Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: effects of pioglitazone and metformin treatment

Abstract

Objective: Chronic low-grade inflammation is a common feature of insulin resistant states, including obesity and type 2 diabetes. Less is known about inflammation in Polycystic Ovary Syndrome (PCOS). Thus we evaluated the impact of PCOS on circulating cytokine levels and the effects of anti-diabetic therapies on insulin action, cytokine and chemokine levels and inflammatory signaling in skeletal muscle.

Methods: Twenty subjects with PCOS and 12 healthy normal cycling (NC) subjects of similar body mass index were studied. PCOS subjects received oral placebo or pioglitazone, 45 mg/d, for 6 months. All PCOS subjects then had metformin, 2 g/day, added to their treatment. Circulating levels of cytokines, chemokines, and adiponectin, skeletal muscle markers of inflammation and phosphorylation of signaling proteins, insulin action evaluated by the hyperinsulinemic/euglycemic clamp procedure and Homeostasis Model Assessment of Insulin Resistance were measured.

Results: Circulating levels of a number of cytokines and chemokines were generally similar between PCOS and NC subjects. Levels in PCOS subjects were not altered by pioglitazone or metformin treatment, even though whole body insulin action and adiponectin levels increased with pioglitazone. In spite of the lack of change in levels of cytokines and chemokines, several markers of inflammation in skeletal muscle were improved with Pio treatment.

Conclusions: PCOS may represent a state of elevated sensitivity of inflammatory cells in skeletal muscle to cytokines and chemokines, a property that could be reversed by pioglitazone treatment together with improved insulin action.

Keywords: ANCOVA; BMI; CV; DHEA; DHEA-S; FG; Ferman-Galloway score; GDR; GROα; HOMA-IR; IFNγ; IGT; IKK; IL; Ikappa B kinase; Inflammation; Insulin resistance; JNK; MAPK; MCP-1; MIP-1β; NC; NF-kB; PCOS; SHBG; T; T2D; TNFα; Thiazolidinediones; VEGF; WHR; analysis of covariance; body mass index; c-jun N-terminal kinase; coefficient of variation; dehydroepiandrosterone; dehydroepiandrosterone sulfate; glucose disposal rate; growth-related oncogene alpha; homeostasis model assessment of insulin resistance; impaired glucose tolerance; interferon gamma; interlukin; macrophage inflammatory protein-1beta; mitogen-activated protein kinase; monocyte chemoattractant protein-1; normal cycling subject; nuclear factor kappa-light-chain-enhancer of activated B cells; polycystic ovary syndrome; sex hormone binding globulin; testosterone; tumor necrosis factor alpha; type 2 diabetes; vascular endothelial growth factor; waist–hip ratio.