| Background:Diabetes mellitus is one of the most common chronic diseases, and its incidence gradually increases each year. The world prevalence of diabetes among adults was 6.4%, affecting 285 million adults, in 2010, and it is predicted to increase to 7.7% (i.e.,439 million adults) by 2030. The prevalence of diabetes was estimated at 11.6% in the Chinese adult population, and China may be home to the world’s largest population of people living with diabetes.The main mechanisms associated with type 2 diabetes are pancreatic beta cell dysfunction and insulin resistance and pancreatic beta cell dysfunction may be the most important factor. Hence, how to protect pancreatic βfunction is the most important thing in the treatment of diabetes. Relative beta-cell volume was increased in obese versus lean nondiabetic cases through the mechanism of increased neogenesis. Obese humans with IFG and type 2 diabetes had a 40% and 63% deficit and lean cases of type 2 diabetes had a 41% deficit in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group. Pancreatic beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.Exercise is one of the important measures of prevention and control of T2DM.The new hormone-irisin which secrete by muscle cell-may be related with prevention and treatment of diabetes. Irisin, a myokine that is produced by proteolytic cleavage of fibronectin type III domain containing protein 5 (FNDC5), is secreted by skeletal muscles and increases with exercise. Exercise activates the expression of peroxisome proliferator-activated receptor-y coactivator-la (PGC-la) and uncoupling protein 1 (UCP1), which stimulate the proton transport chains in the mitochondrial membrane and increase ATP and energy consumption in the form of heat. This process results in weight loss and improved insulin sensitivity. Serum irisin levels were found to be reduced in long-term, new-onset and undefined diabetes as well as in metabolic syndrome (MetS) and in individuals with raised-FPG.Zhang Y and colleagues found that irisin up-regulated PGC-la and UCP1, likely mediated by p38 mitogen-activated protein kinase (p38 MAPK) and the extracellular regulated protein kinase (ERK) signalling pathway. Therefore, the p38 MAPK and ERK signalling pathways play an important role in the process of WAT "browning" mediated by irisin.Betatrophin (also known as angiopoietin-like protein 8 (ANGPTL8), hepatocellular carcinoma-associated protein-TD26, refeeding-induced fat and liver protein (RIFL) and lipasin) is a newly identified hormone. It has been demonstrated that betatrophin, mainly expressed in liver and adipose tissue in mice, promotes pancreatic beta cell proliferation and improves metabolic control. Recently, Gusarova et al. showed that Angptl8 (-/-) mice does not affect the compensatory proliferation of pancreatic beta cells in response to insulin resistance resulting from either a high-fat diet or the administration of the insulin receptor antagonist S961. And Yi et al repeated the experiment in order to find the likely cause of this deviation; finally they obtained results that some mice respond strongly to ANGPTL8/betatrophin expression but many do not, one possible explanation is that ANGPTL8 requires a binding partner that can be induced by tail vein injection; another approach to investigate this issue is to find and investigate the function of the receptor for Angptl8/betatrophin or its protein complex. In all, whether betatrophin does control pancreatic β cell proliferation or not needs further study.Betatrophin is also involved in lipid metabolism; its overexpression increases serum triglyceride (TG) levels and inhibits the activity of lipoprotein lipase (LPL). Additionally, Ren G et al. observed that betatrophin knockout mice have serum TG levels approximately one-third of those in wild-type mice and Hobbs et al. also showed that plasma TG levels were reduced in fed Angptl8-/- mice. Serum betatrophin levels were found to be higher in subjects with T2DM in many studies, but there have also been studies that found no difference in betatrophin levels and even decreased levels in obese and T2DM subjects.The effect of irisin on improvement of insulin resistance and the possible relationship between betarophin and pancreatic βcell appealed a great interest of researchers. The mechanisms underlying type 2 diabetes include insulin secretion by pancreatic P-cells and insulin resistance, which involves hepatocytes, adipocytes and myocytes. We speculate whether or not the interaction of irisin and betatrophin perform in the process.Light inflammation and inflammatory factors (such as TNF-a) which exist for a long time in the body play an important role in apoptosis of pancreatic β cells. Muscle contraction secretes myokine which have an effect of anti-inflammatory and the new myokine-irisin may play a role in the apoptosis of pancreatic β cells induced by TNF-a.Hence, the current study aims to explore the relationship between circulating betatrophin levels and irisin and a potential gender dimorphism with respect to betatrophin levels; And the effect of TNF-a and pretreatment irsin concentration and time on pancreatic β cells viability.Objective1. To investigate the plasma betatrophin levels and irisin levels in NGT and newly-diagnosed T2DM and analyze the relationship between plasma betarophin levels and irisin.2. To investigate the gender dimorphism regarding circulating betatrophin and irisin concentrations in subjects with NGT and T2DM and analyze the relationship between plasma betarophin levels and irisin in gender dimorphism.3. To study the effect of TNF-a and pretreatment irsin concentration and time on cells viability by MTS assay.MethodsA total of 460 permanent residents of Fengxian District, aged 40-60 years and without T2DM, were enrolled. Anthropometric parameters, oral glucose tolerance test (OGTT) results, glycosylated haemoglobin levels, blood lipid levels, insulin sensitivity (homeostasis model assessment of insulin resistance, HOMA-IR), β cell function (homeostasis model assessment-β, HOMA-β), estimated glomerular filtration rate (eGFR) and body fat composition were determined. Matched for age, gender and body mass index (BMI,18-28 kg/m2), newly diagnosed T2DM (n= 50, male/female = 23/27) and NGT (n= 50, male/female= 21/29) subjects were selected based on the results of an OGTT (World Health Organization diagnostic criteria,1999). Serum betatrophin and irisin levels were determined by enzyme linked immune sorbent assay (ELISA).The experiment object was rat insulin-secreting INS-1 cells.INS-1 cells werecultured in RPMI-1640 containing2Mm L-glutamine supplemented with 10% FBS, OOIU/ml penicillin, 100ug/ml streptomycin non-essential amino acids, lOnM HEPES, lmM sodium pyruvate and 50uM 2-mercaptoethanol at 37℃. MTS method was used to detect the cell proliferation.Results1. Compare with the NGT group, the level of Betatrophin was increased in the T2DM group [(412.53±237.67 vs 306.2±283.82) pg/mL, P<0.05], Partial correlation analysis showed that serum Betatrophin was positively correlated with height(r=0.443, P=0.001), weight(r=0.478, P<0.001),BMI(r=0.402, P=0.004), waist circumference(r=0.388, P=0.006) and Cr levels(r=0.348, P=0.013) in T2DM; was positively correlated with age(r=0.331, P=0.029) and Irisin(r=0.336, P=0.017), but negatively correlated with the FINS(r=-0.353, P=0.013), HOMA-IR(r=-0.291, P=0.041)and HOMA-p(r=-0.343, P=0.015) in NGT. Multiple linear regression analysis showed that TC, TG,2h-BG, HOMA-IR were independent risk factors of serum Betatrophin (β=-0.825,-0.119,3.301, P<0. 05).2. Males had higher levels of betatrophin compared with females in both the NGT and T2DM groups. Compared with NGT subjects, the level of betatrophin in the T2DM group was higher, and males in the T2DM group had higher betatrophin levels than males in the NGT group, but there was no significant difference in betatrophin levels in females between the T2DM and NGT groups. Spearman’s correlation analysis revealed that serum betatrophin levels in females with NGT were positively correlated with irisin and FINS (fasting insulin) levels (p<0.05), but no coirelation was found between betatrophin and irisin levels in males with NGT or in males or females with T2DM. In females with T2DM, circulating betatrophin levels were positively correlated with weight, BMI and hip circumference (p< 0.05) but negatively correlated with FPG (fasting plasma glucose) and HOMA-IR (p< 0.05).3. The viability of cells were found to be decreased in TNFa-treated INS-1 and this was observed after exposure to this cytokine for 24 h. Cells viabilities were found to be increased in irisin(10nM) pretreated INS-1 for 0.5-24h and 4h is the best pretreated time.Conclusions1. Serum Betatrophin level in NGT was lower than that in newly-diagnosed T2DM and associated with serum Irisin; Whereas there were no correlations between Betatrophin and Irisin in newly-diagnosed T2DM, but serum Betatrophin level was correlated with BMI, waist circumstance, CHO, TG,2h-PG and HOMA-IR. The results indicate that Betatrophin is related with Irisin in normal glucose tolerance rather than newly-diagnosed type 2 diabetes mellitus.2. The levels of betatrophin were higher in subjects with T2DM and in males with NGT and T2DM. Circulating betatrophin levels were correlated with FINS and irisin in NGT and were correlated with weight, BMI, hip circumference, FPG and HOMA-IR in females with T2DM. Gender differences in the relationship between betatrophin and irisin indicate that there might be cytokine-mediated crosstalk among the liver, adipose tissue and skeletal muscle.3. Irisin may increase the viability of INS-1 which treated by TNF-α and this needs further study. |
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