一种假说——胰岛素被转运到肝外组织。肝外组织产生“第二信号”，该信号释放到血液中，进而控制肝脏葡萄糖输出。几条证据表明第二信号是游离脂肪酸（FFA）：1）在各种实验条件下，FFA与肝脏葡萄糖输出之间存在很强的相关性。2）在给予胰岛素期间，如果FFA维持在基础浓度，葡萄糖输出不会下降。3）如果在不给予胰岛素的情况下降低FFA，葡萄糖输出会降低。这三点支持了胰岛素通过调节脂肪细胞脂解来控制肝脏葡萄糖生成的概念。因此，脂肪细胞是胰岛素与肝脏葡萄糖输出之间的关键介质。FFA还抑制骨骼肌葡萄糖摄取和B细胞胰岛素分泌的证据支持了脂肪细胞在血糖调节中的整体核心作用。由于FFA与葡萄糖生成、葡萄糖摄取和胰岛素释放之间的关系，脂肪细胞处的胰岛素抵抗可能是血糖整体调节的一个重要组成部分。脂肪细胞本身的胰岛素抵抗有可能是糖尿病前期碳水化合物代谢失调的主要原因。
