Regulation of Insulin Signaling and Glucose Transporter 4 (GLUT4) Exocytosis by Phosphatidylinositol 3,4,5-Trisphosphate (PIP3) Phosphatase, Skeletal Muscle, and Kidney Enriched Inositol Polyphosphate Phosphatase (SKIP)

Abstract

Background: Insulin-mediated glucose incorporation in skeletal muscle is negatively regulated by phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) phosphatases. Results: Among PIP 3 phosphatases, skeletal muscle and kidney enriched inositol polyphosphate phosphatase (SKIP) silencing increased insulin signaling in C2C12 cells. Conclusion: SKIP is the predominant PIP 3 phosphatase regulating insulin signaling. Significance: SKIP is a promising target for the regulation of insulin resistance.

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

“…SKIP relocates from the ER to the plasma membrane upon insulin stimulation, where it binds to the activated form of p21-activated kinase 1 (PAK1) and forms a complex with Akt2 (3). The location of SKIP proximal to these PIP 3 effectors determines the efficiency and specificity of the termination of insulin signaling (26). Therefore, it appears likely that SKIP is the specific regulator for diet-induced insulin resistance in skeletal muscle (26).…”

“…The location of SKIP proximal to these PIP 3 effectors determines the efficiency and specificity of the termination of insulin signaling (26). Therefore, it appears likely that SKIP is the specific regulator for diet-induced insulin resistance in skeletal muscle (26). Thus, the expression status of SKIP is likely to contribute to the development of insulin resistance in this tissue.…”

“…PIP 3 phosphatases hydrolyze PIP 3 and attenuate the PI 3-kinase signaling pathway. Skeletal muscle and kidney-enriched inositol polyphosphate 5-phosphatase (SKIP) is one of the PIP 3 phosphatases that negatively regulate insulin-dependent glucose uptake in skeletal muscle (23)(24)(25)(26). SKIP heterozygous knockout mice exhibit improved systemic insulin sensitivity and are resistant to diet-induced insulin resistance (25).…”

Role of Phosphatidylinositol 3,4,5-Trisphosphate (PIP3) 5-Phosphatase Skeletal Muscle- and Kidney-enriched Inositol Polyphosphate Phosphatase (SKIP) in Myoblast Differentiation

“…SKIP is a regulator of insulin-dependent Akt activation in skeletal muscle cells (11,12). Among the Akt species, Akt1 and Akt2 have been implicated in muscle cell differentiation.…”

“…MyoD is required for expression of SKIP in skeletal muscles, partly via cis-acting elements in the Skip promoter, and the expression level of SKIP was up-regulated in early differentiated C2C12 myoblast cells. SKIP is a phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) 5-phosphatase that negatively regulates insulin-induced phosphatidylinositol 3-kinase (PI 3-kinase)-Akt signaling and glucose uptake among PIP 3 phosphatases in the skeletal muscle (11,12). We previously reported that heterozygous SKIP knock-out mice exhibited increased systemic insulin sensitivity and increased insulin signaling in skeletal muscles (13).…”