The insulin receptor concept and its relation to the treatment of diabetes

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.