Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Associations between new obesity indices and abnormal bone density in type 2 diabetes mellitus patients.

The clinical data analysis found that, compared with the traditional obesity index, the waist-weight ratio (WWR) has more advantages in predicting abnormal bone mineral density in subjects with type 2 diabetes. WWR may serve as a new predictive indicator for osteoporosis in T2DM patients. PURPOSE: This study was designed to explore the correlation between obesity-related indices and bone mineral density (BMD) and its influencing factors in type 2 diabetes mellitus (T2DM) patients. METHODS: A total of 528 patients with type 2 diabetes were recruited. Glucose tolerance, insulin stimulation, and blood biochemical tests were conducted on all participants. All subjects underwent dual-energy X-ray bone density testing and were grouped based on the bone density results. RESULTS: Compared with those in the normal BMD group, the waist-to-body weight ratio (WWR) and weight-adjusted-waist index (WWI) in the osteopenia and osteoporosis groups were significantly greater, while body mass index (BMI) was significantly lower (P < 0.05). The logistic regression results showed that the WWR, WWI, and BMI were independently correlated with abnormal BMD in T2DM patients (P < 0.05). WWR and the WWI were negatively correlated with the T-value of bone density in various parts of the body, while BMI was positively correlated with the T-value of bone density (P < 0.05). The area under the working characteristic curve (AUC) for T2DM patients with abnormal bone mass predicted by the WWR [0.806, 95% CI = (0.770-0.843), P < 0.001] was greater than that for patients with other obesity indicators, such as the WWI and BMI. CONCLUSION: We found a positive correlation between the WWR and bone density in T2DM patients. Compared with other obesity indicators, such as BMI and WWI, the WWR has a stronger discriminative ability for T2DM patients with abnormal bone density. Therefore, more attention should be given to the WWR in T2DM patients.

New insights into the roles of olfactory receptors in cardiovascular disease.

Olfactory receptors (ORs) are G protein coupled receptors (GPCRs) with seven transmembrane domains that bind to specific exogenous chemical ligands and transduce intracellular signals. They constitute the largest gene family in the human genome. They are expressed in the epithelial cells of the olfactory organs and in the non-olfactory tissues such as the liver, kidney, heart, lung, pancreas, intestines, muscle, testis, placenta, cerebral cortex, and skin. They play important roles in the normal physiological and pathophysiological mechanisms. Recent evidence has highlighted a close association between ORs and several metabolic diseases. Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality globally. Furthermore, ORs play an essential role in the development and functional regulation of the cardiovascular system and are implicated in the pathophysiological mechanisms of CVDs, including atherosclerosis (AS), heart failure (HF), aneurysms, and hypertension (HTN). This review describes the specific mechanistic roles of ORs in the CVDs, and highlights the future clinical application prospects of ORs in the diagnosis, treatment, and prevention of the CVDs.

Identification of Basement Membrane Genes and Related Molecular Subtypes in Nonalcoholic Fatty Liver Disease.

Basement membranes (BMs) are widely distributed and highly specialized extracellular matrix (ECM). The goal of this study was to explore novel genes associated with nonalcoholic fatty liver disease (NAFLD) from the perspective of BMs. Sequencing results of 304 liver biopsy samples about NAFLD were systematically obtained from the Gene Expression Omnibus (GEO) database. Biological changes during NAFLD progression and hub BM-associated genes were investigated by differential gene analysis and weighted gene co-expression network analysis (WGCNA), respectively. The nonalcoholic steatohepatitis (NASH) subgroups were identified based on hub BM-associated genes expression, as well as the differences in Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways and immune microenvironment between different subgroups were compared. Extracellular matrix (ECM) seems to play an important role in the development of NAFLD. Three representative BM-associated genes (ADAMTS2, COL5A1, and LAMC3) were finally identified. Subgroup analysis results suggested that there were significant changes in KEGG signaling pathways related to metabolism, extracellular matrix, cell proliferation, differentiation, and death. There were also changes in macrophage polarization, neutrophils, and dendritic cells abundance, and so on. In conclusion, the present study identified novel potential BM-associated biomarkers and further explored the heterogeneity of NASH that might provide new insights into the diagnosis, assessment, management, and personalized treatment of NAFLD.

Efficacy and safety benefits of iGlarLixi versus insulin glargine 100 U/mL or lixisenatide in Asian Pacific people with suboptimally controlled type 2 diabetes on oral agents: The LixiLan-O-AP randomized controlled trial.

AIMS: To compare the efficacy and safety of iGlarLixi with insulin glargine 100 units/mL (iGlar) and lixisenatide (Lixi), in Asian Pacific people with suboptimally controlled type 2 diabetes (T2D) on metformin with or without a second oral antihyperglycaemic drug (OAD). MATERIALS AND METHODS: LixiLan-O-AP (NCT03798054) was a 24-week multicentre study in adults (n = 878, mean age 56.0 years, mean body mass index 26.0 kg/m2 ) with glycated haemoglobin (HbA1c) levels ≥53 mmol/mol (7%) and ≤97 mmol/mol (11%) on OAD(s), randomized (2:2:1) to open-label once-daily iGlarLixi, iGlar or Lixi while on continued metformin ± sodium-glucose cotransporter-2 inhibitors. The primary efficacy endpoint was change in HbA1c. RESULTS: After 24 weeks, greater reductions in HbA1c from baseline (67 mmol/mol; 8.3%) were seen with iGlarLixi (-21 mmol/mol; -1.9%) compared with iGlar (-16 mmol/mol; -1.4%; P < 0.0001) and Lixi (-10 mmol/mol; -0.9%; P < 0.0001). Greater proportions of participants achieved HbA1c <53 mmol/mol (<7%) with iGlarLixi versus iGlar or Lixi (79%, 60% and 30%, respectively), overall and as composite endpoints including weight and hypoglycaemia. iGlarLixi improved 2-hour postprandial glucose versus iGlar and Lixi and mitigated the weight gain seen with iGlar (least squares mean difference -1.1 kg; P < 0.0001). Documented ≤3.9 mmol/L (≤70 mg/dL) hypoglycaemia was similar between iGlarLixi and iGlar (both 3.38 events per participant-year). The incidence rates of nausea and vomiting were lower with iGlarLixi (14% and 6%) than Lixi (21% and 11%). CONCLUSIONS: iGlarLixi achieved significant HbA1c reductions, to near-normoglycaemic levels, compared with iGlar or Lixi, with no meaningful additional risk of hypoglycaemia and mitigated body weight gain versus iGlar, with fewer gastrointestinal adverse events versus Lixi. iGlarLixi with specifically adapted ratios may provide an efficacious and well-tolerated treatment option for Asian Pacific people with T2D.

Relationship between FGF21 and drug or nondrug therapy of type 2 diabetes mellitus.

Sedentary and high-calorie diets are associated with increased risk of obesity and type 2 diabetes mellitus, while exercise and diet control are also important nondrug treatments for diabetes. Fibroblast growth factor 21 (FGF21) is an important cytokine, which is mainly expressed in liver, fat and muscle tissue responding to nutrition and exercise, and plays an important role in the improvement of glucose and lipid metabolism. Due to the increasing serum FGF21 level in obesity and diabetes, FGF21 can be used as a predictor or biomarker of diabetes. A variety of clinical antidiabetic drugs can reduce the content of FGF21, possibly for the improvement of FGF21 sensitivity. In this paper, we reviewed the interactions between FGF21 and nondrug therapy (diet and exercise) for diabetes and explored the potential value of the combined application of clinical antidiabetic drugs and FGF21.

The relationship between Schistosoma and glycolipid metabolism.

Diabetes and obesity have become the most popular metabolic diseases in the world. A large number of previous studies have shown that glucose and lipid metabolism disorder is an important risk factor and a main cause of diabetes and obesity. Schistosoma is a parasite transmitted by freshwater snails. It can induce a series of inflammatory and immune reactions after infecting the human body, causing schistosomiasis. However, in recent years, studies have found that Schistosoma infection or Schistosoma related products can improve or prevent some immune and inflammatory diseases, such as severe asthma, inflammatory bowel disease, diabetes and so on. Further experiments have also revealed that Schistosoma can promote the secretion of anti-inflammatory factors and regulate the glucose and lipid metabolism in the host body by polarizing immune cells such as T cells, B cells and dendritic cells (DCs). In this review, we summarize studies that investigated Schistosoma and Schistosoma-derived products and their relationship with glycolipid metabolism and related diseases, highlighting potential protective mechanisms.

Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as add-on to metformin in patients with type 2 diabetes in SUSTAIN China: A 30-week, double-blind, phase 3a, randomized trial.

AIM: To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, versus once-daily sitagliptin as add-on to metformin in patients with type 2 diabetes (T2D) in a multiregional clinical trial. MATERIALS AND METHODS: In the 30-week, randomized, double-blind, double-dummy, active comparator SUSTAIN China trial, 868 adults with T2D inadequately controlled on metformin (HbA1c 7.0%-10.5%) were randomized to receive once-weekly semaglutide 0.5 mg (n = 288), semaglutide 1.0 mg (n = 290) or once-daily sitagliptin 100 mg (n = 290). The primary and confirmatory secondary endpoints were change from baseline to week 30 in HbA1c and body weight, respectively. RESULTS: The trial enrolled ~70% (605/868) of the patients in China, and the remaining patients from four other countries, including the Republic of Korea. Both doses of semaglutide were superior to sitagliptin in reducing HbA1c and body weight after 30 weeks of treatment. The odds of achieving target HbA1c of less than 7.0% (53 mmol/mol), weight loss of 5% or higher, or 10% or higher, and the composite endpoint of HbA1c less than 7.0% (53 mmol/mol) without severe or blood glucose-confirmed symptomatic hypoglycaemia no weight gain, were all significantly higher with both semaglutide doses compared with sitagliptin. The safety profile for semaglutide was consistent with the known class effects of GLP-1 receptor agonists (RAs). Consistent efficacy and safety findings were seen in the Chinese subpopulation. CONCLUSIONS: Once-weekly semaglutide was superior to sitagliptin in improving glycaemic control and reducing body weight in patients with T2D inadequately controlled on metformin. The safety and tolerability profiles were consistent with those of semaglutide and other GLP-1 RAs. Semaglutide is an effective once-weekly treatment option for the Chinese population.

Association of Hepatic Steatosis Index and Fatty Liver Index with Carotid Atherosclerosis in Type 2 Diabetes.

Background/aim: Previous studies have suggested that the hepatic steatosis index (HSI) and fatty liver index (FLI) can be used as a predictor of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to determine whether non-invasive indices of hepatic steatosis (HSI and FLI) are associated with carotid atherosclerosis in type 2 diabetes mellitus (T2DM). Methods: This was a cross-sectional study conducted in the T2DM patients (n=768). Carotid intima-media thickness (CIMT) was measured by the Color Doppler ultrasound. The HSI was calculated based on gender, body mass index (BMI), and transaminases level. The FLI was based on BMI, waist circumference (WC), triacylglycerols (TG) and g-glutamyl transferase (GGT). Results: Raised HSI and FLI levels was associated with increased CIMT levels in T2DM patients. Patients with greater CIMT had higher HSI (39.10 ± 5.70 vs 36.10 ± 4.18, P < 0.001) and FLI (46.35 (29.96, 65.54) vs 36.93 (18.7, 57.93), P < 0.001) than those with lower CIMT. Subjects with existing carotid plaque had higher HSI (38.28 ± 5.63 vs 35.69 ± 3.45 P < 0.001) and FLI (47.41 (27.77, 66.62) vs 37.19 (17.71, 51.78), P < 0.001) accordingly. HSI (r = 0.343, P < 0.001) and FLI (r = 0.184, P < 0.001) were positively related with the CIMT. In the linear regression, after full adjustment metabolic risk factors, smoking, and measures of insulin resistance, HSI and FLI were independently associated with CIMT (HSI: ß = 0.011, FLI: ß = 0.001, all P < 0.01). Further, logistic regression analyses showed that higher HSI and FLI had an impact on the risk for carotid atherosclerosis [HSI: OR (95%CI): 1.174 (1.123-1.228), FLI: OR (95%CI): 1.011(1.004-1.019), all P < 0.01]. Overall, increasing values of HSI and FLI were associated with CIMT (P < 0.05) significantly across different categories of age and hypertension. Conclusion: Current data suggest HSI and FLI are independently correlated with carotid atherosclerosis in T2DM. They may be a simple and useful marker for assessing the progression of diabetic macrovascular complications.

Circulating levels of fibroblast growth factor 21 in gestational diabetes mellitus: a meta-analysis.

In recent times, the role of fibroblast growth factor 21 (FGF21) in patients with gestational diabetes mellitus (GDM) has been increasingly investigated. However, to our knowledge, no systematic analysis has been conducted yet to evaluate the relationship between FGF21 levels and GDM. Confirmed studies related to circulating FGF21 levels and GDM were searched from the databases of PubMed, ISI Web of Science, MEDLINE and EMBASE. Data were reported as standard mean difference (SMD) and associated 95% confidence intervals (CIs). Analysis were performed with Review Manager 5.2 and Stata version 11.0. A total of 392 cases and 435 controls in nine articles were included in this meta-analysis. The circulating FGF21 levels in pregnant women with GDM was higher than that in controls (random effects MD [95% CI] = 0.46, [0.07-0.86], p = 0.02). The result of multivariate meta-regression showed that sample size and point of sample collection contributed to heterogeneity (p = 0.033 and p = 0.047, respectively). Additionally, the results showed that there was no publication bias in this meta-analysis (Z = 1.36, p = 0.175; t = 1.24, p = 0.256, respectively). To conclude, this meta-analysis provides evidence that circulating FGF21 levels are higher in GDM subjects than controls, and it is important to clarify the relationship between circulating FGF21 levels and pregnant women with GDM in accurate prediction of GDM.

Efficacy and safety of insulin glargine 300 U/mL versus insulin glargine 100 U/mL in Asia Pacific insulin-naïve people with type 2 diabetes: The EDITION AP randomized controlled trial.

AIM: To compare the efficacy and safety of Gla-300 versus Gla-100 in insulin-naïve people with type 2 diabetes in Asia Pacific. MATERIALS AND METHODS: In this open-label, randomized, active-controlled, 26-week study, insulin-naïve participants with type 2 diabetes inadequately controlled with non-insulin antihyperglycaemic drugs were randomized (2:1) to Gla-300 or Gla-100. The initial daily dose of basal insulin was 0.2 U/kg and was adjusted at least weekly for 8-12 weeks to a target fasting self-monitored plasma glucose (SMPG) of 4.4-5.6 mmol/L. RESULTS: Of the 604 participants randomized, 570 (Gla-300, n = 375; Gla-100, n = 195) completed the study. Non-inferiority of Gla-300 versus Gla-100 in HbA1c reduction from baseline to week 26 was confirmed. In the Gla-300 and Gla-100 groups, 51.1% and 52.2% of participants achieved the HbA1c target of <7.0% (rate ratio [95% CI]: 0.98 [0.84 to 1.14]) and 19.1% and 21.9% achieved the target without hypoglycaemia during the last 12 weeks of treatment (rate ratio [95% CI]: 0.87 [0.63 to 1.20]). Changes in fasting plasma glucose and 24-hour average eight-point SMPG were comparable between groups. Incidence of hypoglycaemia at any time of day was similar between treatment groups at week 26, but incidence of any nocturnal hypoglycaemia was numerically lower with Gla-300 than Gla-100 over the initial 12-week titration period and 26-week on-treatment period. Rates of adverse events were similar between groups and low for serious adverse events. CONCLUSIONS: Glycaemic control of Gla-300 is non-inferior to Gla-100 with a similar or lower incidence and proportion of hypoglycaemia in people with type 2 diabetes in Asia Pacific, reinforcing the results in the global EDITION programme.

Chemerin enhances the adhesion and migration of human endothelial progenitor cells and increases lipid accumulation in mice with atherosclerosis.

BACKGROUND: The role of adipokines in the development of atherosclerosis (AS) has received increasing attention in recent years. This study aimed to explore the effects of chemerin on the functions of human endothelial progenitor cells (EPCs) and to investigate its role in lipid accumulation in ApoE-knockout (ApoE-/-) mice. METHODS: EPCs were cultured and treated with chemerin together with the specific p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580 in a time- and dose-dependent manner. Changes in migration, adhesion, proliferation and the apoptosis rate of EPCs were detected. ApoE-/- mice with high-fat diet-induced AS were treated with chemerin with or without SB 203580. Weights were recorded, lipid indicators were detected, and tissues sections were stained. RESULTS: The data showed that chemerin enhanced the adhesion and migration abilities of EPCs, and reduced the apoptosis ratio and that this effect might be mediated through the p38 MAPK pathway. Additionally, chemerin increased the instability of plaques. Compared with the control group and the inhibitor group, ApoE-/- mice treated with chemerin protein had more serious arterial stenosis, higher lipid contents in plaques and decreased collagen. Lipid accumulation in the liver and kidney and inflammation in the hepatic portal area were enhanced by treatment with chemerin, and the size of adipocytes also increased after chemerin treatment. In conclusion, chemerin can enhance the adhesion and migration abilities of human EPCs and reduce the apoptosis ratio. In animals, chemerin can increase lipid accumulation in atherosclerotic plaques and exacerbate plaques instability. At the same time, chemerin can cause abnormal lipid accumulation in the livers and kidneys of model animals. After specifically blocking the p38 MAPK pathway, the effect of chemerin was reduced. CONCLUSIONS: In conclusion, this study showed that chemerin enhances the adhesion and migration abilities of EPCs and increases the instability of plaques and abnormal lipid accumulation in ApoE-/- mice. Furthermore, these effects might be mediated through the p38 MAPK pathway.

Determining the optimal fasting glucose target for patients with type 2 diabetes: Results of the multicentre, open-label, randomized-controlled FPG GOAL trial.

The optimal fasting blood glucose (FBG) target of achieving HbA1c less than 7.0% in type 2 diabetes (T2D) patients remains controversial. This open-label trial randomized (1:3:3) 947 adults with uncontrolled T2D (HbA1c >7% to ≤10.5%) who were using one to three oral antidiabetic drugs to achieve an FBG target of 3.9 < FBG ≤5.6 mmol/L (Group 1), 3.9 < FBG ≤6.1 mmol/L (Group 2) or of 3.9 < FBG ≤7.0 mmol/L (Group 3). Targets were achieved using a pre-defined insulin glargine 100 U/mL titration scheme. The primary endpoint was proportion of patients achieving HbA1c <7.0% at 24 weeks. At 24 weeks, 44.4%, 46.1% and 37.7% of patients achieved HbA1c <7.0% in Groups 1, 2 and 3, respectively (P = 0.017; Group 2 vs Group 3). Alert hypoglycaemia (glucose ≤3.9 mmol/L) was significantly more frequent in Group 1 than in Group 3 (38.9 vs 23.3%; P < 0.001) but was not in Group 2 vs Group 3 (27.5% vs 23.3%; P = 0.177). Clinically important hypoglycaemia (glucose ≤3.0 mmol/L) was reported in 4.8%, 2.0% and 3.8% of patients in Groups 1, 2 and 3, respectively. In conclusion, the optimal FBG target for most Chinese patients with T2D appears to be 3.9-6.1 mmol/L.

Regulation of angiopoietin-like protein 8 expression under different nutritional and metabolic status.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with increasing prevalence worldwide. Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein family, is involved in glucose metabolism, lipid metabolism, and energy homeostasis and believed to be associated with T2DM. Expression levels of ANGPTL8 are often significantly altered in metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus. Studies have shown that ANGPTL8, together with other members of this protein family, such as angiopoietin-like protein 3 (ANGPTL3) and angiopoietin-like protein 4 (ANGPTL4), regulates the activity of lipoprotein lipase (LPL), thereby participating in the regulation of triglyceride related lipoproteins (TRLs). In addition, members of the angiopoietin-like protein family are varyingly expressed among different tissues and respond differently under diverse nutritional and metabolic status. These findings may provide new options for the diagnosis and treatment of diabetes, metabolic syndromes and other diseases. In this review, the interaction between ANGPTL8 and ANGPTL3 or ANGPTL4, and the differential expression of ANGPTL8 responding to different nutritional and metabolic status during the regulation of LPL activity were reviewed.

Effects of a diet with or without physical activity on angiopoietin-like protein 8 concentrations in overweight/obese patients with newly diagnosed type 2 diabetes: a randomized controlled trial.

Angiopoietin-like protein 8 (ANGPTL8) is a newly discovered adipokine plays an important role in energy homoeostasis, obesity and type 2 diabetes (T2D). Although lifestyle modification in obesity and T2D is known to offer metabolic benefits, there is paucity of comprehensive data on change in ANGPTL8. We investigated the effect of lifestyle intervention on ANGPTL8 concentrations. 384 obese/overweight adults with newly diagnosed T2D were randomly assigned (1:1:1) to diet (n = 128), diet + activity (n = 128) or usual care (control, n = 128) groups. All patients received usual care. Besides, the diet group received a calorie-restricted diet aiming for a weight loss of 5-10%. The diet + activity group additionally received a pedometer-based walking program. Primary outcome was change in ANGPTL8 concentration at 6 months. Data were analyzed according to intention-to-treat. From baseline to 6 months, the median ANGPTL8 level changed from 804.38 pg/mL to 792.86 pg/mL in control group. Compared with control, ANGPTL8 decreased with diet (baseline-adjusted between-group difference was -121.00 pg/mL, 95% CI -177.47 to -64.53; p < 0.0001) and diet + activity (-126.16 pg/mL, -181.21 to -71.11; p < 0.0001). There was no greater effect of diet + activity compared with diet (-5.16 pg/mL, -53.63 to 43.31; p = 0.8348). Both effects disappeared after adjusting for change in body fat, but did not differ significantly when adjusting for physical activity. A 6-month intervention inducing weight loss by a calorie-restricted diet or diet + activity, resulted in significant decrease on ANGPTL8 concentration. These effects were established by change in total body fat, and not by change in physical activity.

Caveolin-1 regulates autophagy activity in thyroid follicular cells and is involved in Hashimoto's thyroiditis disease.

Hashimoto's thyroiditis (HT) is considered a T helper-type 1 (Th1) cytokine-dominant autoimmune thyroid disease. Caveolin-1 (Cav-1), a part of the thyroxisome multiprotein complex, is localized at the apical pole of thyrocytes and is indispensable for synthesis of thyroid hormones and modulation of oxidative stress in order to avoid cell damage and apoptosis. Reduced autophagy induces thyroid follicular cells (TFC) apoptosis by activating reactive oxygen species (ROS) in HT patients. Nevertheless, whether Cav-1 has roles in the regulation of autophagy remains largely unclear. In this study, we examined Th1 cytokines and Cav-1 expression in HT thyroid tissues, determined the effects of interleukin-1beta (IL-1ß) and interferon-gamma (IFN-γ) on Cav-1 and autophagy activity in TFC, and investigated the association between Cav-1 and autophagy activity in vitro. Our results indicate that higher levels of IL-1ß and IFN-γ and lower levels of Cav-1 were expressed in thyroid tissues of HT patients than in those of normal controls. Cav-1 mRNA and protein levels were significantly decreased in TFC exposed to IL-1ß and IFN-γ, accompanied by decreased expression of autophagy-related protein LC3B-II. Interestingly, small interfering RNA (siRNA)-mediated Cav-1 knockdown in TFC reduced LC3B-II protein expression. Taken together, these results suggest that lack of Cav-1 expression inhibited autophagy activity in TFC exposed to Th1 cytokines (IL-1ß and IFN-γ), which might be a novel pathogenetic mechanism of HT.

Genome-wide association study identifies a novel susceptibility gene for serum TSH levels in Chinese populations.

Thyroid-stimulating hormone (TSH) is a sensitive indicator of thyroid function. High and low TSH levels reflect hypothyroidism and hyperthyroidism, respectively. Even within the normal range, small differences in TSH levels, on the order of 0.5-1.0 mU/l, are associated with significant differences in blood pressure, BMI, dyslipidemia, risk of atrial fibrillation and atherosclerosis. Most of the variance in TSH levels is thought to be genetically influenced. We conducted a genome-wide association study of TSH levels in 1346 Chinese Han individuals. In the replication study, we genotyped four candidate SNPs with the top association signals in an independent isolated Chinese She cohort (n = 3235). We identified a novel serum TSH susceptibility locus within XKR4 at 8q12.1 (rs2622590, Pcombined = 2.21 × 10(-10)), and we confirmed two previously reported TSH susceptibility loci near FOXE1 at 9q22.33 and near CAPZB at 1p36.13, respectively. The rs2622590_T allele at XKR4 and the rs925489_C allele near FOXE1 were correlated with low TSH levels and were found to be nominally associated to patients with papillary thyroid carcinoma (PTC) (OR = 1.41, P= 0.014 for rs2622590_T, and OR = 1.61, P= 0.030 for rs925489_C). The rs2622590 and rs925489 genotypes were also correlated with the expression levels of FOXE1 and XKR4, respectively, in PTC tissues (P = 2.41 × 10(-4) and P= 0.02). Our findings suggest that the SNPs in XKR4 and near FOXE1 are involved in the regulation of TSH levels.

C-reactive protein inhibits high-molecular-weight adiponectin expression in 3T3-L1 adipocytes via PI3K/Akt pathway.

Adiponectin, an adipose-specific protein hormone, is secreted from white adipose tissue and involved in glucose and lipid metabolism. It is assembled into low-molecular-weight trimer (LMW), middle-molecular-weight hexameric (MMW) and high-molecular-weight (HMW), among which HMW exhibits higher activity. In this study, we proved that C-reactive protein (CRP), an inflammatory marker, inhibited adiponectin expression, especially HMW in time-and dose-dependent manners. Furthermore, CRP decreased the HMW/total adiponectin ration and reduced adiponectin assembly by increasing ERp44, and decreasing Ero1-α and DsbA-L. CRP activated pAkt, the downstream of PI3K. Inhibition of PI3K or pAkt abolished the effect of CRP. Our study suggested that CRP decreased adiponectin expression and multimerization, while CRP-induced decline in adiponectin might be mediated through the PI3K/Akt pathway.

Ertapenem versus piperacillin/tazobactam for diabetic foot infections in China: a Phase 3, multicentre, randomized, double-blind, active-controlled, non-inferiority trial.

OBJECTIVES: Few randomized controlled studies have compared antibiotic regimens against diabetic foot infections (DFIs) in Chinese patients. We evaluated the efficacy and safety of ertapenem versus piperacillin/tazobactam for the treatment of DFIs in Chinese patients. METHODS: Patients with moderate to severe DFIs requiring parenteral antibiotics were randomized in a 1 : 1 ratio to receive ertapenem (1.0 g once daily) or piperacillin/tazobactam (4.5 g every 8 h) by 30 min intravenous (iv) infusions for ≥5 days. The primary outcome was favourable clinical response at discontinuation of iv therapy (DCIV). An evaluable-patient population was identified for primary analysis of non-inferiority at -15%. Safety was assessed. ClinicalTrials.gov: NCT01370616. RESULTS: Of 565 patients randomized, 443 patients (ertapenem = 219 and piperacillin/tazobactam = 224) were clinically evaluable for primary analysis. In the clinically evaluable population, the proportions of patients with favourable clinical response at DCIV were 93.6% (205/219) and 97.3% (218/224) in the ertapenem and piperacillin/tazobactam groups, respectively (difference: -3.8%, 95% CI: -8.3%, 0.0%). Ertapenem had a significantly lower favourable clinical response rate (91.5% versus 97.2%, 95% CI for difference: -12.1%, -0.3%) at DCIV in severe DFI patients. In the modified ITT population, 88.8% (237/267) and 90.6% (241/266) of patients in the ertapenem and piperacillin/tazobactam groups, respectively, had favourable clinical responses at DCIV (difference: -1.9%, 95% CI: -7.3%, 3.3%). Microbiological eradications of causative pathogens and adverse events were similar between treatment groups. CONCLUSIONS: Treatment with ertapenem was non-inferior to piperacillin/tazobactam in Chinese patients with DFIs. Ertapenem treatment resulted in a markedly lower rate of clinical resolution in severe DFIs.

Excess iodine promotes apoptosis of thyroid follicular epithelial cells by inducing autophagy suppression and is associated with Hashimoto thyroiditis disease.

The incidence of the autoimmune thyroid disease Hashimoto thyroiditis (HT) has increased in recent years, and increasing evidence supports the contribution of excess iodine intake to thyroid disease. In this study, we examined the status of autophagy and apoptosis in thyroid tissues obtained from patients with HT, and we determined the effects of excessive iodine on the autophagy and apoptosis of thyroid follicular cells (TFCs) in an attempt to elucidate the effects of excess iodine on HT development. Our results showed decreases in the autophagy-related protein LC3B-II, and increases in caspase-3 were observed in thyroid tissues from HT patients. Interestingly, the suppression of autophagy activity in TFCs was induced by excess iodine in vitro, and this process is mediated through transforming growth factor-ß1 downregulation and activation of the Akt/mTOR signaling pathway. In addition, excess iodine induced autophagy suppression and enhanced reactive oxygen species (ROS) production and apoptosis of TFCs, which could be rescued by the activation of autophagy. Taken together, our results demonstrated that excess iodine contributed to autophagy suppression and apoptosis of TFCs, which could be important factors predisposing to increased risk of HT development.