Journal of Antivirals & Antiretrovirals
Open Access

Abstract

Metformin and Resveratrol Induce Beneficial Metabolic Adaptations in L6 Muscle Cells Treated with HIV Protease Inhibitors: Evidence for Inhibition of JNK1/2 Signaling

Lindsey D Bogachus and Lorraine P Turcotte

C-Jun-N-terminal kinase (JNK1/2) pro-inflammatory signaling has been shown to play a role in highly active
antiretroviral therapy (HAART)-induced insulin resistance in skeletal muscle cells. To determine the effectiveness
of metformin and resveratrol in blunting HAART-induced insulin resistance, L6 skeletal muscle cells were treated
± (with or without) HIV protease inhibitors (ritonavir+atazanavir sulfate; RA) and either metformin, resveratrol, or
the JNK1/2 inhibitor SP600125 and incubated ± insulin (100 nM). SP600125 as well as metformin and resveratrol
reduced (P<0.05) JNK1/2 phosphorylation in RA-treated cells but not in healthy cells. In basal and insulin-stimulated
cells, RA treatment significantly increased JNK1/2 phosophorylation (P<0.05). Additionally, when RA-stimulated cells
were treated with metformin, resveratrol or SP6000125, JNK1/2 phosphorylation was reduced (P<0.05) indicating
reduced inflammation. Basal and insulin-stimulated glucose uptake was increased in RA-treated cells (P<0.05). The
presence of insulin resistance in RA-treated cells was partially abrogated (P>0.05) by metformin and SP600125
treatment. RA-treatment increased FA (fatty acid) uptake and oxidation in both the basal and insulin-stimulated
state. Increased percent change of AKTSer473 phosphorylation indicated increased insulin sensitivity in RA+metformin
(P=0.08) and RA+resveratrol (P<0.05) treated cells. Treatment with metformin, resveratrol or SP600125 had very
little impact on p38 phosphorylation in basal and insulin-stimulated cells made insulin-resistant by incubation with RA.
Our data indicate that metformin and resveratrol induce beneficial metabolic changes in cells made insulin resistant
by treatment with protease inhibitors in part via inhibition of JNK1/2 pro-inflammatory signaling and stimulation of
insulin-mediated AKTSer473 phosphorylation.