Reductions in Plasma Cytokine Levels With Weight Loss Improve Insulin Sensitivity in Overweight and Obese Postmenopausal Women

Abstract

OBJECTIVE—The purpose of this study was to determine whether improvements in insulin sensitivity with weight loss are mediated by changes in inflammation in obese, postmenopausal women. RESEARCH DESIGN AND METHODS—We studied 58 sedentary, overweight, and obese (BMI 33 ± 1 kg/m², means ± SEM) postmenopausal (58 ± 1 year) women at baseline and 37 women who completed 6 months of weight loss induced by diet and exercise. The women underwent 3-h hyperinsulinemic-euglycemic clamps (40 mU · m⁻² · min⁻¹) to determine glucose utilization (M). Insulin sensitivity was determined as M/I, the amount of glucose metabolized per unit of plasma insulin (I). Visceral adipose tissue (VAT) and plasma concentrations of C-reactive protein (CRP), cytokines interleukin (IL)-6, and tumor necrosis factor (TNF)-α, as well as their soluble receptors, were measured. RESULTS—At baseline, CRP concentration was a predictor of both glucose utilization and insulin sensitivity, independent of adiposity, race, and aerobic fitness (M: partial r = −0.30, P = 0.03, and M/I: partial r = −0.32, P = 0.02). Weight loss resulted in significant reductions in body weight, fat mass, VAT, and fasting glucose and insulin levels (P < 0.05). Both glucose utilization and insulin sensitivity increased by 16% (P < 0.05). CRP, IL-6, and soluble TNF receptor (sTNFR)-1 concentrations decreased (P < 0.05), but concentrations of TNF-α, sTNFR-2, and soluble IL-6 receptor (IL-6sR) did not change. In stepwise regression models to predict changes in glucose homeostasis, changes in VAT and sTNF-R1 independently predicted changes in glucose utilization (r = −0.49 and cumulative r = −0.64, P < 0.01), while changes in VAT and IL-6 were both independent predictors of changes in insulin sensitivity (r = −0.57 and cumulative r = −0.68, P < 0.01). CONCLUSIONS—Improvements in glucose metabolism with weight loss programs are independently associated with decreases in cytokine concentrations, suggesting that a reduction in inflammation is a potential mechanism that mediates improvements in insulin sensitivity.