Phosphatidylinositol 3-Kinase Redistribution Is Associated With Skeletal Muscle Insulin Resistance in Gestational Diabetes Mellitus
- 1Departments of Pediatrics, Biochemistry and Molecular Genetics, and
- 2Research Service, Veterans Affairs Medical Center, University of Colorado Health Sciences Center, Denver, Colorado
Insulin resistance during pregnancy provokes gestational diabetes mellitus (GDM); however, the cellular mechanisms for this type of insulin resistance are not well understood. We evaluated the mechanisms(s) for insulin resistance in skeletal muscle from an animal model of spontaneous GDM, the heterozygous C57BL/KsJ-db/+ mouse. Pregnancy triggered a novel functional redistribution of the insulin-signaling environment in skeletal muscle in vivo. This environment preferentially increases a pool of phosphatidylinositol (PI) 3-kinase activity associated with the insulin receptor, away from insulin receptor substrate (IRS)-1. In conjunction with the redistribution of PI 3-kinase to the insulin receptor, there is a selective increase in activation of downstream serine kinases Akt and p70S6. Furthermore, we show that redistribution of PI 3-kinase to the insulin receptor increases insulin-stimulated IRS-1 serine phosphorylation, impairs IRS-1 expression and its tyrosine phosphorylation, and decreases the ability of IRS-1 to bind and activate PI 3-kinase in response to insulin. Thus, the pool of IRS-1–associated PI 3-kinase activity is reduced, resulting in the inability of insulin to stimulate GLUT4 translocation to the plasma membrane. These defects are unique to pregnancy and suggest that redistribution of PI 3-kinase to the insulin receptor may be a primary defect underlying insulin resistance in skeletal muscle during gestational diabetes.
Address correspondence and reprint requests to Jacob E. Friedman, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262. E-mail:.
Received for publication 6 July 2001 and accepted in revised form 24 September 2001.
BSA, bovine serum albumin; GDM, gestational diabetes mellitus; ECL, enhanced chemiluminescence; HRP, horseradish peroxidase; IRS, insulin receptor substrate; MBP, myelin basic protein; PI, phosphatidylinositol; PKC, protein kinase C; PMSF, phenylmethylsulfonyl fluoride; PVDF, polyvinylidene difluoride; TBS-T, Tris-buffered saline with Tween; TNF, tumor necrosis factor.