Belfiore F, Iannello S, Rabuazzo A M
Int J Obes. 1979;3(4):301-23.
Based on the consideration that insulin does not act directly on metabolic processes but affects membrane carriers and key-enzymes that regulate metabolic pathways, determination of insulin responsiveness of the various key-enzymes is suggested as a very appropriate method for studying insulin resistance. Insulin resistance, as it occurs in obese or obese-diabetic humans and animals, is most often associated with hyperinsulinemia, and is characterized not only by increased activity of key-enzymes of pathways known to be stimulated by insulin (glycolysis, lipogenesis), with the possible exception of glycogen synthesis, but also by a trend towards increased activity of key-enzymes of 'catabolic pathways', normally depressed by insulin. In the adipose tissue there is a normal-to-enhanced basal lipolysis, which in man would result from the prevalence of the active over the inactive form of triacylglycerol lipase. In muscle, the increased amino-acid release that can be inferred from the elevated blood level of both alanine and branched-chain amino acids suggests an enhanced proteolysis. In liver, there is an elevation in the activity of the key gluconeogenic enzymes, which forms the basis of the augmented gluconeogenesis. In both muscle and liver, phosphorylase is also elevated with no change in glycogen synthase. Therefore, insulin resistance seems to consist of the failure of insulin to depress the key-enzymes of catabolic pathways. Possible resistance of glycogen synthetase, which might account for decreased glucose utilization in muscle, may be due to the opposing effects of the phosphorylation process on glycogen synthetase and phosphorylase, implying that activation of phosphorylase (which occurs in obesity) entails inhibition of the synthetase. The fact that insulin insensitivity concerns only the 'catabolic' but not most 'anabolic' pathways makes it unlikely that the unresponsiveness is due to a reduction in insulin receptors or increase in insulin degradation. Since resistance to insulin is shown by enzymes regulated by such different mechanisms as induction-repression (gluconeogenic enzymes), covalent modifications (lipase, phosphorylase), and changes in lysosome stability (lysosomal proteases responsible for proteolysis, a single basic mechanism for explaining insulin insensitivity cannot be envisaged at present.
基于胰岛素并非直接作用于代谢过程，而是影响调节代谢途径的膜载体和关键酶这一考虑，测定各种关键酶的胰岛素反应性被认为是研究胰岛素抵抗的一种非常合适的方法。肥胖或肥胖糖尿病的人类和动物中出现的胰岛素抵抗，最常与高胰岛素血症相关，其特征不仅在于已知受胰岛素刺激的途径（糖酵解、脂肪生成）的关键酶活性增加，糖原合成可能除外，还在于“分解代谢途径”的关键酶活性有增加的趋势，而这些酶通常会被胰岛素抑制。在脂肪组织中，基础脂解作用正常至增强，在人类中这是由于活性三酰甘油脂肪酶形式相对于无活性形式占优势所致。在肌肉中，从丙氨酸和支链氨基酸的血液水平升高可以推断出氨基酸释放增加，这表明蛋白水解作用增强。在肝脏中，关键糖异生酶的活性升高，这构成了糖异生增加的基础。在肌肉和肝脏中，磷酸化酶也升高，而糖原合酶没有变化。因此，胰岛素抵抗似乎在于胰岛素无法抑制分解代谢途径的关键酶。糖原合酶可能存在的抵抗，这可能解释了肌肉中葡萄糖利用的减少，可能是由于磷酸化过程对糖原合酶和磷酸化酶的相反作用，这意味着磷酸化酶的激活（发生在肥胖中）会导致合酶的抑制。胰岛素不敏感仅涉及“分解代谢”而非大多数“合成代谢”途径这一事实，使得这种无反应性不太可能是由于胰岛素受体减少或胰岛素降解增加所致。由于对胰岛素的抵抗在受诱导 - 阻遏（糖异生酶）、共价修饰（脂肪酶、磷酸化酶）以及溶酶体稳定性变化（负责蛋白水解的溶酶体蛋白酶）等不同机制调节的酶中都有体现，目前无法设想单一的基本机制来解释胰岛素不敏感。
