Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway.

Heart failure with preserved ejection fraction (HFpEF) is closely associated with metabolic derangement. Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) exert anti-HFpEF effects, but the underlying mechanisms remain unclear. In this study, we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF. This model was established by high-fat diet (HFD) feeding plus Nω-nitro-L-arginine methyl ester (L-NAME) treatment. The mice were treated with empagliflozin (20 mg·kg-1·d-1, i.g.) or liraglutide (0.3 mg·kg-1·d-1, i.p.) or their combination for 4 weeks. At the end of the experimental protocol, cardiac function was measured using ultrasound, then mice were euthanized and heart, liver, and kidney tissues were collected. Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing (snRNA-seq). We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function, ameliorated cardiomyocyte hypertrophy and cardiac fibrosis, as well as exercise tolerance but no synergism was observed in the combination group. Furthermore, empagliflozin and/or liraglutide lowered body weight, improved glucose metabolism, lowered blood pressure, and improved liver and kidney function. After the withdrawal of empagliflozin or liraglutide for 1 week, these beneficial effects tended to diminish. The snRNA-seq analysis revealed a subcluster of myocytes, in which Erbb4 expression was down-regulated under HFpEF conditions, and restored by empagliflozin or liraglutide. Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions. In the HFpEF mouse model, both empagliflozin and liraglutide reversed Erbb4 down-regulation. In rat h9c2 cells, we showed that palmitic acid- or high glucose-induced changes in PKCα and/or ERK1/2 phosphorylation at least in part through Erbb4. Collectively, the single-cell atlas reveals the anti-HFpEF mechanism of empagliflozin and liraglutide, suggesting that Erbb4 pathway represents a new therapeutic target for HFpEF. Effects and mechanisms of action of empagliflozin and liraglutide in HFpEF mice. HFpEF was induced with a high-fat diet and L-NAME for 15 weeks, and treatment with empagliflozin and liraglutide improved the HFpEF phenotype. Single nucleus RNA sequencing (snRNA-seq) was used to reveal the underlying mechanism of action of empagliflozin and liraglutide.

A novel mouse model of familial combined hyperlipidemia and atherosclerosis.

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg-1·d-1) and fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies.

The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.

Therapeutic potential of colchicine in cardiovascular medicine: a pharmacological review.

Colchicine is an ancient herbal drug derived from Colchicum autumnale. It was first used to treat familial Mediterranean fever and gout. Based on its unique efficacy as an anti-inflammatory agent, colchicine has been used in the therapy of cardiovascular diseases including coronary artery disease, atherosclerosis, recurrent pericarditis, vascular restenosis, heart failure, and myocardial infarction. More recently, colchicine has also shown therapeutic efficacy in alleviating cardiovascular complications of COVID-19. COLCOT and LoDoCo2 are two milestone clinical trials that confirm the curative effect of long-term administration of colchicine in reducing the incidence of cardiovascular events in patients with coronary artery disease. There is growing interest in studying the anti-inflammatory mechanisms of colchicine. The anti-inflammatory action of colchicine is mediated mainly through inhibiting the assembly of microtubules. At the cellular level, colchicine inhibits the following: (1) endothelial cell dysfunction and inflammation; (2) smooth muscle cell proliferation and migration; (3) macrophage chemotaxis, migration, and adhesion; (4) platelet activation. At the molecular level, colchicine reduces proinflammatory cytokine release and inhibits NF-κB signaling and NLRP3 inflammasome activation. In this review, we summarize the current clinical trials with proven curative effect of colchicine in treating cardiovascular diseases. We also systematically discuss the mechanisms of colchicine action in cardiovascular therapeutics. Altogether, colchicine, a bioactive constituent from an ancient medicinal herb, exerts unique anti-inflammatory effects and prominent cardiovascular actions, and will charter a new page in cardiovascular medicine.

Semen parameters in men recovered from COVID-19.

The novel coronavirus disease (COVID-19) pandemic is emerging as a global health threat and shows a higher risk for men than women. Thus far, the studies on andrological consequences of COVID-19 are limited. To ascertain the consequences of COVID-19 on sperm parameters after recovery, we recruited 41 reproductive-aged male patients who had recovered from COVID-19, and analyzed their semen parameters and serum sex hormones at a median time of 56 days after hospital discharge. For longitudinal analysis, a second sampling was obtained from 22 of the 41 patients after a median time interval of 29 days from first sampling. Compared with controls who had not suffered from COVID-19, the total sperm count, sperm concentration, and percentages of motile and progressively motile spermatozoa in the patients were significantly lower at first sampling, while sperm vitality and morphology were not affected. The total sperm count, sperm concentration, and number of motile spermatozoa per ejaculate were significantly increased and the percentage of morphologically abnormal sperm was reduced at the second sampling compared with those at first in the 22 patients examined. Though there were higher prolactin and lower progesterone levels in patients at first sampling than those in controls, no significant alterations were detected for any sex hormones examined over time following COVID-19 recovery in the 22 patients. Although it should be interpreted carefully, these findings indicate an adverse but potentially reversible consequence of COVID-19 on sperm quality.

MAFLD vs. NAFLD: shared features and potential changes in epidemiology, pathophysiology, diagnosis, and pharmacotherapy.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, placing an increasing burden on human health. NAFLD is a complex multifactorial disease involving genetic, metabolic, and environmental factors. It is closely associated with metabolic syndrome, obesity, and type 2 diabetes, of which insulin resistance is the main pathophysiological mechanism. Over the past few decades, investigation of the pathogenesis, diagnosis, and treatments has revealed different aspects of NAFLD, challenging the accuracy of definition and therapeutic strategy for the clinical practice. Recently, experts reach a consensus that NAFLD does not reflect the current knowledge, and metabolic (dysfunction) associated fatty liver disease (MAFLD) is suggested as a more appropriate term. The new definition puts increased emphasis on the important role of metabolic dysfunction in it. Herein, the shared features and potential changes in epidemiology, pathophysiology, diagnosis, and pharmacotherapy of the newly defined MAFLD, as compared with the formerly defined NAFLD, are reviewed for updating our understanding.

Behavioral Analysis of Chinese Adult Patients with Type 1 Diabetes on Self-monitoring of Blood Glucose.

BACKGROUND: The information-motivation-behavioral skills (IMB) model of health behavior is an effective tool to evaluate the behavior of diabetes self-management. The purpose of this study was to explore behavioral factors affecting the practice of self-monitoring of blood glucose (SMBG) within the frame of IMB model of health behavioral among adult patients with type 1 diabetes in a single diabetes clinic in China. METHODS: A questionnaire with three subscales on SMBG information, motivation, and behavioral skills based on IMB model was developed. Validity and reliability of the measures were examined and guaranteed. Adult patients with type 1 diabetes visiting our diabetes clinic from January to March 2012 (n = 55) were consecutively interviewed. The self-completion questionnaires were administered and finished at face-to-face interviews among these patients. Both descriptive and correlational analyses were made. RESULTS: Fifty-five patients finished the questionnaires, with the median duration of diabetes 4.5 years and the median of SMBG frequency 2.00. Specific SMBG information deficits, motivation obstacles, and behavioral skill limitations were identified in a substantial proportion of participants. Scores of SMBG motivation (r = 0.299, P= 0.026) and behavioral skills (r = 0.425, P= 0.001) were significantly correlated with SMBG frequency. The multiple correlation of SMBG information, SMBG motivation, and SMBG behavioral skills with SMBG frequency was R = 0.411 (R2 = 0.169, P= 0.023). CONCLUSIONS: Adult patients with type 1 diabetes in our clinic had substantial SMBG information deficits, motivation obstacles, and skill limitations. This information provided potential-focused education targets for diabetes health-care providers.

Treatment Patterns and Glycemic Control in Older Adults with Type 2 Diabetes Mellitus Receiving Only Oral Antidiabetes Drugs in China.

BACKGROUND: Only a few studies have reported the use of oral antidiabetes drugs (OADs) for treating older adults with type 2 diabetes mellitus (T2DM) in China. This study assessed the status of OAD therapy and relevant factors associated with OAD treatment patterns and glycemic control among older patients. PATIENTS AND METHODS: We conducted a noninterventional, observational, cross-sectional, multicenter study, which was initiated by the Chinese Diabetes Society, in which 9,872 outpatients with T2DM were recruited who received OADs only. Current antidiabetes treatment regimens and related clinical data were collected from patients' self-reporting and medical records. Participants were divided into two groups: ≥65 years and <65 years. All data were tabulated, and statistical analyses were performed using SPSS version 16 software (SPSS Inc., Chicago, IL). RESULTS: Insulin secretagogues (52.6%): sulfonylureas (SU) (26.6%) and glinides (26.0%) were commonly used as monotherapy in those ≥65 years. The most popular OAD pattern was dual combination therapy (46.8%), with SU plus glucosidase inhibitors (25.1%) being most common in older participants. Age, diabetes duration, body mass index, achieving the glycemic control targets, and hypoglycemia were influencing factors to those ≥65 years in diverse treatment pattern models (P < 0.05). Older patients receiving OADs with triple or more combination treatment and complications were more likely to have substandard glycemic control (hemoglobin A1c level ≥7%). CONCLUSIONS: The pattern of OADs alone in older adults with T2DM was significantly different from those <65 years in China. A comprehensive OAD treatment pattern or insulin combination may be necessary for better glycemic control in older patients with multiple combinations of OADs or complications.

Acute Wnt pathway activation positively regulates leptin gene expression in mature adipocytes.

Genome-wide association studies (GWAS) have revealed the implication of several Wnt signaling pathway components, including its effector transcription factor 7-like 2 (TCF7L2) in diabetes and other metabolic disorders. As TCF7L2 is expressed in adipocytes, we investigated its expression and function in rodent fat tissue and mature adipocytes. We found that TCF7L2 mRNA expression in C57BL/6 mouse epididymal fat tissue was up-regulated by feeding but down-regulated by intraperitoneal insulin injection. In high-fat diet (HFD) fed mice, db/db mice and Zucker (fa/fa) rats, epididymal fat TCF7L2 mRNA levels were lower than the corresponding controls. Treating rat adipocytes with 100nM insulin repressed TCF7L2 mRNA and protein levels, associated with the repression of leptin mRNA level. The treatment with 1nM insulin, however, stimulated TCF7L2 and leptin mRNA levels. This stimulation could be attenuated by iCRT14, an inhibitor of ß-catenin/TCF-responsive transcription. Wnt3a stimulated leptin mRNA level, which was also blocked by iCRT14 co-treatment. Utilizing the leptin-expressing cell line HTR8 as a tool, we defined an evolutionarily conserved CREB binding motif that mediated Wnt3a activation. Although Wnt activation is known to repress the differentiation of 3T3-L1 cells towards mature adipocytes, short-term Wnt3a treatment of differentiated 3T3-L1 cells stimulated leptin mRNA levels. Thus, wnt pathway plays a dual function in adipocytes, including the well-known repressive effect on adipogenesis and the stimulation of leptin production in mature adipocytes in response to nutritional status.

Effectiveness of different waist circumference cut-off values in predicting metabolic syndrome prevalence and risk factors in adults in China.

OBJECTIVE: To study the effectiveness of waist circumference cut-off values in predicting the prevalence of metabolic syndrome (MetS) and risk factors in adults in China. METHODS: A cross-sectional survey was condcuted in 14 provinces (autonomous region, municipality) in China. A total of 47,325 adults aged⋝20 years were selected by multistage stratified sampling, and questionnaire survey and physical and clinical examination were conducted among them. MetS was defined according to the International Diabetes Federation (IDF) criteria and modified IDF criteria. RESULTS: The age-standardized prevalence of MetS was 24.2% (22.1% in men and 25.8% in women) and 19.5% (22.1% in men and 18.0% in women) according to the IDF criteria and modified IDF criteria respectively. The age-standardized prevalence of pre-MetS was 8.1% (8.6% in men and 7.8% in women) according to the modified IDF criteria. The prevalence of MetS was higher in urban residents than rural residents and in northern China residents than in southern China residents. The prevalence of central obesity was about 30% in both men and women according to the ethnicity-specific cut-off values of waist circumference for central obesity (90 cm for men and 85 cm for women). Multivariate regression analysis revealed no significant difference in risk factors between the two MetS definitions. CONCLUSION: Using both the modified IDF criteria and ethnicity-specific cut-off values of waist circumference can provide more useful information about the prevalence of MetS in China. Conclusion Using both the modified IDF criteria and ethnicity-specific cut-off values of waist circumference can provide more useful information about the prevalence of MetS in China.

Tracing type 1 diabetic Tibet miniature pig's bone marrow mesenchymal stem cells in vitro by magnetic resonance imaging (1).

BACKGROUND: Traditional cell-tracking methods fail to meet the needs of preclinical or clinical research. Thus, the aim of the present study was to establish a new method of double labeling bone marrow mesenchymal stem cells (BMSCs) from type 1 diabetic (T1D) minipigs with super-paramagnetic iron oxide (SPIO) and enhanced green fluorescent protein (eGFP) and tracing them using MRI in vitro. METHODS: Isolated BMSCs from T1D minipigs were labeled with eGFP and different concentrations of SPIO. The effects of lentivirus (LV)-eGFP transfection and SPIO on the viability and growth curves of BMSCs were determined by Trypan blue exclusion, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry. Cellular ultrastructure was evaluated by transmission electron microscopy. Magnetic resonance imaging was used to evaluate BMSCs labeled with SPIO-eGFP complexes 6 weeks after labeling. RESULTS: Expression of eGFP in BMSCs peaked 96 h after transfection with LV-eGFP. Prussian blue staining revealed scattered blue granules in the cytoplasm of SPIO-labeled cells. Transmission electron microscopy revealed that the dense granules aggregated mainly in secondary lysosomes. On MRI, T2* -weighted imaging was far more sensitive for SPIO-labeled BMSCs than other image sequences 3 and 6 weeks after the cells had been labeled with SPIO-eGFP. CONCLUSIONS: We have developed a relatively simple and safe method for double labeling of BMSCs from T1D minipigs using SPIO and LV-eGFP and tracing them in vitro by MRI for 6 weeks.

[SIRT1 knockout impairs the differentiation of adipocyte in C57BL/6J mice and its underlying mechanism].

OBJECTIVE: To explore the role and mechanism of SIRT1 (Sirtuin1) in the differentiation of adipocyte. METHODS: SIRT1(-/-) mice with C57BL/6J gene background were generated and litter-mate wild-type (WT) mice were used as controls. Body weight and fat content were detected and their epididymal fat pads were collected at 28 weeks old of age. The tip part of epididymal fat tissue was incubated in phosphate buffered saline (PBS) containing both BODIPY 558/568 (5 µmol/L in PBS) for adipocytes and isolectin Alexa Fluor 488 (40 µg/ml in PBS) for endothelial cells overnight. The stained cells were then visualized under confocal microscope.Reconstruction of 3D data sets was accomplished with image processing software Imaris.Immunohistochemistry was used to detect the protein level of endothelial cell marker CD31.Hematoxylin and eosin staining was performed for fixed epididymal fat tissue. Mouse embryonic fibroblast (MEF) cells were prepared from 13-14 days embryos of SIRT1(-/-) or WT mice and differentiated into adipocytes. Then oil-red O staining was performed. RESULTS: Compared with wild-type controls, both body weight (WT 42.1 g ± 1.6 g vs SIRT1(-/-) 25.4 g ± 1.0 g, P < 0.05) and epididymal fat mass (WT 13.4 g ± 1.0 g vs SIRT1(-/-) 7.8 g ± 0.5 g, P < 0.05) were much smaller in the SIRT1(-/-) mice. HE staining of fat tissue exhibited a significant reduction in adipocyte size and extracellular matrix in SIRT1(-/-) mice.However, the adipogenesis ability of MEF cells was significantly enhanced in vitro in SIRT1(-/-) MEF cells.Further study found that the density of vascular network decreased by 50% in the tip portion of epididymal fat pads of SIRT1(-/-) mice (capillary density:WT 2.92% ± 0.03% vs SIRT1(-/-) 1.34% ± 0.02%, P < 0.05). CD31, a cellular marker of decreased angiogenesis, decreased significantly in epididymal fat pads of SIRT1(-/-) mice. CONCLUSION: SIRT1 knockout impairs adipocyte differentiation in SIRT1(-/-) mice with C57BL/6J gene background through reduced angiogenesis but not adipogenesis.

[The prevalence and risk factors of metabolic syndrome among adult residents in Guangdong and Jiangsu provinces in China].

OBJECTIVE: To determine the current prevalence and risk factors of metabolic syndrome (MS) among adult residents in Chinese developed areas. METHODS: The clinical data of 6614 adult residents, including 4051 women, from Guangdong and Jiangsu provinces from China Diabetes and Metabolic Disorders Study (2007-2008) were analyzed. Age and sex standardized prevalences of MS were calculated according to the criteria of Chinese Diabetes Society (CDS), US National Cholesterol Education Program Adult Treatment Panel III (ATP III), International Diabetes Federation (IDF) and Joint Interim Statement (JIS), respectively. Logistic regression analysis was performed to identify the risk factors of MS. RESULTS: Age and sex standardized prevalences of MS were 17.88% (CDS), 28.50% (ATPIII), 21.99% (IDF) and 31.50% (JIS), respectively. The prevalences of residents with at least one metabolic abnormality were 67.86% (CDS) 79.56% (ATPIII), 79.62% (IDF) and 80.74% (JIS), respectively. MS was more common in female than in male by the ATPIII and IDF criterion (ATPIII: 30.63% vs 26.45%, P < 0.01; IDF: 26.04% vs 17.91%, P < 0.01), while the prevalence was higher in male by CDS criteria (15.94% vs 19.87%, P < 0.01). There was no significant difference in the MS prevalence between the rural and the urban residents. Kappa test showed ATPIII and JIS criteria were most homogenous (κ = 0.95, P < 0.01). The risk factors for MS by the logistic regression model were male, older age, lower degree of education, family history of hypertension and obesity, drinker as well as uncontrolled diet. CONCLUSION: The prevalence of MS is high in the adult residents of Chinese developed areas (Guangdong and Jiangsu provinces), whatever diagnostic criterion was used .Effective measures should be taken to control the modifiable MS risk factors.

[Incidence and related risk factors of diabetic ketoacidosis in Guangdong type 1 diabetics].

OBJECTIVE: To determine the incidence and the predictors of diabetes ketoacidosis (DKA) in Chinese type 1 diabetics so as to lay a foundation for better prevention and treatment. METHODS: For this cross-sectional study, a total of 611 patients with established type 1 diabetes between August 6, 2010 and March 31, 2012 were recruited from 16 hospitals in Guangdong Province. And 491 of them were over 18 years old. A data entry form was used to collect the patient information on demographics, medical history, acute/chronic complications, smoking/drinking status, diet, exercise, physical examination and treatment, etc. Hemoglobin A1c (HbA1c) and stimulated C peptide levels were centrally measured. The incidence rate of diabetic ketoacidosis (DKA) was calculated at events per 100 patient-years. To determine the predictors of DKA, Poisson's regression model was used for analysis. And backward stepwise logistic regression analysis was performed to identify the predictors of DKA recurrence. The protocol and informed consent form were approved by Ethics Committee of Third Affiliated Hospital, Sun Yat-sen University. Written informed consent was obtained from patients (age > 18 years) or their legal guardians (age < 18 years). RESULTS: Among them, 53.7% were females. The mean age was 27.8 years (range: 19.5 - 37.3). The age of onset was 22.7 (14.0 - 31.4) years old and disease duration 4.3 (1.7 - 7.9) years. Overweight and obese patients accounted for 10.8% and 1.0% respectively. Among them, the self-monitoring frequency of blood glucose was 0.4 (0.1 - 1.4) times per day. Overall, 26.4% patients reached the target of age-specific HbA1c values. The overall incidence of DKA was 26.4 per 100 patient-years. Significant predictors of DKA in the Poisson regression model were females (RR = 2.12), medical insurance claiming percentage below 50% (RR = 1.84), uncontrolled diet (never controlled diet vs. usually controlled diet, RR = 1.76), smoking (RR = 2.18) as well as worse glycemic control (HbA1c per 1.0% increment, RR = 1.15). Totally, 34.4% of DKA episodes occurred in 3.8% of type 1 diabetics with recurrent events (no less than 2 episodes). The recurrence of DKA was associated with females (RR = 10.56), smoking (RR = 6.99), worse beta cell function (stimulated C peptide per 100 pmol/L decrement, RR = 4.88) and worse glycemic control (HbA1c per 1.0% increment, RR = 1.16). CONCLUSION: There is a high incidence of DKA in Chinese type 1 diabetics. And it is recurrent in high-risk patients. Comprehensive management should be offered to control modifiable risk factors in these patients.

Glycemic control among patients in China with type 2 diabetes mellitus receiving oral drugs or injectables.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly among Chinese adults, and limited data are available on T2DM management and the status of glycemic control in China. We assessed the efficacy of oral antidiabetes drugs (OADs), glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin for treatment of T2DM across multiple regions in China. METHODS: This was a multicenter, cross-sectional survey of outpatients conducted in 606 hospitals across China. Data from all the patients were collected between April and June, 2011. RESULTS: A total of 238,639 patients were included in the survey. Eligible patients were treated with either OADs alone (n=157,212 [65.88%]), OADs plus insulin (n=80,973 [33.93%]), or OADs plus GLP-1 receptor agonists (n=454 [0.19%]). The OAD monotherapy, OAD + insulin, and OAD + GLP-1 receptor agonist groups had mean glycosylated hemoglobin (HbA1c) levels (±SD) of 7.67% (±1.58%), 8.21% (±1.91%), and 7.80% (±1.76%), respectively. Among those three groups, 34.63%, 26.21%, and 36.12% met the goal of HbA1c <7.0%, respectively. Mean HbA1c and achievement of A1c <7.0% was related to the duration of T2DM. CONCLUSIONS: Less than one third of the patients had achieved the goal of HbA1c <7.0%. Glycemic control decreased and insulin use increased with the duration of diabetes.

[Association of TNF-1031T/C and clinical efficacy of insulin therapy in newly diagnosed type 2 diabetics].

OBJECTIVE: Tumor necrosis factor (TNF ) locus has been a long-standing type 2 diabetes (T2D) candidate gene. Few studies have been conducted on TNF SNP (single nucleotide polymorphism) as rs1799964 (T-1031C), rs1800630 (A-863C) and rs1799724 (C-857T) in T2D. The purpose of this study is to examine the association of TNF SNP and T2D in a case control study and further explore whether these SNPs influence the clinical efficacy of insulin therapy. METHODS: A total of 109 newly diagnosed type 2 diabetics and 168 healthy individuals were recruited. Three tag SNPs (rs1799964 (T-1031C), rs1800630 (A-863C), rs1799724 (C-857T)) were selected across the TNF locus and polymerase chain reaction (PCR) directed sequencing was performed. The patients received Lispro 25 twice daily to achieve glycemic control and they were followed up for 1 year. Plasma glucose level, lipid profile, homeostatic model assessment for insulin resistance (HOMA-IR) and homeostatic model assessment for beta-cell function (HOMA-ß) were compared among groups with different haplotypes of SNPs. RESULTS: Haplotype of TNF-1031C-863C-857C increased the risk of T2D (OR = 2.7, P < 0.05) . Comparing with homozygote of TNF-1031T-863C-857C diabetics (TCC), those carrying CCC allele had higher fasting serum insulin (16.1(12.0-20.3) mU/L) and HOMA-IR (lnHOMA-IR 1.8 ± 0.4) levels (TCC group: 10.6(8.1-14.3) mU/L and 1.42 ± 0.54 respectively, P < 0.05)). One-year insulin treatment decreased HbA1c effectively in both TCC and CCC groups (P < 0.05). However, higher HOMA-IR was still observed in CCC group than that of TCC after normoglycemia (lnHOMA-IR: 2.5(0.9-3.9) vs 1.1(0.8-1.8) respectively, P < 0.05) . Moreover HOMA-ß showed no significant improvement in CCC group as it was in TCC group by the endpoint of follow-up. CONCLUSIONS: TNF-1031C-863C-857C is a risk haplotype for T2D. CCC carrying patients failed to achieve HOMA-ß improvement. And it might be due to increased endogenous HbOMA-IR level comparing with TCC homozygote.

[Protection effect and mechanism of Compound Xueshuantong Capsule on diabetic nephropathy rats].

OBJECTIVE: To explore the renoprotective effect of Compound Xueshuantong Capsule (XST) on diabetic rat model with nephropathy. METHODS: Twenty-eight male Sprague Dawley diabetic rats were induced to hyperglycaemia (3 days later, fasting blood glucose > 16.7 mmol/L) by peritoneal injection with streptozotocin (STZ, 50 mg/kg). And they were divided into four groups: diabetic nephropathy (vehicle treatment), irbesartan (20 mg×kg(-1)×d(-1)), low-dosage XST (900 mg×kg(-1)×d(-1)) and high-dosage XST (1800 mg×kg(-1)×d(-1)). Seven normal rats were used as control. After a 12-week intervention, urine protein was examined. Pathological morphology was observed by hematoxylin-eosin (HE), Masson and (periodic acid Schiff) PAS stains. Blood nitric oxide (NO), malondialdehyde (MDA) and blood superoxide dismutase (SOD) and urine SOD were detected. And the expression of (matrix metalloproteinase-2) MMP-2 was detected by Western blot in each group. RESULTS: The model rats presented with hyperglycemia, polydipsia, hyperphagia, polyuria and hyper microalbuminuria. The intervention groups showed decreased microalbuminuria and there was no effect on blood glucose or body weight. Glomerular sclerosis and extracellular matrix (ECM) increased in model group and improved in irbesartan and XST groups as judged by HE, Masson and PAS stains. Three intervention groups had no effect on the elevated expression of MMP-2 in diabetic rats. Compared with the model group, the irbesartan, low-dosage and high-dosage XST groups had significantly decreased blood levels of NO ((104.9 ± 11.0) µmol/L vs (41.9 ± 9.6) µmol/L and (14.7 ± 1.9) µmol/L, P < 0.05) and MDA ((19.6 ± 1.6) nmol/L vs (6.6 ± 0.9) mol/L and (4.5 ± 1.2) nmol/L, P < 0.05), increased blood and urine activities of SOD (blood: (222 ± 20)×10(3) vs (231 ± 18)×10(3) and (237 ± 24)×10(3) U/L,P < 0.05), urine: (11.8 ± 1.1)×10(3) vs (23.3 ± 2.0)×10(3) and (25.7 ± 1.8)×10(3) U/L). CONCLUSION: Compound Xueshuantong Capsule may decrease proteinuria through its suppression of oxidative stress and not its improvement of ECM metabolism.