Abstract

Therapeutic interventions that increase plasma high density lipoprotein (HDL) and apolipoprotein (apo) A-I levels have been reported to reduce plasma glucose levels and attenuate insulin resistance. The present study asks if this is a direct effect of increased glucose uptake by skeletal muscle. Incubation of primary human skeletal muscle cells (HSKMCs) with apoA-I increased insulin-dependent and insulin–independent glucose uptake in a time- and concentration-dependent manner. The increased glucose uptake was accompanied by enhanced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), the serine/threonine kinase Akt and Akt substrate of 160 kDa (AS160). Cell surface levels of the glucose transporter type 4, GLUT4, were also increased. The apoA-I-mediated increase in glucose uptake by HSKMCs was dependent on phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt, the ATP binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-B1). Taken together, these results establish that apoA-I increases glucose disposal in skeletal muscle by activating the IR/IRS-1/PI3K/Akt/AS160 signal transduction pathway. The findings suggest that therapeutic agents that increase apoA-I levels may improve glycemic control in people with type 2 diabetes.

Highlights

  • Apolipoprotein A-I is the most abundant apolipoprotein constituent of high density lipoproteins (HDLs)[1]

  • The outcome of the present study provides a human skeletal muscle cells (HSKMCs) were transfected with scrambled siRNA, ATP binding cassette transporter A1 (ABCA1) siRNA or scavenger receptor class B type 1 (SR-B1) siRNA

  • Glucose uptake was measured in the ABCA1 siRNA-transfected (C) and SR-B1 siRNA-transfected cells (D) as described in the legend to Fig. 1

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Summary

Introduction

Apolipoprotein (apo) A-I is the most abundant apolipoprotein constituent of high density lipoproteins (HDLs)[1]. Phosphorylated PI3K activates a downstream signal transduction pathway that phosphorylates serine/threonine kinase Akt (protein kinase B)[14,15] and the Rab GTPase-activating protein, Akt substrate of 160 kDa (AS160)[16] This culminates in the translocation of glucose transporter 4 (GLUT4) to the www.nature.com/scientificreports/. The apoA-I was removed, and the cells were incubated for 1 h in the (C) presence or (D) absence of insulin (0.1 μmol/L final concentration). (E,F) Glucose uptake was assessed from 0.5 to 5 h in HSKMCs pre-incubated with (closed symbols) or without (open symbols) apoA-I as in Panel A, incubated for a further 1 h in the (E) presence or (F) absence of insulin (0.1 μmol/L final concentration). Glucose uptake was normalized to 1 nmol/mg/h for cells incubated under basal conditions (open bar, Panels A, C,D). *p < 0.05, **p < 0.01, ***p < 0.001 vs. control (open bars and circles)

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