Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor.

Adiponectin, an adipokine produced and secreted by adipocytes, is involved in regulating the development and progression of insulin resistance, diabetes, and diabetic complications. Heat shock protein 60 (HSP60) is a molecular chaperone, most commonly presenting in mitochondria and participating in the maintenance of protein homeostasis. Accumulating studies have demonstrated that the elevated circulating HSP60 and the decreased intracellular HSP60 are closely associated with diabetic complications such as diabetic cardiomyopathy. However, the underlying mechanism remains poorly understood. In the present study, we reported that HSP60 interacted directly with adiponectin receptors. Its abundance was positively associated with adiponectin action. Furthermore, HSP60 depletion markedly mitigated the protective impacts of adiponectin on high glucose-induced oxidative stress and cell apoptosis in rat cardiac H9c2 cells. In addition, HSP60 knockdown significantly enhanced proteasome activity leading to the degradation of adiponectin receptor 1. Taken together, we showed for the first time that HSP60 interacted with adiponectin receptors and mediated adiponectin signaling through stabilizing adiponectin receptor. This in vitro study also provides an alternative explanation for mechanism by which adiponectin exerts its action. Video abstract.

Association of serum calcium and heart failure with preserved ejection fraction in patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a recognized trigger factor for heart failure with preserved ejection fraction (HFpEF). Recent studies show that higher serum calcium level is associated with greater risk of both T2DM and heart failure. We speculate that increased serum calcium is related to HFpEF prevalence in patients with T2DM. METHODS: In this cross-sectional echocardiographic study, 807 normocalcemia and normophosphatemia patients with T2DM participated, of whom 106 had HFpEF. Multinomial logistic regression was carried out to determine the variables associated with HFpEF. The associations between serum calcium and metabolic parameters, as well as the rate of HFpEF were examined using bivariate linear correlation and binary logistic regression, respectively. The predictive performance of serum calcium for HFpEF was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: Patients with HFpEF have significantly higher serum calcium than those without HFpEF. Serum calcium was positively associated with total cholesterol, triglycerides, low-density lipoprotein cholesterol, serum uric acid, HOMA-IR and fasting plasma glucose. Compared with patients in the lowest serum calcium quartile, the odds ratio (OR) for HFpEF in patients in the highest quartile was 2.331 (95 % CI 1.088-4.994, p = 0.029). When calcium was analyzed as a continuous variable, per 1 mg/dL increase, the OR (95 % CI) for HFpEF was [2.712 (1.471-5.002), p = 0.001]. Serum calcium can predict HFpEF [AUC = 0.673, 95 % CI (0.620-0.726), p < 0.001]. CONCLUSIONS: An increase in serum calcium level is associated with an increased risk of HFpEF in patients with T2DM.

Metformin protects against hyperglycemia-induced cardiomyocytes injury by inhibiting the expressions of receptor for advanced glycation end products and high mobility group box 1 protein.

Metformin (MET), an anti-diabetic oral drug with antioxidant properties, has been proved to provide cardioprotective effects in patients with diabetic disease. However, the mechanism is unclear. This study aimd to investigate the effects of MET on the expressions of receptor for advanced glycation end products (RAGE) and high mobility group box 1 protein (HMGB1) in hyperglycemia-treated neonatal rat ventricular myocytes. Cardiocytes were prepared and cultured with high glucose and different concentrations of MET. The expressions of RAGE and HMGB1 were evaluated by Western blot analysis. The superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), lactate dehydrogenase (LDH) and creatine kinase (CK) were measured. After 12 h-incubation, MET significantly inhibited the increase of MDA, TNF-α, LDH and CK levels induced by high glucose, especially at the 5 × 10(-5) to 10(-4 )mol/L concentrations while inhibiting the decrease of SOD level. Meanwhile, RAGE and HMGB1 expression were significantly increased induced by hyperglycaemia for 24 h (P < 0.05). MET inhibited the expressions of RAGE and HMGB1 in a dose-dependent manner, especially at the 5 × 10(-5) to 10(-4 )mol/L concentrations (P < 0.05). In conclusion, our study suggested that MET could reduce hyperglycemia-induced cardiocytes injury by inhibiting the expressions of RAGE and HMGB1.

Liraglutide ameliorates diabetic kidney disease by modulating gut microbiota and L-5-Oxoproline.

The gut microbiome-metabolites-kidney axis is a potential target for treating diabetic kidney disease (DKD). Our previous study found that Liraglutide attenuated DKD in rats by decreasing renal tubular ectopic lipid deposition (ELD) and serum metabolites levels, including L-5-Oxoproline (5-OP). However, the response of gut microbiome-metabolites-kidney axis to Liraglutide in DKD rats and the effect of 5-OP on ELD remain unknown. In this study, Sprague-Dawley rats were used as an animal model of DKD. They were subjected to a high fat diet, streptozotocin and uninephrectomy, followed by Liraglutide treatment (0.4 mg/kg d). Additionally, HK-2 cells were incubated with 30 mM glucose and 200 µM palmitate for 24h, and exposed to different concentrations of 5-OP. In DKD rats, Liraglutide dramatically improved the renal tubule structure. It increased the Simpson index (F = 4.487, p = 0.035) and reduced the Actinobacteria-to-Bacteroidetes ratio (F = 6.189, p = 0.014). At the genus level, Liraglutide increased the relative abundance of Clostridium, Oscillospira, Sarcina, SMB53, and 02d06 while decreasing that of Allobaculum. Meanwhile, 13 metabolites were significantly altered after Liraglutide treatment. Multi-omics analysis found that 5-OP levels were positively correlated with Clostridium abundance but negatively correlated with renal injury related indicators. In HK-2 cells, 5-OP significantly reduced the ELD in a dose-dependent manner through inhibiting the expression of SREBP1 and FAS. Overall, the renoprotective effect of Liraglutide in DKD rats is linked to the improvement of the gut microbiota composition and increased serum 5-OP levels, which may reduce ELD in renal tubular cells by lowering lipid synthesis.

Environmental-friendly, flexible silk fibroin-based film as dual-responsive shape memory material.

Bio-based shape memory materials have attracted wide attention due to their biocompatibility, degradability and safety. However, designing and manufacturing wearable bio-based shape memory films with excellent flexibility and toughness is still a challenge. In this work, silk fibroin substrate with a ß-sheet structure was combined with a tri-block shape memory copolymer to prepare a transparent composited shape memory film. The silk fibroin-based film showed a dual-responsive shape memory function, which can respond to both temperature and water stimuli. This film has a sensitive water-responsive shape memory, which starts deforming after exposure to water for 3 s and fully recovers in 30 s. In addition, the composite film shows highly stretchable (>300 %) and could maintain its high tensile properties after 5 cycles of regeneration. The films also exhibited rapid degradation ability. This study provides new insights for the design of dual-responsive shape memory materials by combining biocompatible matrix and multi-block SMP to simultaneously enhance the mechanical properties, which can be used for intelligent packaging, medical supplies, soft actuators and wearable devices.

Tyrosine-phosphorylated DNER sensitizes insulin signaling in hepatic gluconeogenesis by inducing proteasomal degradation of TRB3.

OBJECTIVE: Hepatic insulin resistance, which leads to increased hepatic gluconeogenesis, is a major contributor to fasting hyperglycemia in type 2 diabetes mellitus (T2DM). However, the mechanism of impaired insulin-dependent suppression of hepatic gluconeogenesis remains elusive. Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER), firstly described as a neuron-specific Notch ligand, has been recently identified as a susceptibility gene for T2DM through genome-wide association studies. We herein investigated whether DNER regulates hepatic gluconeogenesis and whether this is mediated by enhanced insulin signaling. METHODS: The association between DNER, tribbles homolog 3 (TRB3) and Akt signaling was evaluated in C57BL/6J, ob/ob and db/db mice by western blot analysis. DNER loss-of-function and gain-of-function in hepatic gluconeogenesis were analyzed by western blot analysis, quantitative real-time PCR, glucose uptake and output assay in AML-12 cells and partially validated in primary mouse hepatocytes. Hepatic DNER knockdown mice were generated by tail vein injection of adenovirus to confirm the effects of DNER in vivo. The interaction between DNER and TRB3 was investigated by rescue experiments, cycloheximide chase analysis, co-immunoprecipitation and immunofluorescence. The potential insulin-stimulated phosphorylation sites of DNER were determined by co-immunoprecipitation, LC-MS/MS analysis and site-specific mutagenesis. RESULTS: Here we show that DNER enhanced hepatic insulin signaling in gluconeogenesis by inhibiting TRB3, an endogenous Akt inhibitor, through the ubiquitin-proteasome degradation pathway. In AML-12 hepatocytes, insulin-stimulated activation of Akt and suppression of gluconeogenesis are attenuated by DNER knockdown, but potentiated by DNER over-expression. In C57BL/6J mice, hepatic DNER knockdown is accompanied by impaired glucose and pyruvate tolerance. Furthermore, the in vitro effects of DNER knockdown or over-expression on both Akt activity and hepatic gluconeogenesis can be rescued by TRB3 knockdown or over-expression, respectively. In response to insulin stimulation, DNER interacted directly with insulin receptor and was phosphorylated at Tyr677. This site-specific phosphorylation is essential for DNER to upregulate Akt activity and then downregulate G6Pase and PEPCK expression, by interacting with TRB3 directly and inducing TRB3 proteasome-dependent degradation. CONCLUSIONS: Taken together, the crosstalk between insulin-Akt and DNER-TRB3 pathways represents a previously unrecognized mechanism by which insulin regulates hepatic gluconeogenesis.

Glucagon-like peptide-1 receptor agonist protects against hyperglycemia-induced cardiocytes injury by inhibiting high mobility group box 1 expression.

Glucagon-like peptide-1 (GLP-1), a gut incretin hormone secreted from L cells, and a GLP-1 receptor agonist, exendin-4 (Ex-4) has been shown to be cardioprotective and could exert beneficial effects through its anti-inflammatory property. However, the mechanism remains unclear. The purpose of this study was to investigate whether Ex-4 could ameliorate myocardial cell injury by inhibiting high mobility group box 1 (HMGB1) expression under high glucose condition. Neonatal rat ventricular myocytes were prepared and then cultured with high glucose and different concentration of Ex-4. Lactate dehydrogenase (LDH), creatine kinase (CK), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. HMGB1 expression was assessed by western blotting. Ex-4 significantly inhibited the increase in LDH, CK, TNF-α, IL-1ß and MDA levels induced by high glucose, especially at the 1 and 10 nM concentrations as well as suppressed the decrease in SOD level. Meanwhile, HMGB1 expression was markedly increased after 12 h of hyperglycaemia (P < 0.05), which was significantly inhibited by Ex-4, especially at the 1 and 10 nM concentrations (P < 0.05). The present study suggested that Ex-4 could reduce high glucose-induced cardiocytes injury, which may be associated with the inhibition of HMGB1 expression.

Pathophysiology roles for adenosine 2A receptor in obesity and related diseases.

Obesity, a burgeoning worldwide health system challenge, is associated with several comorbidities, including non-alcoholic fatty liver disease (NAFLD), diabetes, atherosclerosis, and osteoarthritis, leading to serious problems to people's health. Adenosine is a critical extracellular signaling molecule that has essential functions in regulating most organ systems by binding to four G-protein-coupled adenosine receptors, denoted A1 , A2A , A2B , and A3 . Among the receptors, a growing body evidence highlights the key roles of the adenosine 2A receptor (A2A R) in obesity and related diseases. In the current review, we summarize the effects of A2A R in obesity and obesity-associated non-alcoholic fatty liver disease, diabetes, atherosclerosis, and osteoarthritis, to clarify the complicated impacts of A2A R on obesity and related diseases.

Effect of hyperglycemia on the immune function of COVID-19 patients with type 2 diabetes mellitus: a retrospective study.

Purpose: To analyze the clinical characteristics and immune function parameters and to explore the effect of hyperglycemia on the immune function in patients with Corona Virus Disease 2019 (COVID-19) with type 2 diabetes mellitus (T2DM). Methods: This retrospective study included patients with COVID-19 with T2DM hospitalized in Renmin Hospital of Wuhan University between January 31, 2020, and February 10, 2020. The clinical data were collected and patients were divided into a well-controlled group (blood glucose 3.9-10.0 mmol/L) and a poorly-controlled group (blood glucose >10.0 mmol/L). The differences in routine blood tests, peripheral lymphocyte subsets, humoral immune components, C-reactive protein (CRP) level, and cytokines were compared, and the correlation between blood glucose and immune parameters as well as the severity of the disease was analyzed. Results: A total of 65 patients with COVID-19 and T2DM were included in the final analysis. Compared with the well-controlled group, patients in the poorly-controlled group had decreased lymphocytes, CD16+ 56+ NK cells, CD3+ T cells, CD8+ T cells and increased neutrophil percentage, IL-6 levels, CRP levels and serum concentration of IgA. Blood glucose was inversely correlated with CD16+ 56+ NK cells, CD3+ T cells, CD4+ T cells, and CD8+ T cells and positively correlated with IL-6 and CRP levels. There was a positive correlation between blood glucose and the severity of the COVID-19. Conclusion: Hyperglycemia will aggravate the immune dysfunction of COVID-19 patients with T2DM and affect the severity of COVID-19.

Epidemiological and clinical characteristics of 214 families with COVID-19 in Wuhan, China.

OBJECTIVE: To investigate the epidemiological dynamics, transmission patterns, and the clinical outcomes of Coronavirus disease 2019 (COVID-19) in familial cluster patients in Wuhan, China. METHODS: Between January 22, 2020, and February 4, 2020, we enrolled 214 families for this retrospective study. The COVID-19 cases were diagnosed using real-time reverse-transcriptase polymerase chain reaction (RT-PCR). The number of COVID-19 subjects in a family, their relationship with index patients, the key time-to-event, exposure history, and the clinical outcomes were obtained through telephone calls. RESULTS: Overall, 96 families (44.9%) met the criteria of a familial cluster, which is at least one confirmed case in addition to the index patient in the same household. The secondary attack rate was 42.9%, and nearly 95% of index patients transmitted the infection to ≤2 other family members. High transmission pattern was noted between couples (51.0%) and among multi-generations (27.1%). The median serial interval distribution in familial clusters was 5 days (95% CI, 4 to 6). The case fatality rate was 8.7% in index patients and 1.7% in non-familial clusters patients (p = 0.023). CONCLUSIONS: There is a related higher attack rate and worse clinical outcomes in COVID-19 family clusters.

[Influences and mechanism of verapamil on ischemia/reperfusion injury in cardiomyocytes of streptozotocin-induced diabetes mellitus rats].

OBJECTIVE: To investigate the effects and mechanism of verapamil preventing ischemia/reperfusion (I/R) injury by cardiac performance intracellular free [Ca(2+)](i) and L-type calcium current (I(Ca-L)) in cardiomyocytes of diabetes mellitus rats. METHODS: Diabetic rats were streptozotocin-induced and received verapamil (8 mg×kg(-1)×d(-1)) from 6 - 14 weeks old. The in vitro heart models of I/R rats were randomly divided into normal control group diabetes group, verapamil control group. the changes of heart functions were observed through a Langendorff-perfusion system. The fluorescence intensity of intracellular Ca(2+) was detected with Fluo-3/AM loading by laser scanning confocal microscope. I(Ca-L) was recorded by the whole-cell technique of patch clamp in enzymatically dissociated single rat ventricular myocytes. RESULTS: (1) In verapamil diabetes group, the values of left ventricular developed pressure [(91.3 ± 4.6) mm Hg], diastolic end pressure [(1535 ± 280) mm Hg], the maximum rising rates of left ventricular pressure [(5833 ± 256) mm Hg/s] and coronary arterial flow [(13.7 ± 0.9) ml/min] were all significantly increased, and the maximum dropping rates of left ventricular pressure [(3504 ± 319) mm Hg/s] was obviously decreased (compared with diabetes group, P < 0.01, respectively). (2) The fluorescence intensities of intracellular free Ca(2+)[(155.6 ± 10.9) nmol/L] in verapamil diabetes group were significantly reduced compared with diabetes group (245.2 ± 17.5 nmol/L, P < 0.01). (3) When clamp voltage was -20mV, I(Ca-L) was (-6.81 ± 0.76) pA/pF in verapamil diabetes group (compared with normal group (-8.17 ± 2.07) pA/pF, P < 0.05, and with diabetes group (-3.21 ± 0.54) pA/pF, P < 0.01, and with verapamil control group (-7.14 ± 2.17) pA/pF, P > 0.05). The current-voltage curve was changed to the lower position with -20mV of peak clamp potential in verapamil diabetes group compared with diabetes group. CONCLUSION: A poor heart function is closely correlated with a rising [Ca(2+)]i and a declining I(Ca-L) associated with I/R injury in diabetic rats hearts. Along-term verapamil therapy may significantly improve the severe cardiac impairment. The mechanism is probably attributed to the fact that verapamil can adjust I(Ca-L) influx, normalize the balance of intercellular [Ca(2+)]i, and block the Ca(2+) overload trigger by the effects of Ca(2+)-induced Ca(2+) release in diabetic cardiomyocytes.

Angiopoietin-like 8 Improves Insulin Resistance and Attenuates Adipose Tissue Inflammation in Diet-Induced Obese Mice.

Angiopoietin-like 8 (ANGPTL8) is closely linked to obesity-associated metabolic diseases and insulin resistance. The aim of the current study was to investigate the ability of ANGPTL8 to reverse insulin resistance in obese mice. The administration of ANGPTL8 reduced weight gain and improved glucose tolerance in mice with diet-induced obesity. In addition, ANGPTL8 administration modified macrophage infiltration, reduced monocyte chemoattractant protein-1 (MCP-1) and interleukin-1ß(IL-1ß) levels, and increased adiponectin gene expression in inguinal white adipose tissue (iWAT). Moreover, the exposure of a cultured peritoneal macrophage line to ANGPTL8 reduced the mRNA expression of M1 macrophage markers (TNF-α and IL-1ß) upon stimulation with lipopolysaccharides in a dose-dependent manner. By contrast, when incubated with IL-4, exposure of macrophages to ANGPTL8 increased the mRNA expression of M2 macrophage markers (Arg1 and Chi3l3) in a dose-dependent manner. Collectively, the results of the present study demonstrated that treatment with ANGPTL8 can attenuate adipose tissue inflammation through regulation of macrophage polarization, and thus, it could be useful for improving insulin resistance.

Identification of differentially expressed mRNA and the Hub mRNAs modulated by lncRNA Meg3 as a competing endogenous RNA in brown adipose tissue of mice on a high-fat diet.

Obesity is associated with insulin resistance, diabetes, and obesity-related metabolic disorders. Brown adipocytes have emerged as potential targets for the treatment of obesity and obesity-related diseases. However, changes that occur in brown adipose tissue during various stages of high fat diet (HFD)-induced obesity remain poorly understood. The present study aimed to determine the changes occurring in brown adipose tissue during various stages of an HFD by analyzing two microarray expression profiles. A total of 1,337 differentially expressed RNAs (DE RNAs) were identified between the HFD and ND groups, using the limma package in R. The DE RNAs included 1,249 mRNAs, 74 long non coding RNAs (lncRNAs), and 14 pseudogenes. Functional annotation of the DE mRNAs, including GO terms and KEGG pathways were identified using the Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction network was constructed using STRING and clusters were obtained through the Molecular Complex Detection plug-in. In the present study, the lncRNA,maternally expressed gene 3 (Meg3), was identified as the DE lncRNA with a significant fold change. The network of Meg3 as a ceRNA was constructed, which demonstrated that Meg3 modulated five hub DE mRNAs via competitive binding to microRNAs.

Hypertrophic Adipocyte-Derived Exosomal miR-802-5p Contributes to Insulin Resistance in Cardiac Myocytes Through Targeting HSP60.

OBJECTIVE: This study aimed to elucidate the mechanism by which hypertrophic adipocytes regulate insulin signaling in cardiac myocytes. METHODS: Palmitate was used to induce hypertrophic 3T3-L1 adipocytes. Exosomes were purified from normal control or hypertrophic 3T3-L1 adipocyte-associated conditioned medium. Exosome-exposed neonatal rat ventricular myocytes were stimulated with insulin to investigate the effects of exosomes on insulin signaling. Small interfering RNA techniques were used to downregulate protein levels, and their efficiency was evaluated by Western blot. RESULTS: Hypertrophic adipocyte-derived exosomes highly expressed miR-802-5p. Insulin sensitivity of neonatal rat ventricular myocytes was negatively regulated by miR-802-5p. TargetScan and luciferase reporter assays revealed that heat shock protein 60 (HSP60) was a direct target of miR-802-5p. HSP60 silencing was found to induce insulin resistance and to mitigate the insulin-sensitizing effects of adiponectin. In addition, HSP60 depletion significantly increased the expression levels of C/EBP-homologous protein and enhanced oxidative stress, accompanied by the increases in the phosphorylation of JNK and IRS-1 Ser307. Moreover, the effects of HSP60 knockdown on C/EBP-homologous protein and oxidative stress were abolished by the inhibition of either miR-802-5p or endocytosis. CONCLUSIONS: Hypertrophic adipocyte-derived exosomal miR-802-5p caused cardiac insulin resistance through downregulating HSP60. These findings provide a novel mechanism by which epicardial adipose tissue impairs cardiac function.

Fasting blood glucose level is a predictor of mortality in patients with COVID-19 independent of diabetes history.

AIM: No study elucidated the role of fasting blood glucose (FBG) level in the prognosisof coronavirus disease 2019 (COVID-19). METHODS: This cohort study was conducted in a single center at Renmin Hospital of Wuhan University, Wuhan, China. Clinical laboratory, and treatment data of inpatients with laboratory-confirmed COVID-19 were collected and analyzed. Outcomes of patients with and without pre-existing diabetes were compared. The associations of diabetes history and/or FBG levels with mortality were analyzed. Multivariate cox regression analysis on the risk factors associated with mortality in patients with COVID-19 was performed. RESULTS: A total of 941 hospitalized patients with COVID-19 were enrolled in the study. There was a positive relationship between pre-existing diabetes and the mortality of patients who developed COVID-19 (21 of 123 [17.1%] vs 76 of 818 [9.3%]; P = 0.012). FBG ≥7.0 mmol/L was an independent risk factor for the mortality of COVID-19 regardless of the presence or not of a history of diabetes (hazard ratio, 2.20 [95% CI, 1.21-4.03]; P = 0.010). CONCLUSIONS: We firstly showed FBG ≥7.0 mmol/L predicted worse outcome in hospitalized patients with COVID-19 independent of diabetes history. Our findings indicated screening FBG level is an effective method to evaluate the prognosis of patients with COVID-19.

APPL1 knockdown blocks adipogenic differentiation and promotes adipocyte lipolysis.

Adipocyte dysfunction is closely associated with the development of obesity, insulin resistance, and type 2 diabetes. In addition to having a positive effect on adiponectin pathway and insulin signaling through direct and/or indirect mechanisms, adapter protein APPL1 has also been reported to regulate body weight, brown fat tissues thermogenesis, and body fat distribution in diabetic individuals. However, there is dearth of data on the specific role of APPL1 on adipogenic differentiation and adipocyte lipolysis. In this study, APPL1's function in adipocyte differentiation and adipocyte lipolysis was evaluated, and the possible mechanisms were investigated. We found that APPL1 knockdown (KD) impeded differentiation of 3T3-L1 preadipocytes into mature 3T3-L1 adipocytes and enhanced basal and insulin-suppressed lipolysis in mature 3T3-L1 adipocytes. APPL1 KD cells presented a reduced autophagic activity in 3T3-L1 preadipocytes and mature 3T3-L1 adipocytes. In 3T3-L1 preadipocytes, APPL1 KD reduced PPARγ protein levels, which was prevented by administration with proteasome inhibitor MG132. Furthermore, APPL1 KD-reduced autophagic activity in mature 3T3-L1 adipocytes was markedly restored by inhibition of PKA, accompanied with prevention of APPL1-induced lipolysis. In addition, APPL1 KD caused insulin resistance in mature 3T3-L1 adipocytes. Unexpectedly, we found that APPL1 overexpression did not appear to play a role in adipogenic differentiation and adipocyte lipolysis. Our results confirmed that APPL1 KD inhibits adipogenic differentiation by suppressing autophagy and enhances adipocyte lipolysis through activating PKA respectively. These findings may deepen our understanding of APPL1 function, especially its regulation on adipocyte biology.

Efficacy and safety of DBPR108 monotherapy in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled, phase II clinical trial.

Objective: DBPR108, a novel dipeptidyl-peptidase-4 inhibitor, has shown great antihyperglycemic effect in animal models. This study was to evaluate the efficacy and safety of DBPR108 monotherapy in type 2 diabetes mellitus (T2DM).Methods: This was a 12-week, double-blind, placebo-controlled phase II clinical trial. The newly diagnosed or inadequately controlled untreated T2DM patients were randomized to receive 50, 100, 200 mg DBPR108 or placebo in a ratio of 1:1:1:1. The primary efficacy outcome was HbA1c change from baseline to week 12. Relevant secondary efficacy parameters and safety were assessed. The clinical trial registration is NCT04124484.Results: Overall, 271 of the 276 randomized patients, who received 50 mg (n = 68), 100 mg (n = 67), 200 mg (n = 69) DBPR108 or placebo (n = 67), were included in full analysis set. At week 12, HbA1c change from baseline was -0.04 ± 0.77 in placebo group, -0.51 ± 0.71, -0.75 ± 0.73, and -0.57 ± 0.78 (%, p < .001 vs. placebo) in 50, 100, and 200 mg DBPR108 groups, respectively. Since week 4, DBPR108 monotherapy resulted in significant improvements in secondary efficacy parameters. At end of 12-week treatment, the goal of HbA1c ≤7% was achieved in 29.85, 58.82, 55.22, and 47.83% of the patients in placebo, 50, 100, and 200 mg DBPR108 groups, respectively. The incidence of adverse events did not show significant difference between DBPR108 and placebo except mild hypoglycemia in DBPR108 200 mg group.Conclusions: The study results support DBPR108 100 mg once daily as the primary dosing regimen for T2DM patients in phase III development program.

Ethnic Differences in Efficacy and Safety of Alogliptin: A Systematic Review and Meta-Analysis.

INTRODUCTION: Alogliptin is a highly selective, potent, and orally available dipeptidyl peptidase-4 (DPP-4) inhibitor. This study compared the glucose-lowering efficacy and safety of alogliptin between Asian and non-Asian patients with type 2 diabetes. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, and ISI Web of Science databases for articles published June 2017 and earlier in English. We identified randomized controlled trials (RCTs) of adults with type 2 diabetes that compared alogliptin with placebo as either monotherapy or add-on therapy. We divided subgroups by ethnicity, and compared the results of alogliptin use in Asian and non-Asian-dominant studies. RESULTS: A total of 15 RCTs with 4456 patients with type 2 diabetes were included in this study. Alogliptin lowered glycated hemoglobin (HbA1c) to a much greater extent in Asian-dominant studies [- 0.75% (95% CI - 0.84 to - 0.65)] than in non-Asian-dominant studies [- 0.61% (95% CI - 0.68 to - 0.54)] (P = 0.02). The risk ratio of achieving HbA1c goal was larger in Asian-dominant studies [2.88 (95% CI 2.15-3.87)] than in non-Asian-dominant studies [1.93 (95% CI 1.55-2.41)] (P = 0.03). The postprandial blood glucose-lowering efficacy was higher in Asian-dominant studies [- 2.42 mmol/l (95% CI - 2.99 to - 1.85)] than in non-Asian-dominant studies [- 0.60 mmol/l (95% CI - 1.60 to 0.40)] (P = 0.002), while the fasting blood glucose and body weight changes were similar between the two subgroups. The incidence of adverse events, including hypoglycemia, nasopharyngitis, upper respiratory tract infection, headache, and diarrhea, were comparable between the two groups. CONCLUSIONS: Alogliptin is more effective in improving glycemic levels in Asians than in other ethnic populations. Future studies are required to explore the potential mechanisms.

MTHFR A1298C polymorphisms reduce the risk of congenital heart defects: a meta-analysis from 16 case-control studies.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in the hyperhomocysteinemia, which is a risk factor related to the occurrence of congenital heart defect (CHD). However, the association between MTHFR polymorphism and CHD has been inconclusive. METHODS: We conducted an updated meta-analysis to provide comprehensive evidence on the role of MTHFR A1298C polymorphism in CHD. Databases were searched and a total of 16 studies containing 2207 cases and 2364 controls were included. RESULTS: We detected that a significant association was found in the recessive model (CC vs. AA + AC: OR = 1.38, 95% CI: 1.10-1.73) for the overall population. Subgroup analysis showed that associations were found in patients without Down Syndrome in genetic models for CC vs. AA (OR = 1.47, 95% CI: 1.01-2.14), CC vs. AC (OR = 1.29, 95% CI: 1.00-1.66) and recessive model (OR = 1.44, 95% CI: 1.14-1.82). We conducted a meta-regression analysis, Galbraith plots and a sensitivity analysis to assess the sources of heterogeneity. CONCLUSIONS: In summary, our present meta-analysis supports the MTHFR 1298C allele as a risk factor for CHD. However, further studies should be conducted to investigate the correlation of plasma homocysteine levels, enzyme activity, and periconceptional folic acid supplementation with the risk of CHD.

Association between alcohol consumption during pregnancy and risks of congenital heart defects in offspring: meta-analysis of epidemiological observational studies.

BACKGROUND: To explore the association between maternal alcohol consumption and/or binge drinking and congenital heart defects (CHDs), we conducted a meta-analysis for more sufficient evidence on this issue. METHODS: We searched Medline, EMBASE, and the Cochrane Library from their inceptions to December 2014 for case-control and cohort studies that assessed the association between maternal alcohol consumption and CHD risk. Study-specific relative risk estimates were calculated using random-effect or fixed-effect models. RESULTS: A total of 19 case-control studies and 4 cohort studies were included in the meta-analysis. We observed a null association between maternal alcohol consumption during pregnancy and the risk of CHDs. Even in the analysis of different trimesters of pregnancy, we found little association between the two. CONCLUSIONS: This meta-analysis suggests that maternal alcohol consumption is modestly not associated with the risk of CHDs. However, further investigation is needed to confirm this conclusion.