NDRG1 Activity in Fat Depots Is Associated With Type 2 Diabetes and Impaired Incretin Profile in Patients With Morbid Obesity

OBJECTIVE: We aimed to investigate insulin-, mTOR- and SGK1-dependent signaling basal states in morbidly obese patients’ fat. We analyzed the correlation between the signaling activity, carbohydrate metabolism, and incretin profiles of patients. METHODS: The omental and subcutaneous fat was obtained in patients with obesity. The omental study included 16 patients with normal glucose tolerance (NGT) and 17 patients with type 2 diabetes mellitus (T2DM); the subcutaneous study included 9 NGT patients and 12 T2DM patients. Insulin resistance was evaluated using the hyperinsulinemic euglycemic clamp test and HOMA-IR index. The oral glucose tolerance test (OGTT) for NGT patients and mixed meal tolerance test (MMTT) for T2DM patients were performed. The levels of incretins (GLP-1, GIP, oxyntomodulin) and glucagon were measured during the tests. Signaling was analyzed by Western blotting in adipose tissue biopsies. RESULTS: We have shown equal levels of basal phosphorylation of insulin- and mTOR-dependent signaling in omental fat depot in NGT and T2DM obese patients. Nevertheless, pNDRG1-T346 was decreased in omental fat of T2DM patients. Correlation analysis has shown an inverse correlation of pNDRG1-T346 in omental fat and diabetic phenotype (HbA1c, impaired incretin profile (AUC GLP-1, glucagon)). Moreover, pNDRG1-T346 in subcutaneous fat correlated with impaired incretin levels among obese patients (inverse correlation with AUC glucagon and AUC GIP). CONCLUSIONS: According to results of the present study, we hypothesize that phosphorylation of pNDRG1-T346 can be related to impairment in incretin hormone processing. pNDRG1-T346 in adipose tissue may serve as a marker of diabetes-associated impairments of the systemic incretin profile and insulin sensitivity.