Thiazolidine derivatives ameliorate high glucose-induced insulin resistance via the normalization of protein-tyrosine phosphatase activities.
The mechanisms for the insulin resistance induced by hyperglycemia were investigated by studying the effect of high glucose concentration (HG) and its modulation by thiazolidine derivatives, on insulin signaling using Rat 1 fibroblasts expressing human insulin receptors (HIRc). Incubating HIRc cells in 27 mM D-glucose for 4 days impaired the insulin-stimulated phosphorylation of pp185 and receptor beta-subunits. Both protein kinase C activities and phorbol dibutyrate binding to intact cells were unchanged; however, cytosolic protein-tyrosine phosphatase (PTPase) activity increased within 1 h prior to the impairment of insulin receptor kinase in HG cells (Maegawa, H., Tachikawa-Ide, R., Ugi, S., Iwanishi, M., Egawa, K., Kikkawa, R., Shigeta, Y., and Kashiwagi, A. (1993) Biochem. Biophys. Res. Commun. 197, 1078-1082). Increased PTPase activity was consistent with a 2-fold increase in the amount of PTP1B, and anti-PTP1B antibody inhibited this increment of cytosolic PTPase activity in HG cells. Co-incubating cells with pioglitazone prevented these abnormalities in cytosolic PTPase, the PTP1B content and the impaired phosphorylation of pp185 and receptor beta subunits in HG cells. Finally, HG cells had impaired insulin-stimulated alpha-amino-isobutyric acid uptake, which was ameliorated by exposure to thiazolidine derivatives. In conclusion, exposing cells to high glucose levels desensitizes insulin receptor function, and thiazolidine derivatives can reverse the process via the normalization of cytosolic PTPase, but not of protein kinase C.
Maegawa
H
H
Third Department of Medicine, Shiga University of Medical Science, Japan.
Ide
R
R
Hasegawa
M
M
Ugi
S
S
Egawa
K
K
Iwanishi
M
M
Kikkawa
R
R
Shigeta
Y
Y
Kashiwagi
A
A
D000621:Aminoisobutyric Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D007700:Kinetics; D046911:Macromolecular Substances; D019000:Phosphotyrosine; D000077205:Pioglitazone; D017027:Protein Tyrosine Phosphatases / Q000302:isolation & purification / Q000378:metabolism*; D011887:Raffinose / Q000494:pharmacology; D051381:Rats; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D000621:Aminoisobutyric Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; C100049:2-aminoisobutyric acid; D019000:Phosphotyrosine; D014443:Tyrosine; D011972:Receptor, Insulin; D017027:Protein Tyrosine Phosphatases; D005947:Glucose; D011887:Raffinose; D000077205:Pioglitazone