Prolonged glucose infusion into conscious rats inhibits early steps in insulin signalling and induces translocation of GLUT4 and protein kinase C in skeletal muscle

• Published in: Diabetologia 2002-03, Vol.45 (3), p.356-368
• Main Authors: HOUDALI, B, NGUYEN, V, AMMON, H. P. T, HAAP, M, SCHECHINGER, W, MACHICAO, F, RETT, K, HÄRING, H-U, SCHLEICHER, E. D
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Body fat; Diabetes; Endocrinology; Female; Gene Expression Regulation; Glucose; Glucose - administration & dosage; Glucose - pharmacology; Glucose Transporter Type 4; Glycogen - metabolism; Hyperglycemia; Hypotheses; Infusions, Intravenous; Insulin - physiology; Insulin Receptor Substrate Proteins; Insulin resistance; Kinases; Metabolism; Models, Animal; Monosaccharide Transport Proteins - genetics; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Musculoskeletal system; Phosphoproteins - metabolism; Plasma; Protein Kinases - metabolism; Protein Subunits; Protein Transport; Proteins; Rats; Rats, Wistar; Signal transduction; Signal Transduction - physiology; Transcription, Genetic; Triglycerides - metabolism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-001-0754-9

Previous studies on diabetic patients have shown that hyperglycaemia increases glucose uptake in an apparently insulin-independent manner. However, the molecular mechanism has not been clarified. We studied rats receiving continuous glucose infusion to address this question. In this animal model, rats accommodate systemic glucose oversupply and rapidly develop insulin resistance. Glucose infusion increased both plasma glucose and insulin concentrations to peak after one day. In spite of continuous glucose infusion normoglycaemia was reached after 5 days while insulin concentrations remained higher. Focusing our studies in day 2 (hyperglycaemia/hyperinsulinaemia) and day 5 (normoglycaemia/hyperinsulinaemia) we found, particularly in day 5, that the early steps of the insulin signalling cascade in skeletal muscle of glucose-infused rats were not more activated when compared to control animals as assessed by a comparable phosphorylation of the insulin receptor, IRS-1 and PKB and by an unaltered IRS-1-associated Ptd(Ins) 3' kinase activity. Continuous glucose infusion induced GLUT4 protein expression and translocation to the plasma membrane while neither expression nor translocation of GLUT1 was affected. Translocation of PKC- betaI, - betaII (> threefold) and -alpha, -theta (to a lesser extent) to the plasma membrane was significantly induced after 2 days but not after 5 days of glucose infusion when normoglycaemia was reached. Our data support the hypothesis that continuous glucose infusion induces translocation of GLUT4 while the early steps of the insulin signalling cascade were not increased. These effects could be mediated by activation of PKC.