Analysis of molecular mechanisms underlying induction of insulin resistance in skeletal muscle

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460365
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kobe University
• Principal Investigator: IJUIN TAKESHI 神戸大学, 医学(系)研究科(研究院), 助教 (00361626)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: SKIP / 骨格筋 / インスリンシグナル / インスリン抵抗性 / 小胞体ストレス / GRP78

Outline of Final Research Achievements

Insulin resistance is characterized as a pathogenic factor in Type 2 diabetes. Here we show that skeletal muscle and kidney-enriched inositol polyphosphate phosphatase (SKIP), a phosphatidylinositol-3,4,5-trisphosphate (PIP3) phosphatase, and glucose-regulated protein 78 (GRP78) are implicated in inhibition of insulin-dependent PI 3-kinase signaling in skeletal muscle. We also show that SKIP 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 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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