Divergence between GLUT4 mRNA and protein abundance in skeletal muscle of insulin resistant rats
S R Hager1, D Pastorek, A L Jochen
1Department of Medicine, Medical College of Wisconsin, Milwaukee 53226.
Abstract:
Hyperglycemia and skeletal muscle insulin resistance coexist in uncontrolled type 2 diabetes mellitus. Similar defects in insulin action were observed in glucose-infused, normal rats, a model of glucose toxicity. In these rats insulin-stimulated glucose uptake by skeletal muscle was decreased due to a post-receptor defect. We investigated whether the impaired glucose uptake resulted from a decrease in the abundance of the predominant muscle glucose transporter (GLUT4) mRNA and/or protein. GLUT4 protein abundance in the hyperglycemic rats was not different from the control group despite a 50% decrease in muscle glucose uptake. GLUT4 mRNA abundance was 2.5-fold greater in the hyperglycemic rats as compared to the control animals. We conclude that the coexistence of hyperglycemia and hyperinsulinemia results in (1) a defect in GLUT4 compartmentalization and/or functional activity and (2) a divergence between GLUT4 mRNA levels and translation.
Insights
In type 2 diabetes, high blood sugar (hyperglycemia) impairs muscle glucose uptake despite normal GLUT4 protein levels. This suggests a defect in glucose transporter function or regulation, not just quantity.
Area of Science:
- Biochemistry
- Physiology
- Endocrinology
Background:
- Type 2 diabetes is characterized by hyperglycemia and skeletal muscle insulin resistance.
- Glucose toxicity, induced by glucose infusion in rats, mimics defects in insulin action seen in type 2 diabetes.
- Insulin resistance in these models involves post-receptor defects affecting muscle glucose uptake.
Purpose of the Study:
- To investigate the role of the glucose transporter type 4 (GLUT4) in impaired muscle glucose uptake during hyperglycemia.
- To determine if reduced GLUT4 mRNA or protein abundance contributes to insulin resistance in a glucose toxicity model.
Main Methods:
- Utilized a rat model of glucose toxicity induced by glucose infusion.
- Measured GLUT4 protein and mRNA abundance in skeletal muscle.
- Assessed insulin-stimulated glucose uptake in skeletal muscle.
Main Results:
- Skeletal muscle glucose uptake was reduced by 50% in hyperglycemic rats compared to controls.
- GLUT4 protein abundance remained unchanged in hyperglycemic rats.
- GLUT4 mRNA abundance was significantly increased (2.5-fold) in hyperglycemic rats.
Conclusions:
- Hyperglycemia and hyperinsulinemia lead to impaired GLUT4 function or localization, not reduced expression.
- A disconnect exists between GLUT4 mRNA levels and protein translation in this model.
- These findings highlight post-translational regulation of GLUT4 in insulin resistance.
