Abstract
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.
Highlights
Active antiretroviral therapy (HAART) is prescribed to human immunodeficiency virus (HIV)-infected patients to slow down the progression of HIV and the development of acquired immunodeficiency syndrome (AIDS) [1]
Our data provide new evidence for a central role of JNK1/2 proinflammatory signaling in the induction of insulin resistance by treatment with protease inhibitors such as ritonavir and atazanavir sulfate
Representative gels for total and phosphorylated AKT for cells treated with ritonavir+atazanavir sulfate and metformin (M), resveratrol (Res), SP600125 (SP) or no drug (C: control) under basal or insulin stimulation (I)
Summary
Active antiretroviral therapy (HAART) is prescribed to human immunodeficiency virus (HIV)-infected patients to slow down the progression of HIV and the development of acquired immunodeficiency syndrome (AIDS) [1]. While HAART has many positive effects in HIV-infected patients, it induces insulin resistance in a significant number of patients [2,3]. In line with the notion that tissue inflammation plays a significant role in the induction of insulin resistance [4,6,8,9] we have shown that C-Jun-N-terminal Kinase (JNK1/2) pro-inflammatory signaling, but not p38 Mitogen Activated Protein Kinase (MAPK) signaling, is upregulated in HAART-induced insulin resistance in skeletal muscle cells [10]. Due to its potent anti-oxidative and anti-inflammatory effects, the plantderived polyphenol resveratrol (3,5,4’–trihydroxystilbene) might be another potential agent for the treatment of HAART-induced insulin resistance [20,21]. Resveratrol may be capable of blunting HAART-induced insulin resistance
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