Phosphorylated S6K1 (Thr389) is a molecular adipose tissue marker of altered glucose tolerance

Abstract

Molecular tissue markers of altered glucose metabolism will be useful as potential targets for antidiabetic drugs. S6K1 is a downstream signal of insulin action. We aimed to evaluate pThr389S6K1 and total S6K1 levels in human and rat fat depots as candidate markers of altered glucose metabolism. pThr389S6K1 and total S6K1 levels were measured using enzyme linked immune sorbent assay (ELISA) in 49 adipose tissue samples from subjects with morbid obesity and in 18 peri-renal white adipose tissue samples from rats. The effects of high glucose and rosiglitazone have been explored in human preadipocytes. pThr389S6K1/totalS6K1 in subcutaneous adipose tissue was significantly increased subjects with Type 2 diabetes (0.78±0.26 vs. 0.55±0.14, P=.02) and associated with fasting glucose (r=0.46, P=.04) and glycated hemoglobin (r=0.63, P=.02) in SAT. Similar associations with fasting glucose (r=0.43, P=.03) and IRS1 (r=-0.41, P=.04) gene expression were found in visceral adipose tissue. In addition, rat experiments confirmed the higher pThr389S6K1/totalS6K1 levels in adipose tissue in association with obesity-associated metabolic disturbances. pThr389S6K1/totalS6K1 was validated using western blot in rat adipose tissue. Both ELISA and western blot data significantly correlated (r=0.85, P=.005). In human preadipocytes, high glucose medium led to increased pThr389S6K1/total S6K1 levels in comparison with normal glucose medium, which was significantly decreased under rosiglitazone administration. In conclusion, in human and rat adipose tissue, phosphorylated S6K1 is a marker for increased glucose levels.