Objective: In our study we have compared basal insulin and mTOR signaling in subcutaneous fat of obese T2DM vs. obese subjects with normal glucose tolerance (NGT). We have performed correlation analysis of phosphorylation’s parameters against clinical parameters of carbohydrate metabolism and incretin secretion profiles.
Methods: 22 patients with long (>10 years) and morbid (BMI > 35 kg/m2) obesity, 12 of which had NGT and 10 had T2DM were enrolled in this study. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to measure insulin resistance. Blood samples taken at 0, 30 and 120 min of food load test were used to assess incretin profile, insulin and glucose levels. Amount of total and visceral fat was determined by bioelectrical impedance analysis. Subcutaneous fat biopsies were obtained during bariatric surgery for all patients and signaling state was analyzed by western blots.
Results: As assessed by western blots of insulin receptor substrate (IRS), Akt, Raptor, Rictor, mTOR and S6K1, the basal insulin signaling and mTORC activities were comparable in NGT and T2DM groups, whereas phosphorylation of AS160 (pAS160-S318) was significantly lower and serum and glucocorticoid-induced kinase (SGK; pSGK-S422) was significantly higher in T2DM group. Various correlations were found between the degree of insulin resistance and amount of visceral fat, changes in incretin profile, glucose metabolic parameters and phosphorylation level of AS160, incretin secretion profile and phosphorylated levels of AS160 or SGK1.
Conclusions: Altered phosphorylation of AS160 and SGK1 is associated with obese T2DM phenotype and impaired incretin profile. We think that AS160 and SGK1 phosphorylations can be important markers of the prediabetes-to-diabetes transition.
I. Stafeev: None. I. Sklyanik: None. S. Michurina: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Yurasov: None. K. Yahyaev: None. A. Karmadonov: None. E. Ratner: None. M. Menshikov: None. A.V. Vorotnikov: None. Y.V. Parfyonova: None. M.V. Shestakova: None.
Russian Science Foundation (17-15-01435)