Differential modulation of insulin actions by dexamethasone: studies in primary cultures of adult rat hepatocytes.
OBJECTIVE
Steroid diabetes is associated with hepatic insulin resistance; in hepatic cell models, however, mainly insulin-permissive effects have been described. Here we investigate modulation by dexamethasone of a larger number of insulin actions.


METHODS
Adult rat hepatocytes were cultured+/-dexamethasone for 48 h; insulin actions were studied subsequently.


RESULTS
Stimulation of glycolysis by insulin but not by glucose required culture with dexamethasone. Activation of glycogen synthesis by insulin or glucose was strongly enhanced by dexamethasone, the insulin effects on glycogenolysis and amino acid uptake were not modulated. When dexamethasone was omitted from the culture, insulin was incapable to activate glycogen synthase, inactivate glycogen phosphorylase or elevate the level of fructose 2,6-bisphosphate. Dexamethasone did not alter insulin binding, insulin receptor number or kinase activity, insulin receptor substrate-1 and Akt protein expression/phosphorylation. Insulin-stimulated association of phosphatidylinositol 3-kinase with insulin receptor substrates-1 and -2 was increased with dexamethasone, the increased association with IRS-2 may, at least partially, be explained by higher IRS-2 protein expression.


CONCLUSIONS
The steroid does not cause hepatic resistance in vitro. The differential attenuation under steroid deprivation points to defects in branches of the insulin signal chain and/or loss of hormonal regulation at the level of target enzymes.
Klein
Harald H
HH
Department of Internal Medicine I, Medizinische Universität zu Lübeck, Lübeck, Germany.
Ullmann
Stephanie
S
Drenckhan
Maren
M
Grimmsmann
Thomas
T
Unthan-Fechner
Kirsten
K
Probst
Irmelin
I
D000367:Age Factors; D000596:Amino Acids / Q000493:pharmacokinetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004347:Drug Interactions; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D000596:Amino Acids; D003470:Culture Media; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin; D003907:Dexamethasone; D006003:Glycogen; D024981:Glycogen Phosphorylase; D011972:Receptor, Insulin; D005947:Glucose