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Diabetes 50:83-90, 2001
© 2001 by the American Diabetes Association, Inc.

Decreased In Situ Insulin Receptor Dephosphorylation in Hyperglycemia-Induced Insulin Resistance in Rat Adipocytes

Shangguo Tang, Hoang Le-Tien, Barry J. Goldstein, Phillip Shin, Robert Lai, and I. George Fantus

From the Department of Medicine (I.G.F.), Mount Sinai Hospital and the University Health Network; the Department of Physiology (P.S., I.G.F.) and Banting and Best Diabetes Centre (S.T., H.L.-T., P.S., R.L., I.G.F.), University of Toronto, Toronto, Ontario, Canada; and the Department of Medicine and the Dorrance H. Hamilton Research Laboratories (B.J.G.), Jefferson Medical College, Philadelphia, Pennsylvania.

Address correspondence and reprint requests to Dr. I.G. Fantus, Department of Medicine, Mount Sinai Hospital, 600 University Ave., Rm. 780, Toronto, ON M5G 1X5, Canada. E-mail: fantus{at}mshri.on.ca .

The regulation of insulin receptor (IR) tyrosine (tyr) phosphorylation is a key step in the control of insulin signaling. Augmented IR tyr dephosphorylation by protein tyrosine phosphatases (PTPs) may contribute to insulin resistance. To investigate this possibility in hyperglycemia-induced insulin resistance, primary cultured rat adipocytes were rendered insulin-resistant by chronic exposure (18 h) to 15 mmol/l glucose combined with 10-7 mol/l insulin. Insulin-resistant adipocytes showed a decrease in insulin sensitivity and a maximum response of 2-deoxyglucose uptake, which was associated with a decrease in maximum insulin-stimulated IR tyr phosphorylation in situ. To assess tyr dephosphorylation, IRs of insulin-stimulated permeabilized adipocytes were labeled with [{gamma}-32P]ATP and chased for 2 min with unlabeled ATP in the presence of EDTA. In a nonradioactive protocol, insulin-stimulated adipocytes were permeabilized and exposed to EDTA and erbstatin for 2 min, and IRs were immunoblotted with anti-phosphotyrosine (pY) antibodies. Both methods showed a similar diminished extent of IR tyr dephosphorylation in resistant cells. Immunoblotting of four candidate IR-PTPs demonstrated no change in PTP1B or the SH2 domain containing phosphatase-2 (SHP-2), whereas a significant decrease in leukocyte antigen-related phosphatase (LAR) (51 ± 3% of control) and an increase in PTP-{alpha} (165 ± 16%) were found. Activity of immunoprecipitated PTPs toward a triple tyr phosphorylated IR peptide revealed a correlation with protein content for PTP1B, SHP-2, and LAR but a decrease in apparent specific activity of PTP-{alpha}. The data indicate that decreased IR tyr phosphorylation in hyperglycemia-induced insulin resistance is not due to enhanced dephosphorylation. The diminished IR tyr dephosphorylation observed in this model is associated with decreased LAR protein content and activity.


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