Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects.
- 1 May 1995
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 95 (5), 2195-2204
- https://doi.org/10.1172/jci117909
Abstract
To determine whether the impaired insulin-stimulated glucose uptake in obese individuals is associated with altered insulin receptor signaling, we measured both glucose uptake and early steps in the insulin action pathway in intact strips of human skeletal muscle. Biopsies of rectus abdominus muscle were taken from eight obese and eight control subjects undergoing elective surgery (body mass index 52.9 +/- 3.6 vs 25.7 +/- 0.9). Insulin-stimulated 2-deoxyglucose uptake was 53% lower in muscle strips from obese subjects. Additional muscle strips were incubated in the basal state or with 10(-7) M insulin for 2, 15, or 30 min. In the lean subjects, tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), measured by immunoblotting with anti-phosphotyrosine antibodies, was significantly increased by insulin at all time points. In the skeletal muscle from the obese subjects, insulin was less effective in stimulating tyrosine phosphorylation (maximum receptor and IRS-1 phosphorylation decreased by 35 and 38%, respectively). Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase (PI 3-kinase) activity also was markedly lower in obese subjects compared with controls (10- vs 35-fold above basal, respectively). In addition, the obese subjects had a lower abundance of the insulin receptor, IRS-1, and the p85 subunit of PI 3-kinase (55, 54, and 64% of nonobese, respectively). We conclude that impaired insulin-stimulated glucose uptake in skeletal muscle from severely obese subjects is accompanied by a deficiency in insulin receptor signaling, which may contribute to decreased insulin action.This publication has 51 references indexed in Scilit:
- Skeletal muscle protein tyrosine phosphatase activity and tyrosine phosphatase 1B protein content are associated with insulin action and resistance.JCI Insight, 1994
- Intrinsic differences of insulin receptor kinase activity in red and white muscle.Online Journal of Public Health Informatics, 1986
- Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity.JCI Insight, 1986
- Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucoseCell, 1986
- Diabetes-induced functional and structural changes in insulin receptors from rat skeletal muscle.JCI Insight, 1986
- The Disposal of an Oral Glucose Load in Healthy Subjects: A Quantitative StudyDiabetes, 1985
- Tyrosine phosphorylation of the insulin receptor beta subunit activates the receptor-associated tyrosine kinase activity.Online Journal of Public Health Informatics, 1984
- Insulin activates a tyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes and human placenta.Proceedings of the National Academy of Sciences of the United States of America, 1982
- Insulin secretion, insulin resistance, and obesity.1982
- A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye BindingAnalytical Biochemistry, 1976