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PIP3 but not PIP2 increases GLUT4 surface expression and glucose metabolism mediated by AKT/PKCζ/λ phosphorylation in 3T3L1 adipocytes

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Abstract

Phosphatidylinositol-3,4,5-triphosphate (PIP3) and phosphatidylinositol-4,5-biphosphate (PIP2) are two well-known membrane bound polyphosphoinositides. Diabetes is associated with impaired glucose metabolism. Using a 3T3L1 adipocyte cell model, this study investigated the role of PIP3 and PIP2 on insulin stimulated glucose metabolism in high glucose (HG) treated cells. Exogenous PIP3 supplementation (1, 5, or 10 nM) increased the phosphorylation of AKT and PKCζ/λ, which in turn upregulated GLUT4 total protein expression as well as its surface expression, glucose uptake, and glucose utilization in cells exposed to HG (25 mM); however, PIP2 had no effect. Comparative signal silencing studies with antisense AKT2 and antisense PKCζ revealed that phosphorylation of PKCζ/λ is more effective in PIP3 mediated GLUT4 activation and glucose utilization than in AKT phosphorylation. Supplementation with PIP3 in combination with insulin enhanced glucose uptake and glucose utilization compared to PIP2 with insulin, or insulin alone, in HG-treated adipocytes. This suggests that a decrease in cellular PIP3 levels may cause impaired insulin sensitivity in diabetes. PIP3 supplementation also prevented HG-induced MCP-1 and resistin secretion and lowered adiponectin levels. This study for the first time demonstrates that PIP3 but not PIP2 plays an important role in GLUT4 upregulation and glucose metabolism mediated by AKT/PKCζ/λ phosphorylation. Whether PIP3 levels in blood can be used as a biomarker of insulin resistance in diabetes needs further investigation.

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Acknowledgments

The authors thank Ms. Georgia Morgan for excellent editing of this manuscript. The authors were supported by Grants from NIDDK and the Office of Dietary Supplements of the National Institutes of Health RO1 DK072433 and the Malcolm Feist Endowed Chair in Diabetes. This study was also funded by a fellowship from the Malcolm Feist Cardiovascular Research Endowment, LSU Health Sciences Center, Shreveport.

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The authors have declared that no conflict of interest exists.

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  1. Department of Pediatrics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA

    Prasenjit Manna & Sushil K. Jain

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  1. Prasenjit Manna
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  2. Sushil K. Jain
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Correspondence to Sushil K. Jain.

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Manna, P., Jain, S.K. PIP3 but not PIP2 increases GLUT4 surface expression and glucose metabolism mediated by AKT/PKCζ/λ phosphorylation in 3T3L1 adipocytes. Mol Cell Biochem 381, 291–299 (2013). https://doi.org/10.1007/s11010-013-1714-7

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  • DOI: https://doi.org/10.1007/s11010-013-1714-7

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