Henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, placebo-controlled, phase 3 trial.

AIM: To evaluate the efficacy and safety of henagliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. MATERIAL AND METHODS: This multicentre phase 3 trial included a 24-week randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. Patients with a glycated haemoglobin (HbA1c) level of 7.0% (53 mmol/mol) to 10.5% (91 mmol/mol) were randomized and treated with once-daily placebo (n = 161), henagliflozin 5 mg (n = 162), or henagliflozin 10 mg (n = 160). After 24 weeks, patients on placebo were switched to 5 mg or 10 mg henagliflozin for the additional 28-week treatment, and patients on henagliflozin during 24-week treatment period maintained this initial therapy. The primary endpoint was change in HbA1c from baseline to Week 24. RESULTS: At Week 24, the least squares mean HbA1c changes versus placebo from baseline were - 0.76% (-8.3 mmol/mol) and - 0.80% (-8.7 mmol/mol) for henagliflozin 5 and 10 mg, respectively (all P < 0.0001). Compared with the placebo group, both doses of henagliflozin lowered fasting plasma glucose, 2-hour postprandial plasma glucose, body weight and blood pressure, and increased the proportions of patients achieving HbA1c <7.0% (53 mmol/mol) at Week 24. The trends in these improvements were sustained over an additional 28 weeks. Slightly higher proportions of ketosis and presence of urine ketone bodies were observed in patients treated with henagliflozin compared to placebo at Week 24. No diabetic ketoacidosis or episodes of severe hypoglycaemia were reported. CONCLUSIONS: Henagliflozin 5 mg or 10 mg as add-on therapy to metformin provided a new therapeutic option for the treatment of T2DM patients who have inadequate glycaemic control with metformin alone, and was generally well tolerated.

ß-catenin mediates the effect of GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose diet.

The hypoglycemic drug GLP-1 receptor agonist can ameliorate hepatic steatosis but the mechanism is not clear. Intake of high fructose leads to non-alcoholic fatty liver disease by stimulating lipid synthesis, and ß-catenin is the key molecule for realizing GLP-1 function in extrahepatic tissues; with the discovery of GLP-1 receptor in liver, we speculate that ß-catenin might mediate GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose. Wistar rats were fed with high fructose diet for 8 weeks and then treated with GLP-1 receptor agonist exenatide for 4 weeks; the changes of lipid synthesis pathway factors, the expression and nuclear translocation of ß-catenin, and the hepatic steatosis of the rats were observed. After the intervention of exenatide, the hepatic steatosis induced by high fructose was improved, the nuclear translocation and expression of ß-catenin were facilitated, and the mRNA and protein expression of the upstream regulator SREBP-1 and the downstream key enzymes ACC, FAS and SCD-1 of de novo lipogenesis were down-regulated. GLP-1 receptor agonist may ameliorate hepatic steatosis induced by high fructose by ß-catenin regulating de novo lipogenesis pathway. GLP-1 receptor agonist may be a potential new drug for the treatment of non-alcoholic fatty liver disease, and the ß-catenin may be an important target for the drug therapy.

Relationship between Serum Asymmetric Dimethylarginine Level and Microvascular Complications in Diabetes Mellitus: A Meta-Analysis.

OBJECTIVE: The purpose of the meta-analysis was to evaluate the relationship between serum asymmetric dimethylarginine (ADMA) level and microvascular complications in diabetes mellitus (DM) including diabetic retinopathy (DR), diabetic neuropathy (DN), and diabetic nephropathy. METHODS: Studies were comprehensively identified by searching Web of Science, Embase, and PubMed databases up to August 30, 2018. The meta-analysis was carried out to compare the difference of serum ADMA concentrations of DR, DN, and diabetic nephropathy patients with healthy controls. The Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality were applied to assess the methodological quality. Chi-squared Q test and I2 statistics were applied to evaluate statistical heterogeneity. Subgroup analyses were conducted and publication bias was assessed by Egger's test. RESULT: Ten studies were finally entered in the meta-analysis. Statistically significant heterogeneity was observed across these studies (I 2 = 77.0%, p < 0.001). Compared with DM without microvascular complications, circulating level of ADMA was significantly higher in DM with microvascular complications (all p < 0.05). Sensitivity analysis suggested that the results of this meta-analysis were shown to be stable. There was no significant publication bias (P=0.823). CONCLUSION: Elevated ADMA levels correlate with diabetic microangiopathies such as DR and diabetic nephropathy. ADMA may play an important role in the pathobiology of microvascular complications of diabetes.

Association of RBP4 levels with increased arterial stiffness in adolescents with family history of type 2 diabetes.

BACKGROUND: The aim of this study was to explore the impact of family history of type 2 diabetes (FH2D) on arterial stiffness in young people and its relationship to adipocytokines. METHODS: This case-control study included 52 adolescents (male/female 28/24) with FH2D (FH2D+) and 40 adolescents (male/female 21/19) without FH2D (FH2D-). Anthropometric measurements, including height, weight, waist circumference (WC), and blood pressure, were obtained. Blood samples were collected, fasting plasma glucose (FPG), serum lipids, Retinol Binding Protein 4 (RBP4), C reactive protein (CRP), adiponectin and visfatin were examined. Brachial-ankle pulse wave velocity (baPWV) was used to evaluate arterial stiffness. Visceral fat area (VFA) was measured by computerized tomography. RESULTS: Compared with FH2D- group, FH2D+ group had a significantly higher oral glucose tolerance test (OGTT) 2-hour insulin, RBP4 and baPWV levels, a lower adiponectin and glucose infusing rate (GIR) (P<0.05). BaPWV was positively correlated with age, systolic blood pressure (SBP), diastolic blood pressure (DBP), 2-hour (OGTT) insulin, RBP4, and VFA, and negatively correlated with GIR in FH2D+ group. After multivariate analysis, age, SBP, RBP4 and VFA maintained an independent association with baPWV in FH2D+ group (P<0.05), while only age, SBP, and VFA were independent predictors of baPWV in FH2D- group (P<0.05). CONCLUSIONS: These findings led to the conclusion that RBP4 level was associated with increased arterial stiffness in young subjects with family history of type 2 diabetes.

Meta-analysis: overweight, obesity, and Parkinson's disease.

Objective. Parkinson's disease (PD) is a severe neurological disease and its risk factors remain largely unknown. A meta-analysis was carried out to investigate the relationship of overweight and obesity with PD. Methods. We used PubMed, EMBASE, and the Chinese National Knowledge Infrastructure (CNKI) databases to identify studies of associations between overweight/obesity and PD. Overweight, obesity, and PD were used as keywords, and published works were retrieved until September 30, 2013. The extracted data were classified (BMI ≥ 30, 25 ≤ BMI < 30, and BMI < 25) according to BMI values and analyzed using RevMan5.2 and Stata11.0. Results. Four cohort studies and three case-control studies were used to evaluate the association between overweight/obesity and PD, including 2857 PD patients and 5, 683, 939 cases of non-PD controls. There was a statistically significant difference between 25 ≤ BMI < 30 and BMI < 25 in the cohort study (RR = 1.17, 95% CI, 1.03-1.32, P = 0.03), but there was no difference between BMI ≥ 30 and BMI < 25 or BMI ≥ 30 and 25 ≤ BMI < 30, where the respective RR was 1.16 and 0.84; the respective 95% CI was 0.67-2.01 and 0.61-1.15, respectively, and the P values were 0.60 and 0.28, respectively. Case-control studies showed that there was no statistical difference between any two groups. Conclusion. Meta-analysis showed that overweight might be a potential risk factor of PD. Demonstration of a causal role of overweight/obesity in PD development could have important therapeutic implications.

[A study on endothelial function and inflammation factors in the first degree relatives of type 2 diabetics with normal glucose tolerance].

OBJECTIVE: To study the vascular endothelial function and the level of inflammation factors in the first degree relatives (FDR) of type 2 diabetes (T2DM) patients with normal glucose tolerance and related factors. METHODS: Vascular endothelial function, plasma plasminogen activator inhibitor-1 (PAI-1), vascular cell adhesion molecule-1 (VCAM-1) and insulin active index (IAI) were measured in 57 FDR and 31 controls. RESULTS: As compared with the controls, there were less endothelium-dependent vasodilation [(12.45 +/- 3.37)% vs (5.03 +/- 0.34)%] and IAI [(-3.79 +/- 0.57) vs (-4.11 +/- 0.46)], higher PAI-1 [(30.46 +/- 12.28) microg/L vs (39.25 +/- 6.54) microg/L] and higher VCAM-1 [(637.31 +/- 107.32) microg/L vs (742.39 +/- 124.31) microg/L] in the FDR (P < 0.05). CONCLUSION: There were decreased IAI, damaged endothelial function and impaired fibrinolysis in the first degree relatives of T2DM patients with normal glucose tolerance.