Abstract
ObjectiveWe 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.MethodsThe 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.ResultsWe 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).ConclusionsAccording 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.
Highlights
Overweight, obesity, and type 2 diabetes mellitus (T2DM) are strongly associated with different comorbidities [1, 2]
Adiponectin was suppressed in the T2DM group, whereas leptin level was comparable in normal glucose tolerance (NGT) and T2DM
No differences between NGT and T2DM groups were observed in mTORC1 or mTORC2 signaling in subcutaneous fat except that only serum and glucocorticoid-induced kinase type 1 (SGK1) phosphorylation at S422 was increased in the T2DM group [29]
Summary
Overweight, obesity, and type 2 diabetes mellitus (T2DM) are strongly associated with different comorbidities [1, 2]. Some patients with obesity can demonstrate a “metabolically healthy” phenotype during a long time without any alterations in carbohydrate metabolism and insulin sensitivity. In this light, the search for new markers and mechanisms of the transition from non-diabetic obesity to severe insulin resistance and T2DM is of much interest to both clinic and basic research [3, 4]. The heterogeneity and altered distribution of adipose tissue determine metabolic risks. Accumulation of visceral fat is a predictor for threatening metabolic complications such as insulin resistance [6, 7], pro-atherogenic changes in lipid profile [8, 9], and myocardial infarction [10, 11]. The investigation of visceral (omental) fat metabolism and signaling may hold great potential for understanding T2DM development
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