Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation

• Published in: Diabetologia 1994-09, Vol.37 Suppl 2 (S2), p.S149-S154
• Main Authors: Häring, H U, Kellerer, M, Mosthaf, L
• Format: Article
• Language: English
• Subjects: Animals; Awards and Prizes; Diabetes Mellitus - history; Diabetes Mellitus - physiopathology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Europe; Gene Expression; Germany; History of medicine; History, 20th Century; Humans; Hyperglycemia - physiopathology; Häring; Isoenzymes - metabolism; Muscles - metabolism; Protein Kinase C - metabolism; Receptor, Insulin - biosynthesis; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Receptor, Insulin - physiology; Signal Transduction; Societies, Medical
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/BF00400838

Insulin resistance of the skeletal muscle plays a key role in the development of the metabolic endocrine syndrome and its further progression to non-insulin dependent diabetes (NIDDM). Available data suggest that insulin resistance is caused by an impaired signal 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 mutations within the insulin receptor gene. We investigated two potential mechanisms that might be relevant for the abnormal function of the insulin receptor in NIDDM, i.e. changes in the expression of the receptor isoforms and the effect of hyperglycaemia on insulin receptor tyrosine kinase activity. The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). We found that HIR-B expression in the skeletal muscle is increased in NIDDM. However, the characterisation of the functional properties of HIR-A and HIR-B revealed no difference in their tyrosine kinase activity in vivo. The increased expression of HIR-B might represent a compensatory event. In contrast, hyperglycaemia might directly inhibit insulin-receptor function. We have found that in rat-1 fibroblasts which overexpressing human insulin receptor an inhibition of the tyrosine kinase activity of the receptor may be induced by high glucose levels. This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit.