Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

Insulin resistance is critical in the pathogenesis of type 2 diabetes. Endoplasmic reticulum (ER) stress in liver and adipose tissues plays an important role in the development of insulin resistance. Although skeletal muscle is a primary site for insulin-dependent glucose disposal, it is unclear if ER stress in those tissues contributes to insulin resistance. In this study, we show that skeletal muscle kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP3 (phosphatidylinositol-3,4,5-trisphosphate) phosphatase, links ER stress to insulin resistance in skeletal muscle. SKIP expression was increased due to ER stress and was higher in the skeletal muscle isolated from high-fat-diet-fed mice and db/db mice than in that from wild-type mice. Mechanistically, ER stress promotes activating transcription factor 6 (ATF6) and X-box binding protein 1 (XBP1)-dependent expression of SKIP. These findings underscore the specific and prominent role of SKIP in the development of insulin resistance in skeletal muscle.