Circulating Serum Myonectin Levels in Obesity and Type 2 Diabetes Mellitus.

OBJECTIVE: Myonectin is one of the myokines and has gained interest as a potential new strategy to combat obesity and its associated disorders, such as type 2 diabetes mellitus (T2DM).The objective of this study was to investigate circulating serum myonectin levels in nondiabetes and T2DM and elucidate possible relationships between serum myonectin levels and metabolic parameters in patients with T2DM. DESIGN: A total of 362 Chinese patients with T2DM and 100 age- and sex-matched healthy controls were recruited in this study. Clinical characteristics, blood biochemistry, and circulating myonectin levels were measured by enzyme-linked immunosorbent assay. RESULTS: Circulating myonectin levels were significantly decreased in T2DM compared with controls. Obese nondiabetic controls had significantly lower serum myonectin levels compared with lean nondiabetic controls. In diabetic patients, serum myonectin concentrations were significantly negatively correlated with body mass index (BMI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), hemoglobin A1c (HbA1c), fasting insulin (Fins), the homeostatic model assessment of insulin resistance (HOMA-IR), visceral fat area, and subcutaneous fat area. After adjusting for covariates, multivariate stepwise regression analysis demonstrated that BMI, LDL-C, TG, HOMA-IR, and visceral fat were the main independent predictors of low serum myonectin concentrations. CONCLUSIONS: Circulating myonectin levels were decreased in T2DM patients and in obese subjects. Moreover, serum myonectin levels were correlated with metabolic markers of T2DM. These data suggest that myonectin may be a useful marker in predicting the development of obesity and T2DM.

miRNA­342 suppresses renal interstitial fibrosis in diabetic nephropathy by targeting SOX6.

Diabetic kidney disease (DKD) is one of the major microvascular complications in patients with type 1 and/or type 2 diabetes, the first cause of end­stage renal disease (ESRD) in several countries and regions. However, the pathogenesis of DKD and the mechanisms through which it leads to ESRD remain unknown. Thus, in this study, we aimed to elucidate some of these mechanisms. The expression of microRNA (miRNA or miR)­342­3p and SRY­box 6 (SOX6) in the renal tissues of mice with DKD and mouse renal mesangial cells (MCs) was determined by RT­qPCR and western blot analysis. The diabetic kidney environment was established using high­glucose medium. SOX6 was verified as a target gene of miR­342­3p by dual­luciferase activity assay. In addition, western blot analysis was employed to determine the changes in the levels of several biomarkers of fibrosis [transforming growth factor (TGF)­ß1, fibronectin (FN), collagen IV (referred to as C­IV) and phosphatase and tensin homolog (PTEN)]. Compared with THE control mice, the expression of miR­342­3p in the kidney tissues of mice with DKD was downregulated, whereas that of SOX6 was upregulated. The same phenomenon was observed in the MCs cultured in high­glucose medium. Subsequently, miR­342­3p inhibited SOX6 expression, promoted cell proliferation and inhibited the apoptosis of MCs. Moreover, the overexpression of miR­342­3p suppressed high glucose­induced renal interstitial fibrosis. In addition, it was found that miR­342­3p inhibited SOX6 expression by binding to the 3'­UTR of SOX6. On the whole, the findings of this study demonstrate that miR­342­3p suppresses the progression of DKD by inducing the degradation of SOX6. Thus, the miR­342­3p/SOX6 axis may serve as a novel therapeutic target in the treatment of DKD.

Apigenin prevents metabolic syndrome in high-fructose diet-fed mice by Keap1-Nrf2 pathway.

Chronic dietary high fructose leads to various kinds of undesirable metabolic effects. Apigenin, a naturally occurring plant flavone, is plentiful in fruits and vegetables. The aim of this study was to identify the protective effects of apigenin on metabolic syndrome and elucidate potential underlying mechanisms. The animal model was established by 4-weeks high fructose feeding. Insulin resistance was estimated by oral glucose tolerance test and homeostasis model assessment-insulin resistance index. Liver function was evaluated by serum AST and ALT, hepatic histopathological alternation, and lipid accumulation in the liver. The alterations of lipid profile was evaluated by TG, TC, LDL-C and HDL-C levels in serum. Administration of apigenin exerted beneficial effects through improving insulin resistance, alleviating liver injury, and inhibiting the alterations of lipid profile in high fructose-fed mice. In addition, apigenin potently facilitated the accumulation of Nrf2 nuclear translocation and accompanied by increasing HO-1 and NQO1 protein expressions, which are responsible for attenuating oxidative stress. Molecular docking results demonstrated that potential interaction of apigenin with the Nrf2-binding site in the Keap1 protein. In summary, we demonstrated that apigenin prevented high fructose-induced metabolic syndrome probably by inhibiting binding of Keap1 to Nrf2, and thus Nrf2 nuclear translocation, subsequently resulting in increased the expressions of anti-oxidative genes including HO-1 and NQO1.

Honokiol protects pancreatic ß cell against high glucose and intermittent hypoxia-induced injury by activating Nrf2/ARE pathway in vitro and in vivo.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with glucose intolerance, insulin resistance and type 2 diabetes mellitus (T2DM). Although several studies have revealed that intermittent hypoxia (IH) in OSAHS may further aggravate pancreatic ß cell damage and promote the evolution of type 2 diabetes (T2DM) by increasing oxidative stress, the underlying mechanisms are unclear. Honokiol, a potent radical scavenger, has been demonstrated to ameliorate oxidative stress in many cases. The present study aimed to explore the potential mechanism of IH and diabetes synergistically damage and destruct the pancreatic ß cell, examine the effects of honokiol on ameliorating pancreatic ß cell injury in this context and explore the mechanism of such effects. High glucose (HG) cultured INS-1 cells were exposed to 50 µM of honokiol for 24, 48 and 72 h with or without IH intervention. T2DM rats were treated with honokiol and exposed to 80 s of IH followed by 160 s of normoxia for 8 weeks. The cell proliferation, apoptosis and oxidative stress were measured. Blood glucose, insulin, glucagon and HOMA-IR (Homeostasis model assessment -insulin resistence) were also detected, and the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by immunofluorescence staining and western blotting. Honokiol can reduce oxidative stress, cytotoxicity and apoptosis in the INS-1 cells of rats receiving HG treatment or both HG and IH treatment. IH can further aggravate pancreas dysfunction, cause a marked elevation in fasting blood glucose, glucagon, HOMA-IR and oxidative stress levels in DM rats. In addition, honokiol can effectively activate the Nrf2/ARE pathway and reverse this pancreatic dysfunction in vivo and in vitro. These findings indicate that honokiol acts as a potent ROS scavenger via Nrf2/ARE pathway and effectively attenuates oxidative stress and improves pancreatic ß cell function of DM rats under IH treatment.

The relationship between circulating irisin levels and tissues AGE accumulation in type 2 diabetes patients.

Advanced glycation end-products (AGEs), measured by skin autofluorescence (AF), are a factor in the development or worsening of many degenerative diseases, such as diabetes and atherosclerosis. Irisin levels have been associated with diabetes, endothelial dysfunction and atherosclerosis. The objective of the present study was to investigate whether circulating irisin levels are correlated with skin AF values in type 2 diabetes patients. A total of 362 Chinese type 2 diabetic patients and 100 age- and sex-matched healthy controls were recruited in the present study. Clinical characteristics, blood biochemistry and circulating irisin levels were measured. Skin AF was measured using an AGE reader. Circulating irisin levels were significantly lower, while skin AF values were increased in type 2 diabetes compared with controls (P<0.05 respectively). By dividing the distribution of skin AF values into tertiles, serum irisin levels gradually lowered with increasing skin AF values (P<0.05). After adjusting for covariates, multivariate stepwise regression analysis demonstrated that serum lower irisin levels were independently associated with skin AF (P=0.009). Circulating irisin levels were lower in type 2 diabetes patients compared with healthy controls. Lower levels of irisin are independently associated with elevated skin AF values, indicating that circulating irisin levels could be associated with AGEs accumulation, which is one of the reasons causing vascular complications in diabetic patients.

Efficacy and safety of vildagliptin, sitagliptin, and linagliptin as add-on therapy in Chinese patients with T2DM inadequately controlled with dual combination of insulin and traditional oral hypoglycemic agent.

OBJECTIVE: We aimed to evaluate the efficacy and safety of the three dipeptidyl peptidase 4 (DPP-4) inhibitors (vildagliptin, sitagliptin, and linagliptin) as add-on therapy in Chinese patients with type 2 diabetes mellitus (T2DM)inadequately controlled on dual combination of insulin and metformin or acarbose. METHODS: A total of 535 T2DM patients who failed to achieve glycemic control with insulin and a traditional oral hypoglycemic agent were randomized to receive vildagliptin, sitagliptin, or linagliptin. Body mass index, glycosylated hemoglobin (HbA1c), fasting and postprandial plasma glucose (FPG and PPG), insulin dose, and adverse events were evaluated during the study. RESULTS: The baseline HbA1c was 9.59 ± 1.84 % (vildagliptin group), 9.22 ± 1.60 % (sitagliptin group), and 9.58 ± 1.80 % (linagliptin group). At week 12 it was 8.16 ± 1.29 % (vildagliptin), 8.56 ± 1.96 % (linagliptin), and 8.26 ± 1.10 % (sitagliptin). The changes in HbA1c from baseline were -1.33 ± 0.11 % (vildagliptin), -0.84 ± 0.08 % (sitagliptin) and -0.81 ± 0.08 % (linagliptin), the vildagliptin group had the greatest reduction in HbA1c (P < 0.05). The proportions of patients that reached target HbA1c were 66.27 % (vildagliptin), 52.73 % (sitagliptin), and 55.49 % (linagliptin), the vildagliptin group had the highest one (P < 0.05). The baseline FPG and PPG values in the three groups were at the same level. At week 12, mean FPG levels in the vildagliptin (7.31 ± 1.50 mmol/L) and linagliptin (6.90 ± 1.55 mmol/L) groups were significantly lower than in the sitagliptin group (8.02 ± 4.48 mmol/L; P < 0.05); the linagliptin group had the lowest mean PPG followed by the vildagliptin group which was also significant lower (P = 0.000) than the sitagliptin group. Additionally, the required insulin dosage in the vildagliptin group was the lowest among the groups at weeks 6 and 12. Only mild AEs were reported during the study. CONCLUSION: The three DPP-4 inhibitors appear to be effective and safe as add-on therapy for T2DM patients on dual combination of insulin and a traditional OHA. Vildagliptin was more effective in decreasing insulin requirement and achieving glycemic control when compared to the other two.

Impact of inflammatory markers on the relationship between sleep quality and incident cardiovascular events in type 2 diabetes.

AIMS: To analyze relevance of sleep quality with CVD in T2D patients and determine whether inflammation prompted by poor sleep has impact on the CVD. METHODS: 332 T2D patients were recruited and their sleep qualities were evaluated by PSQI. The patients with PSQI score >7 were in the poor sleep group, and the others were in the good sleep group. Plasma samples of the patients were obtained to measure inflammatory markers. Correlation analyses and regression analyses were performed to examine the cross-sectional relationships among the poor sleep, inflammatory markers and CVD. RESULTS: The morbidity of CVD was significantly higher in the poor sleep patients compared to the good sleep patients (P=0.000). PSQI score ORs were both >1 for CVD in model 1 and model 2 (P<0.05). PSQI score were positively related to IL-6 and ICAM-1(P<0.05), negatively to FBI (P<0.05), but not related to CRP in linear regression models. Multiple logistic regression analysis showed IL-6 and ICAM-1, but not FBI and CRP, were related to CVD (P<0.05). CONCLUSIONS: Poor sleep is regarded as a plausible risk factor for CVD in T2D patients, and may be mediated by certain inflammatory markers.

The intestinal fatty acid binding protein-2 Ala54Thr polymorphism is associated with diabetic retinopathy in Chinese population.

OBJECTIVE: Endothelial dysfunction which is induced by serum saturated fatty acids increasing is one of pathogenesis of diabetic retinopathy (DR). The intestinal fatty acid binding protein-2 (FABP2) Ala54Thr polymorphism results in serum saturated fatty acids elevating. In the present study, we assessed the association of FABP2 gene polymorphism (Ala54Thr) with DR in Chinese population. MATERIALS/METHODS: In this case-control association study, 810 T2DM patients were recruited. 420 patients with retinal neovascularization, microneurysms and hemorrhages were considered as cases (DR) and 390 patients with T2DM and no clinical signs of retinopathy (DNR), were recruited as controls. Genotypes for FABP2(Ala54Thr) polymorphisms were assessed with the PCR-RFLP method. RESULTS: A significant difference in genotype distribution and allele frequency was observed between cases and controls. Patients with DR had significantly higher frequency of the Ala/Thr + Thr/Thr genotypes compared to DNR group [62.6% vs. 46.2%; OR (95% CI), 1.95 (1.48-2.59); p < 0.001]. The DR group showed a significantly higher frequency of the the Thr allele compared to the DNR group [39.5% vs. 29.4%; OR (95% CI), 1.56 (1.16-2.09); p = 0.003]. Binary logistic analyses showed FFA levels (p = 0.014) and Ala54Thr (p = 0.011) were independent correlates of the presence of DR. CONCLUSIONS: We examined that FABP2 polymophism on the Ala54Thr is significant and independent associated with DR.

Liraglutide enhances glucose transporter 4 translocation via regulation of AMP-activated protein kinase signaling pathways in mouse skeletal muscle cells.

OBJECTIVE: Liraglutide is an anti-diabetic drug and human glucagon-like peptide-1 (GLP-1) analog that primarily functions in the pancreas. However, its extra-pancreatic functions are not clear. Skeletal muscle tissue is an important determinant of blood glucose and cells take in approximately 80% of dietary glucose via glucose transporter 4 (GLUT4) on the plasma membrane. Insulin and muscle contraction are two physiological stimuli of GLUT4 translocation to the cell membrane from intracellular storage compartments, but the signaling mechanisms that mediate these processes are different. AMP-activated protein kinase (AMPK) and Akt are the key signal molecules mediating the effects of muscle contraction and insulin, respectively, on GLUT4 translocation. Here, we investigate the effect of liraglutide on GLUT4 translocation and the roles of AMPK and Akt in this mechanism in skeletal muscle cells by stably expressing GLUT4myc with an exofacial myc-epitope C(2)C(12)-GLUT4myc. MATERIALS/METHODS: The cell surface GLUT4myc levels were determined by an antibody-coupled colorimetric assay. The phosphorylation levels of AMPK, Akt, AS160, TBC1D1, and GLUT4 were determined by western blotting. The cAMP levels were measured by an ELISA kit. siRNA was transfected with Lipofectamine 2000. Analysis of variance (ANOVA) was used for data analysis. RESULTS: Liraglutide stimulated GLUT4 translocation in C(2)C(12)-GLUT4myc myotubes. Liraglutide increased the intracellular cAMP levels and the phosphorylation of AMPK, AS160, and TBC1D1. Akt phosphorylation and GLUT4 expression were not affected. Inhibition of AMPK by siRNA or Compound C reduced liraglutide-induced GLUT4 translocation. CONCLUSION: Our results suggest that liraglutide may induce GLUT4 translocation by activation of AMPK in muscle cells.