4.5 Article

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

Journal

MOLECULAR AND CELLULAR BIOLOGY
Volume 36, Issue 1, Pages 108-118

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00921-15

Keywords

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Funding

  1. Japan Society for the Promotion of Science [25460365]
  2. Japan Diabetes Foundation
  3. Novo Nordisk Pharma
  4. Hyogo Science and Technology Association
  5. Ministry of Education, Culture, Sports, Science, and Technology (MEXT) [23227005]
  6. Japan Society for the Promotion of Science (JSPS) [25460365]
  7. Novo Nordisk Pharma Ltd.
  8. Ministry of Education, Culture, Sports, Science and Technology, Japan (Kakenhi grant) [23227005]
  9. Grants-in-Aid for Scientific Research [23227005, 25460365] Funding Source: KAKEN

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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.

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