Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: Potential role of p38 in the downregulation of GLUT4 expression

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 3; pp. 634 - 641
• Main Authors: CARLSON, Christian J, KOTERSKI, Sandra, SCIOTTI, Richard J, POCCARD, German Braillard, RONDINONE, Cristina M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2003
• Subjects: 3T3 Cells; Adipocytes; Adipocytes - enzymology; Adult; Animals; Biological and medical sciences; Body fat; Development and progression; Diabetes; Diabetes Mellitus, Type 2 - enzymology; Enzyme Activation; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Glucose; Glucose Transporter Type 4; Humans; Insulin - pharmacology; Insulin Receptor Substrate Proteins; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Kinases; Male; MAP Kinase Kinase 4; Medical research; Mice; Middle Aged; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Monosaccharide Transport Proteins - analysis; Muscle Proteins; p38 Mitogen-Activated Protein Kinases; Phosphoproteins - analysis; Phosphorylation; Physiological aspects; Proteins; Signal transduction; Transduction; Transduction (Genetics); Type 2 diabetes; Argentina
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.3.634

Serine and threonine kinases may contribute to insulin resistance and the development of type 2 diabetes. To test the potential for members of the mitogen-activated protein (MAP) kinase family to contribute to type 2 diabetes, we examined basal and insulin-stimulated Erk 1/2, JNK, and p38 phosphorylation in adipocytes isolated from healthy and type 2 diabetic individuals. Maximal insulin stimulation increased the phosphorylation of Erk 1/2 and JNK in healthy control subjects but not type 2 diabetic patients. Insulin stimulation did not increase p38 phosphorylation in either healthy control subjects or type 2 diabetic patients. In type 2 diabetic adipocytes, the basal phosphorylation status of these MAP kinases was significantly elevated and was associated with decreased IRS-1 and GLUT4 in these fat cells. To determine whether MAP kinases were involved in the downregulation of IRS-1 and GLUT4 protein levels, selective inhibitors were used to inhibit these MAP kinases in 3T3-L1 adipocytes treated chronically with insulin. Inhibition of Erk 1/2, JNK, or p38 had no effect on insulin-stimulated reduction of IRS-1 protein levels. However, inhibition of the p38 pathway prevented the insulin-stimulated decrease in GLUT4 protein levels. In summary, type 2 diabetes is associated with an increased basal activation of the MAP kinase family. Furthermore, upregulation of the p38 pathway might contribute to the loss of GLUT4 expression observed in adipose tissue from type 2 diabetic patients.