Objective: We have performed the comparative study of basal state of SGK-dependent signaling among obese patients with/without type 2 diabetes mellitus (T2DM). We have accomplished correlation analysis of glucose metabolism and incretin profile parameters against phosphorylation and expression parameters for SGK1 and its substrate NDRG1.
Methods: 36 patients with long (>10 years) and morbid (BMI>35 kg/m2) obesity, 18 of which had normal glucose tolerance (NGT) and 18 had T2DM were enrolled in this study. Hyperinsulinemic-euglycemic clamp test and HOMA-IR were used to evaluate the 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. Biopsies from subcutaneous and omental fat depots were obtained during bariatric surgery for all patients and signaling states were analyzed by western blot.
Results: Analysis of SGK signaling for subcutaneous fat has shown single significant intergroup difference: enhancing of pSGK-S422 phosphorylation in T2DM group, but also pNDRG-T346 level has tendency to accumulation in subcutaneous fat of NGT patients. Analysis of SGK signaling for omental fat has shown similar results: in this case accumulation of pNDRG-T346 in NGT patients was statistically significant. Correlation analysis has shown strong direct correlation of pNDRG-T346 level with BMI and AUC for GLP-1 and reverse correlation of pNDRG-T346 with Hb1Ac and AUC for glucagon. For pSGK-S422 we have observed opposite characters of correlations with the similar parameters of carbohydrate metabolism and incretin profile.
Conclusions: In present work we have taken more patients and have shown critical relevance and general character of stress-dependent SGK1-NDRG1 signal axis as a marker of insulin resistance for different fat depots.
Disclosure
I. Stafeev: None. A. V. Vorotnikov: None. Y. V. Parfyonova: None. M. V. Shestakova: None. I. Sklyanik: None. E. Mamontova: None. S. Michurina: None. E. Shestakova: None. K. Yahyaev: None. A. Yurasov: None. E. Ratner: None. M. Menshikov: None.
Funding
Russian Science Foundation (17-15-01435)
Background: Under normal physiological conditions, adipose derived stem cells (ADSC) maintain adipose tissue homeostasis by responding to metabolic loading through proliferation and differentiation. Nevertheless, in T2DM their properties might be compromised. ADSC give rise to thermogenic beige adipocytes that make a significant contribution into excess energy utilization in obesity. We compared ADSC response to beiging inductors in obese patients with type 2 diabetes mellitus (T2DM) and with normal glucose tolerance (NGT).
Methods: We collected subcutaneous fat biopsies from 5 obese NGT (BMI>35kg/m2) and 5 obese T2DM patients during bariatric surgery. ADSC were enzymatically isolated and underwent white and beige adipogenic differentiation. UCP-1 level was evaluated by RT-PCR and Western blot. Expression of lipid metabolism and electron transport chain (ETC) genes were analyzed by RT-PCR. ROS production was evaluated by fluorescent microscopy.
Results: UCP-1 expression was decreased in beige adipocytes from T2DM patients in mRNA and protein levels. Nevertheless, expression and phosphorylation of lipolytic proteins were equal in beige adipocytes of NGT and T2DM groups. Expression analysis of ETC genes also has not shown any statistically significant differences. All the while, we revealed increased mitochondrial ROS production in T2DM beige adipocytes during beige differentiation.
Conclusions: These results indicate association of ADSC thermogenic potential and T2DM development. Decreased UCP1 level in complex with normal lipolysis and ETC activity in beige adipocytes from T2DM patients may be liable to elevated ROS level, known to initiate mitochondria damage and insulin resistance.
Disclosure
S. Michurina: None. I. Stafeev: None. I. Sklyanik: 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. E. Ratner: None. M. Menshikov: None. M.V. Shestakova: None. Y.V. Parfyonova: None.
Funding
Russian Science Foundation (17-15-01435)
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