H2S and L‐Cysteine Increase the Glucose Utilization via the PIP3 Mediated Insulin Dependent (PI3K/AKT) and the Insulin Independent (SIRT1/AMPK/PPAR gamma) Signaling Cascades in U937 Human Monocytes Exposed to High Glucose (HG)

Abstract

Diabetic patients have lower blood levels of hydrogen sulfide (H2S) and L‐cysteine (LC). Using U937 human monocytes, this study examined the role of H2S and LC in the impaired glucose metabolism and insulin signaling cascades in diabetes. Monocytes were treated with HG (25 mM,20 h) in presence or absence of LC (100, 500, 1000 μM) or H2S (10, 100 μM). Both LC and H2S treatment caused PI3K activation, PTEN inhibition, increase in intracellular PIP3 (phosphatidylinositol‐3,4,5‐trisphosphate), AKT phosphorylation (Ser 473) and glucose utilization in HG‐treated cells. The effect of LC on PIP3 and glucose utilization was prevented by propargylglycine, an inhibitor of cystathionine‐γ‐lyase that catalyzes H2S formation from LC. This demonstrates that H2S mediates the effect of LC on increased PIP3 and glucose utilization. Treatment with PIP3, H2S and LC caused activation of SIRT1, AMPK phosphorylation (Thr 172) and PPARγ and inhibition of GSK3β (Ser 9) in HG treated cells. Thus, LC/H2S supplementation increases the glucose utilization via the PIP3 mediated activation of SIRT1, AMPK and PPARγ and inhibition of GSK3β. This study reports a novel molecular mechanism by which H2S or LC can up‐regulate the insulin stimulated (PI3K/AKT) and insulin independent (SIRT1/AMPK/PPARγ) glucose metabolism pathways essential for maintenance of glucose homeostasis. (Supported by NIH RO1 DK072433 and Malcolm Feist Chair in Diabetes)