PATHOGENESIS OF INSULIN-RESISTANCE - MODULATION OF THE INSULIN SIGNALAT RECEPTOR LEVEL

The insulin resistance of skeletal muscle plays an important role in t he pathogenesis of the metabolic endocrine syndrome and diabetes melli tus Type II. Impairment of the signal transmission from the insulin re ceptor to glycogen synthase and the glucose transport system was shown in insulin resistant subjects. A reduced receptor activation contribu tes also to insulin resistance. We investigated the mechanisms of modu lation of receptor function in isolated cell systems which are transfe cted with human insulin receptor. Action of TNF alpha and acute hyperg lycaemic effects were studied in particular. Acute hyperglycaemia give s rise, in the isolated cell system, to inhibition of the tyrosine kin ase activity of the insulin receptor within a few minutes. This inhibi tory effect seems to be mediated by translocation and activation of va rious isoforms of protein kinase C. Activation of protein kinase C pro bably leads to phosphorylation of the beta-subunit of the insulin rece ptor at serine residues. The domains of the insulin receptor, which ar e responsible for the inhibitory effect of hyperglycaemia do not seem to be localized either in the C terminus or in the juxtamembranary reg ion of the insulin receptor. The hyperglycaemic effect can be antagoni zed in the isolated cell system both by protein kinase C inhibitors an d so-called insulin sensitizers such as thiazolidindiones. Similar inh ibitory effects, as induced by hyperglycaemia, can also be mediated by administration of the cytokine TNF alpha. As TNF alpha is probably in creasingly expressed in obesity, the modulation of receptor kinase act ivity by TNF alpha could be an important factor for insulin resistance in obesity.