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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 A

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...

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.

Additional file 1: Table S1. The comparison of COVID-19 patients with and without core examination results. Figure S1. The incidence of complications of COVID-19 patients with and without DM. Figure S2. The percent of immunocyte subsets in COVID-19 patients with cardiac injury grouped by DM and non-DM. Figure S3. ROC analysis of immune-inflammatory parameters for in-hospital mortality of all COVID-19 patients.

Synthetic aperture radar interferometry can obtain information on the surface of the earth. In fact, the accuracy of phase unwrapping directly affects the accuracy of the digital elevation model, but the problem that has been puzzling people is the low accuracy of unwrapping in high-noise regions. To solve this problem, we propose a new approach based on an improved branch-cut method, which classifies the branch cut. First, connect the short branch cuts and then use the network-flow method to connect the long branch cuts. By categorized branch cuts, each type of branch cut processes part of the residues and divides the region with high residue density into two regions with low residue density for unwrapped, which solves the problem of low phase unwrapping accuracy in high-noise regions. The experimental results of simulation and measured data show that RCBC method shows high unwrapping accuracy in high-noise regions, very short total length of connected branch cuts, and strong robustness.

Highlights • FBG is an independent risk factor for the mortality of COVID-19. • Diabetes history was not an independent risk factor for the mortality of COVID-19. • Screening FBG is an effective method to evaluate the prognosis of COVID-19., Aim No study elucidated the role of fasting blood glucose (FBG) level in the prognosis of 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.

Background : Epicardial adipose tissue (EAT) is implicated in insulin resistance, which has been recognized as a strongest predictor of the development of diabetic cardiomyopathy and subsequent heart failure. However, the underlying mechanism remains incompletely understood. Herein, we investigated the effect of hypertrophic adipocytes on cardiac insulin resistance. 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 (NRVMs) were treated with insulin to investigate the effects of exosomes on insulin signaling. Insulin sensitivity was evaluated by measuring insulin-stimulated Akt phosphorylation and glucose uptake. SiRNA techniques were used to downregulate protein levels and its efficiency was evaluated by western blot.Results : Hypertrophic adipocyte-derived exosomes (h-Exo) induced insulin resistance in NRVMs. Furthermore, h-Exo high-expressed miR-802-5p. Insulin sensitivity of NRVMs was impaired by miR-802-5p mimic but improved by its inhibitor. TargetScan and luciferase reporter assays revealed that heat shock protein 60 (HSP60) was a direct target of miR-802-5p. Both h-Exo and miR-802-5p mimic could downregulate HSP60 protein levels. In addition, HSP60 silencing induced insulin resistance and mitigated the insulin-sensitizing effects of adiponectin. HSP60 depletion also significantly increased the expression levels of CHOP, a marker of the unfolded protein response (UPR), and enhanced oxidative stress, accompanied by the increased phosphorylation of JNK and IRS-1 Ser307. Inhibition of both miR-802-5p and endocytosis abolished the impacts of HSP60 knockdown on the UPR and oxidative stress. Conclusion : Hypertrophic adipocyte-derived exosomal miR-802-5p caused cardiac insulin resistance in NRVMs through downregulating HSP60. These findings provide a novel mechanism by which EAT impairs cardiac function.

Background: Diabetes may exacerbate severe coronavirus disease 2019 (COVID-19). We explored the clinical characteristics of diabetic patients with COVID-19, analyzed the relationship between pre-existing diabetes and mortality rate, and elucidated the role of glycemic control in the prognosis of COVID-19. Methods: This cohort study was conducted from January 20, 2020, to February 20, 2020, in a single center at Renmin Hospital of Wuhan University, Wuhan, China. All consecutive inpatients with laboratory-confirmed COVID-19 were included in this study. Clinical laboratory, and treatment data were collected and analyzed. Outcomes of patients with and without pre-existing diabetes were compared. The associations of diabetes history and/or fasting blood glucose (FBG) levels with mortality were analyzed. Findings: A total of 941 hospitalized patients with COVID-19 were enrolled in the study. Compared to patients without diabetes, the clinical characteristics of diabetic patients with COVID-19 included older age, much severe inflammatory response, and increased incidence of ARDS, cardiovascular and renal disease. 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). Moreover, 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, 2.11 [95% CI, 1.15-3.86]; P =0.015). Interpretation: While pre-existing diabetes was associated with the mortality of patients hospitalized with COVID-19, FBG ≥7.0 mmol/L was an independent factor of the death rate. The findings highlight a role of glycemic control in COVID-19 management. Funding Statement: This research was supported by grants from the Nature Science Foundation of Hubei province (grants 2018CFB140 and 2017CFB204), and the Nature Science Foundation of China (grants 81800447). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the National Health Commission of China and the institutional review board at Renmin Hospital of Wuhan University. Written informed consent was waived by the ethics commission of the designated hospital for patients with emerging infectious diseases.

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-1β(IL-1β) 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-1β) 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.

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.

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.

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.

Activation of the receptor for advanced glycation end products (RAGE) axis may have an important role in apoptosis. Glucagon-like peptide-1 (GLP-1) is a gut hormone that has been proposed as a therapeutic target for the treatment of diabetes, and GLP-1 receptor agonists have been reported to protect against myocardial injury associated with diabetes. The aim of the present study was to investigate the cardioprotective mechanism of exendin-4 (EX-4), a GLP-1 receptor agonist, against myocardial cell apoptosis induced by hyperglycemia. Neonatal rat ventricular myocytes were prepared by enzymatic dissociation and then cultured with high levels of glucose (HG) in the presence or absence of EX-4. Cell apoptosis was detected using an annexin V-fluorescein isothiocyanate/propidium iodide kit, and cell viability was measured using an MTT assay. RAGE expression levels and the activity of caspase-3 were assessed by western blot analysis. The results demonstrated that the incubation of myocytes with HG led to a time-dependent activation of RAGE, and the protein expression of RAGE was increased at 6 h and peaked at 24 h (P

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.

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

Objective: To clarify the role of VEGF polymorphisms in CHD, we performed a meta-analysis to determine the association between these three variants and risk of CHD. Methods: Our meta-analysis included a total of 6, 4, and 6 research articles for each of the C2578A, G1154A, and G634C polymorphisms, respectively. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) of allele contrast and genotype contrast were estimated using either a fixed or random effects model. The Q-statistic test was used to identify heterogeneity and a funnel plot was adopted to evaluate publication bias. Results: Six articles containing 1080 cases and 2289 controls were relevant to C2578A, 4 researches containing 528 cases and 1036 controls were relevant to G1154A, and 6 articles containing 1081 cases and 2281 controls were relevant to G634C. The results of overall meta-analysis showed that none of the VEGF C2578A, G1154A, G634C increased the susceptibility of CHD. In summary, this meta-analysis demonstrates that the three analyzed VEGF polymorphisms do not increase the risk of CHD. Conclusions: Our meta-analysis suggests that the common VEGF polymorphisms C2578A, G1154A, and G634C do not alter CHD risk.

Objective Nicorandil exerts a protective effect on ischemia–reperfusion (I/R) injury in the brain and kidney through anti-apoptotic mechanisms. However, the mechanism by which nicorandil protects against I/R injury induced by deep hypothermic low flow (DHLF) remains unclear. Methods We used a cerebral I/R model induced by DHLF to determine the neuroprotective effects and possible mechanisms of nicorandil. Results Hematoxylin–eosin (HE) staining and in situ terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL) assay were used to detect changes in cell morphology and the number of apoptotic cells in hippocampus, respectively. The apoptotic regulators including Bcl-2, Bax, Akt, and p-Akt (the active, phosphorylated form of Akt) were examined by Western blot (WB). Histopathological findings showed that nicorandil significantly alleviated morphological damage in hippocampal and reduced the number of TUNEL-positive nuclei induced by DHLF. Nicorandil also increased the expression of Bcl-2 and decreased the expression of Bax, while increasing p-Akt level. Consistent with these results, nicorandil-mediated neuroprotection was reduced in the Akt1 +/− mutant mice and inhibited by LY294002, a PI3K inhibitor. Conclusions These findings showed that nicorandil provides a neuroprotective role in DHLF-induced I/R injury by inhibiting apoptosis via activation of the PI3K/Akt1 signaling pathway.

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-1β (IL-1β), 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-1β 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.