Insulin action is severely impaired in adipocytes of apparently healthy overweight and obese subjects.

Abstract

Many overweight/obese subjects appear metabolically healthy with normal invivo insulin sensitivity. Still, they have increased long-term risk of developing type 2 diabetes. We hypothesized that adipose tissue dysfunction involving decreased insulin action in adipocytes is present in apparently healthy overweight/obese subjects. Subjects with normal metabolic health according to Adult Treatment Panel-III or Framingham risk score criteria were subdivided into 67 lean, 32 overweight and 37 obese according to body mass index. They were compared with 200 obese individuals with metabolic syndrome. Insulin sensitivity and maximum action on inhibition of lipolysis and stimulation of lipogenesis was determined in subcutaneous adipocytes. Gene expression was determined by micro-array and qPCR. DNA methylation was assessed by array, pyrosequencing and reporter assays. Compared with lean, adipocytes in overweight/obese displayed marked reductions in insulin sensitivity in both antilipolysis and lipogenesis as well as an attenuated maximum lipogenic response. Among these, only antilipolysis sensitivity correlated with whole-body insulin sensitivity. These differences were already evident in the overweight state, were only slightly worse in the unhealthy obese state and were not related to fat cell size. Adipose tissue analyses linked this to reduced expression of the insulin signalling protein AKT2, which associated with increased methylation at regulatory sites in the AKT2 promoter. Apparently healthy subjects have severely disturbed adipocyte insulin signalling already in the overweight state which involves epigenetic dysregulation of AKT2. This may constitute an early defect in insulin action that appears even upon modest increases in fat mass.