Catecholamines and tumour promoting phorbolesters inhibit insulin receptor kinase and induce insulin resistance in isolated human adipocytes.
The effect of the catecholamine isoprenaline (10(-5) mol/l) and of the tumour promoting phorbolester tetradecanoyl-beta-phorbol acetate (10(-9) mol/l) on insulin stimulated 3-O-methyl-glucose transport was studied in freshly isolated human adipocytes. Both substances reduced the maximal responsiveness of the glucose transport system to insulin by approximately 50%. To test if this is caused by inhibition of the insulin receptor kinase the receptor from phorbolester and isoprenaline treated cells was solubilized, partially purified and its kinase activity studied in vitro. Insulin stimulated 32P-incorporation into the beta-subunit of the insulin receptor of phorbolester or isoprenaline treated cells was reduced to 20-60% of the values found with receptor from control cells at insulin concentrations between 10(-10) mol/l and 10(-7) mol/l. This inhibition of kinase activity of receptor from phorbolester and isoprenaline treated cells was observed at nonsaturating adenosine triphosphate levels (5 mumol/l), and it could be overcome with higher concentrations of gamma-32P-adenosine triphosphate in the phosphorylation assay. A Lineweaver Burk analysis of the insulin stimulated receptor phosphorylation revealed that the Michaelis constant for adenosine triphosphate of the receptor kinase from phorbolester and isoprenaline treated cells was increased to greater than 100 mumol/l compared with less than 50 mumol/l for receptor from control cells. We conclude from the data that catecholamine and phorbolester treatment of human adipocytes modulates the kinase activity of the insulin receptor by increasing its Michaelis constant for adenosine-triphosphate, and propose that this modulation of receptor kinase is a mechanism that can contribute to the pathogenesis of insulin resistance in human fat cells.
D019325:3-O-Methylglucose; D000255:Adenosine Triphosphate / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007545:Isoproterenol / Q000494:pharmacology*; D008757:Methylglucosides / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D007328:Insulin; D008757:Methylglucosides; D019325:3-O-Methylglucose; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate