Ward G M
Drugs. 1987 Feb;33(2):156-70. doi: 10.2165/00003495-198733020-00004.
The initial step in insulin action is binding to specific receptors. Two covalent receptor modifications possibly involved in producing pharmacodynamic effects as a result of insulin receptor binding are autophosphorylation and disulphide insulin binding. Insulin receptor numbers are 'down regulated' by insulin, but this effect may be minimised by pulsatile insulin secretion. Insulin receptor affinity is modulated rapidly by fasting, exercise and dietary composition. In non-insulin-dependent diabetes coupling of receptor binding to bioeffects is impaired. Binding is also reduced in those subjects with hyperinsulinaemia and non-insulin-dependent diabetes. Insulin-dependent diabetics have reduced insulin sensitivity, which is only partially reversed by conventional insulin therapy. 'Post-binding defects' in some diabetics could be related to defective covalent receptor modifications resulting from genetic receptor defects. High carbohydrate diets improve diabetes control through effects on the binding and coupling defects. In addition to stimulating insulin secretion, oral hypoglycaemics stimulate post-binding insulin action in vivo and in vitro. Insulin therapy in diabetes also tends to reverse post-binding defects. Pulsatile insulin delivery is more effective in lowering blood sugar than continuous administration, and produces less 'down regulation' of receptors. Combined insulin and sulphonylurea drugs reduce insulin requirements only in insulin-dependent diabetics with some endogenous insulin secretion, whereas metformin reduces insulin requirement in C-peptide negative insulin-dependent diabetes mellitus.
胰岛素作用的起始步骤是与特定受体结合。胰岛素与受体结合后可能产生药效学效应的两种共价受体修饰是自身磷酸化和二硫键胰岛素结合。胰岛素可使胰岛素受体数量“下调”，但脉冲式胰岛素分泌可使这种效应降至最低。禁食、运动和饮食组成可迅速调节胰岛素受体亲和力。在非胰岛素依赖型糖尿病中，受体结合与生物效应之间的偶联受损。高胰岛素血症和非胰岛素依赖型糖尿病患者的胰岛素结合也减少。胰岛素依赖型糖尿病患者的胰岛素敏感性降低，传统胰岛素治疗只能部分逆转这种情况。一些糖尿病患者的“结合后缺陷”可能与遗传受体缺陷导致的共价受体修饰缺陷有关。高碳水化合物饮食通过对结合和偶联缺陷的影响来改善糖尿病控制。除了刺激胰岛素分泌外，口服降糖药在体内和体外均可刺激结合后的胰岛素作用。糖尿病患者的胰岛素治疗也往往会逆转结合后缺陷。脉冲式胰岛素给药在降低血糖方面比持续给药更有效，并且对受体的“下调”作用更小。胰岛素与磺脲类药物联合使用仅在有一定内源性胰岛素分泌的胰岛素依赖型糖尿病患者中可减少胰岛素需求，而二甲双胍可降低C肽阴性胰岛素依赖型糖尿病患者的胰岛素需求。
