High glucose condition desensitizes insulin action at the levels of receptor kinase.
The mechanisms for the insulin resistance induced by hyperglycemia were investigated by studying the in vitro effects of a high glucose concentration on insulin signaling with Rat 1 fibroblasts expressing human insulin receptors (HIRc). Incubation of HIRc cells for 4 days in 27 mM D-glucose led to impaired insulin-stimulation of both alpha-aminoisobutyric acid uptake (AIB) and phosphorylation of pp185 and receptor beta-subunits in vivo. In vitro autophosphorylation and tyrosine kinase activities toward poly Glu80 Tyr20 of insulin receptors from cells exposed to high glucose media (HG) were also impaired (46-48% of control), although the binding of insulin to HG cells was unchanged. One possible explanation for these high glucose effects is that they are mediated by the activation of protein kinase C (PKC). However, a 4-day-high glucose culture had no effect on cytosolic and membrane PKC activities or on phorbol dibutyrate binding to whole cells. This is in accordance with the orthophosphate labeling study, in which basal autophosphorylation activity in HG cells did not increase, suggesting that phosphorylation of serine and threonine residues in the basal state might not increase in HG cells. These results indicate that in cells exposed to high glucose, desensitization of insulin receptors was induced via several intracellular events, but might not be due to persistent activation of PKC in HIRc cells.
Ide
R
R
Third Department of Medicine, Shiga University of Medical Science, Japan.
Maegawa
H
H
Kashiwagi
A
A
Kikkawa
R
R
Shigeta
Y
Y
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011972:Receptor, Insulin / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007328:Insulin; D011972:Receptor, Insulin; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate