Insulin resistance in skeletal muscle plays a key role in the development of the metabolic-endocrine syndrome and its further progression to non-insulin-dependent diabetes mellitus (NIDDM). Available data suggest that insulin resistance is caused by impaired signalling from the insulin receptor to the glucose transport system and to glycogen synthase. The impaired response of the insulin receptor tyrosine kinase, which is found in NIDDM, appears to contribute to the pathogenesis of the signalling defect. The reduced kinase activation is not caused by mutation of the receptor. Two potential mechanisms were investigated that might be relevant to the abnormal function of the insulin receptor in NIDDM. That is, changes of the receptor isoforms and the effect of hyperglycaemia. The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). HIR-B expression in skeletal muscle is increased in NIDDM. Characterization of the functional properties of HIR-B, however, revealed that increased HIR-B expression did not cause impaired tyrosine kinase activity, but more probably represented a compensatory event. In contrast, hyperglycaemia is able to inhibit insulin receptor function. In a rat-1 fibroblast cell line overexpressing human insulin receptor, inhibition of the tyrosine kinase activity of the receptor can be induced by high glucose levels. This effect appears to be mediated through activation of certain protein kinase C isoforms, which are able to form stable complexes with the insulin receptor and modulate its tyrosine kinase activity through serine phosphorylation of the receptor β-subunit. This mechanism might also be relevant in human skeletal muscle and thereby contribute to the pathogenesis of insulin resistance.