Visceral mesenchymal stem cells from type 2 diabetes donors activate triglycerides synthesis in healthy adipocytes via metabolites exchange and cytokines secretion.

BACKGROUND: In recent years, there has been an increase in the prevalence of obesity and type 2 diabetes mellitus (T2DM). Development of visceral instead of subcutaneous adipose tissue is pathogenic and increases the risk of metabolic abnormalities. We hypothesize that visceral adipocytes and stromal cells are able to deteriorate other fat depots metabolism via secretory mechanisms. METHODS: We study the regulatory role of visceral adipose-derived stem cells (vADSC) from donors with obesity and T2DM or normal glucose tolerance (NGT) on healthy subcutaneous ADSC (sADSC) in the Transwell system. Lipid droplets formation during adipogenesis was assessed by confocal microscopy. Cell metabolism was evaluated by 14C-glucose incorporation analysis and western blotting. vADSC secretome was assessed by Milliplex assay. RESULTS: We showed that both NGT and T2DM vADSC had mesenchymal phenotype, but expression of CD29 was enhanced, whereas expressions of CD90, CD140b and IGF1R were suppressed in both NGT and T2DM vADSC. Co-differentiation with T2DM vADSC increased lipid droplet size and stimulated accumulation of fatty acids in adipocytes from healthy sADSC. In mature adipocytes T2DM vADSC stimulated triglyceride formation, whereas NGT vADSC activated oxidative metabolism. Secretome of NGT vADSC was pro-inflammatory and pro-angiogenic in comparison with T2DM vADSC. CONCLUSIONS: The present study has demonstrated the critical role of secretory interactions between visceral and subcutaneous fat depots both in the level of progenitor and mature cells. Mechanisms of these interactions are related to direct exchange of metabolites and cytokines secretion.

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.