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. 2013 Jun 1;591(11):2897-909.
doi: 10.1113/jphysiol.2012.247510. Epub 2013 Mar 25.

Effect of a sustained reduction in plasma free fatty acid concentration on insulin signalling and inflammation in skeletal muscle from human subjects

Hanyu Liang  1 , Puntip Tantiwong, Apiradee Sriwijitkamol, Karthigayan Shanmugasundaram, Sumathy Mohan, Sara Espinoza, Ralph A Defronzo, John J Dubé, Nicolas Musi
Affiliations

Effect of a sustained reduction in plasma free fatty acid concentration on insulin signalling and inflammation in skeletal muscle from human subjects

Hanyu Liang et al. J Physiol. .

Abstract

Free fatty acids (FFAs) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacological FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signalling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signalling, IBα protein, c-Jun phosphorylation, inflammatory gene (toll-like receptor 4 and monocyte chemotactic protein 1) expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for 7 days, and the results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signalling in obese and T2DM subjects. Acipimox increased IBα protein (an indication of decreased IB kinase-nuclear factor B signalling) in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacological FFA reduction improves insulin signalling in muscle from insulin-resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements in insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs.

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Figures

Figure 1
Figure 1. Effect of acipimox on insulin signalling in muscle from obese and T2DM subjects
Insulin signalling was assessed by Western blotting before and during (30 min and 180 min) a hyperinsulinaemic clamp. Photographs of representative Western blotting are shown for IRS-1 tyrosine phosphorylation in obese (A) and T2DM (B) subjects, for Akt phosphorylation in obese (D) and T2DM (E) subjects, and for AS160 phosphorylation in obese (G) and T2DM (H) subjects. Quantifications of IRS-1 tyrosine phosphorylation (C), Akt phosphorylation (F), and AS160 phosphorylation (I) are determined from the Western blotting. All values are mean ± SEM. Data are expressed as fold change from baseline. B: baseline; Pre: before acipimox; Post: after acipimox; OB: obese; DM: type 2 diabetes mellitus. *P < 0.05 vs. the same time point of lean group; #P < 0.05 vs. the same time point of either obese or T2DM before acipimox treatment.
Figure 2
Figure 2. Effect of acipimox on IκBα protein content and c-Jun phosphorylation in muscle from obese and T2DM subjects
IκBα protein content (A) and c-Jun phosphorylation (B) were determined by Western blotting. Representative blots for one lean, two obese, and two T2DM subjects are shown. In the IκBα gel equal protein loading was verified by Ponceau S staining. All values are mean ± SEM. Data are expressed as arbitrary units (AU). OB: obese; DM: type 2 diabetes mellitus. *P < 0.05 vs. lean; #P < 0.05 vs. before acipimox of respective group.
Figure 3
Figure 3. Effect of acipimox on inflammatory gene expression in muscle from obese and T2DM subjects
TLR4(A), MCP1 (B), VEGF (C) and SOD2 (D) mRNA expression was determined by quantitative RT-PCR as described under Methods. Data are expressed as arbitrary units (AU). OB: obese; DM: type 2 diabetes mellitus. *P < 0.05 vs. lean; #P < 0.05 vs. T2DM before acipimox.
Figure 4
Figure 4. Effect of acipimox on DAG and ceramides in muscle from obese and T2DM subjects
DAG (A) and ceramide (B) concentration was determined as described under Methods. All values are the mean ± SEM. Data are expressed as pmol (mg protein)−1. OB: obese; DM: type 2 diabetes mellitus. *P < 0.05 vs. lean.
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