ABSTRACT
In vitro-generation of ß-cells from Wharton's jelly mesenchymal stem cells (WJ-MSCs) could provide a potential basis for diabetes mellitus cell therapy. However, the generation of functional insulin-producing cells (IPCs) from WJ-MSCs remains a challenge. Recently, obestatin, a gut hormone, was found to promote ß-cell generation from pancreatic precursor cells. Accordingly, we hypothesize that obestatin can induce the differentiation of WJ-MSCs into IPCs. Therefore, the purpose of the current study is to examine the ability of obestatin to generate IPCs in comparison to well-known extrinsic factors that are commonly used in IPCs differentiation protocols from MSCs, namely exendin-4 and glucagon-like peptide-1 (GLP-1). To achieve our aims, WJ-MSCs were isolated, cultured and characterized by immunophenotyping and adipocytes differentiation. Afterwards, WJ-MSCs were induced to differentiate into IPCs using two differentiation protocols incorporating either exendin-4, GLP-1 or obestatin. The pancreatic progenitor marker, nestin and ß-cell differentiation markers were assessed by qRT-PCR, while the functionality of the generated IPCs was assessed by glucose-stimulated insulin secretion (GSIS). Our results showed that WJ-MSCs exhibit all the characteristics of MSCs. Interestingly, using obestatin in both the short and long differentiation protocols managed to induce the expression of ß-cell markers, similar to exendin-4. In GSIS, IPCs generated using either GLP-1 or obestatin showed higher secretion of insulin as compared to those generated using exendin-4 under low-glucose conditions but failed to show a significant response to increased glucose. These results indicate obestatin can be considered as a novel potential factor to consider for generation of IPCs from WJ-MSCs.
Subject(s)
Cell Differentiation/drug effects , Ghrelin/pharmacology , Insulin-Secreting Cells/cytology , Mesenchymal Stem Cells/cytology , Wharton Jelly/cytology , Cryopreservation , Exenatide/pharmacology , Gene Expression Regulation/drug effects , Glucagon-Like Peptide 1/pharmacology , Humans , Insulin-Secreting Cells/drug effectsABSTRACT
AIMS: The aim of the current study is to investigate the effect of fenofibrate alone and in combination with pioglitazone on serum sirtuin 1 and fetuin A of obese patients with Type 2 Diabetes Mellitus (T2DM). METHODS: Intervention effect on inflammatory parameters was assessed before and after treatment. The study was conducted on 60 postmenopausal females of whom, only 44 patients completed the study. They were distributed as follows; obese patients without T2DM (n=15) who administered fenofibrate (160 mg/day) once for 8 weeks, obese patients with T2DM (n=15) who administered fenofibrate (160 mg/day) once for 8 weeks, obese patients with T2DM (n=14) who administered fenofibrate (160 mg/day) and pioglitazone (15 mg/day) combination once for 8 weeks. We measured fasting plasma glucose, glycated hemoglobin (HbA1c), serum lipids. Inflammatory markers (high sensitivity C-reactive protein "hs-CRP", interleukin-6 "IL-6", fetuin A, and sirtuin 1) of patients were measured in serum using enzyme-linked immunoassay (ELISA) kits. RESULTS: Sirtuin 1 levels in obese patients with T2DM were significantly lower than its levels in obese patients while fetuin A levels were significantly higher (P<0.001). Fenofibrate, alone and in combination with pioglitazone, significantly decreased triacylglycerol, hs-CRP, IL-6, fetuin A and increased sirtuin 1 levels (P<0.001) which suggests that it can be used to delay the complications of obesity and T2DM. There is a strong correlation between fetuin A, sirtuin 1, IL-6 and hs-CRP levels suggesting a shared common pathway. CONCLUSIONS: Fenofibrate was shown to increase serum sirtuin 1 and decrease serum fetuin A levels in obese patients. TRIAL NUMBER: PACTR201407000856135.