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Pathogenesis of insulin resistance: modulation of the insulin signal at receptor level
1Institut für Diabetesforschung, München, Germany.
Abstract:
The insulin resistance of skeletal muscle plays an important role in the pathogenesis of the metabolic endocrine syndrome and diabetes mellitus Type II. Impairment of the signal transmission from the insulin receptor to glycogen synthase and the glucose transport system was shown in insulin resistant subjects. A reduced receptor activation contributes also to insulin resistance. We investigated the mechanisms of modulation of receptor function in isolated cell systems which are transfected with human insulin receptor. Action of TNF alpha and acute hyperglycaemic effects were studied in particular. Acute hyperglycaemia gives rise, in the isolated cell system, to inhibition of the tyrosine kinase activity of the insulin receptor within a few minutes. This inhibitory effect seems to be mediated by translocation and activation of various isoforms of protein kinase C. Activation of protein kinase C probably leads to phosphorylation of the beta-subunit of the insulin receptor at serine residues. The domains of the insulin receptor, which are responsible for the inhibitory effect of hyperglycaemia do not seem to be localized either in the C terminus or in the juxtamembranary region of the insulin receptor. The hyperglycaemic effect can be antagonized in the isolated cell system both by protein kinase C inhibitors and so-called insulin sensitizers such as thiazolidindiones. Similar inhibitory effects, as induced by hyperglycaemia, can also be mediated by administration of the cytokine TNF alpha. As TNF alpha is probably increasingly expressed in obesity, the modulation of receptor kinase activity by TNF alpha could be an important factor for insulin resistance in obesity.
Insights
High blood sugar and TNF alpha can inhibit insulin receptor function, contributing to insulin resistance. Protein kinase C activation is implicated, but this effect can be reversed by insulin sensitizers.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Syndrome Research
Background:
- Skeletal muscle insulin resistance is key in metabolic syndrome and Type II diabetes.
- Impaired insulin receptor signaling affects glucose transport and glycogen synthesis.
- Reduced insulin receptor activation contributes to overall insulin resistance.
Purpose of the Study:
- To investigate mechanisms modulating human insulin receptor function.
- To examine the effects of TNF alpha and acute hyperglycemia on insulin receptor activity.
- To understand the role of protein kinase C in insulin resistance.
Main Methods:
- Utilized isolated cell systems transfected with the human insulin receptor.
- Studied the impact of acute hyperglycemia and TNF alpha administration.
- Investigated protein kinase C activation and its downstream effects on the insulin receptor.
Main Results:
- Acute hyperglycemia rapidly inhibits insulin receptor tyrosine kinase activity via protein kinase C activation.
- Protein kinase C activation leads to serine phosphorylation of the insulin receptor beta-subunit.
- Hyperglycemia-induced inhibition is antagonized by protein kinase C inhibitors and thiazolidindiones.
- TNF alpha mediates similar inhibitory effects, potentially linking obesity to insulin resistance.
Conclusions:
- Hyperglycemia and TNF alpha impair insulin receptor function, contributing to insulin resistance.
- Protein kinase C pathway is a critical mediator of these inhibitory effects.
- Insulin sensitizers can counteract hyperglycemia-induced insulin resistance.
- TNF alpha's role in obesity-related insulin resistance warrants further investigation.