Hydrogen Sulfide and L-Cysteine Increase Phosphatidylinositol 3,4,5-Trisphosphate (PIP3) and Glucose Utilization by Inhibiting Phosphatase and Tensin Homolog (PTEN) Protein and Activating Phosphoinositide 3-Kinase (PI3K)/Serine/Threonine Protein Kinase (AKT)/Protein Kinase Cζ/λ (PKCζ/λ) in 3T3l1 Adipocytes

This work examined the novel hypothesis that reduced levels of H2S or L-cysteine (LC) play a role in the impaired glucose metabolism seen in diabetes. 3T3L1 adipocytes were treated with high glucose (HG, 25 mM) in the presence or absence of LC or H2S. Both LC and H2S treatments caused an increase in phosphatidylinositol-3,4,5 trisphosphate (PIP3), AKT phosphorylation, and glucose utilization in HG-treated cells. The effect of LC on PIP3 and glucose utilization was prevented by propargylglycine, an inhibitor of cystathionine gamma-lyase that catalyzes H2S formation from LC. This demonstrates that H2S mediates the effect of LC on increased PIP3 and glucose utilization. H2S and LC caused phosphatidylinositol 3-kinase activation and PTEN inhibition. Treatment with LC, H2S, or PIP3 increased the phosphorylation of IRS1, AKT, and PKC zeta/lambda as well as GLUT4 activation and glucose utilization in HG-treated cells. This provides evidence that PIP3 is involved in the increased glucose utilization observed in cells supplemented with LC or H2S. Comparative signal silencing studies with siAKT2 or siPKC zeta revealed that PKC zeta phosphorylation is more effective for the GLUT4 activation and glucose utilization in LC-, H2S-,or PIP3-treated cells exposed to HG. This is the first report to demonstrate that H2S or LC can increase cellular levels of PIP3, a positive regulator of glucose metabolism. The PIP3 increase is mediated by PI3K activation and inhibition of PTEN but not of SHIP2. This study provides evidence for a molecular mechanism by which H2S or LC can up-regulate the insulin-signaling pathways essential for maintenance of glucose metabolism.