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Background Optimal non-invasive biomarkers for diagnosis and treatment of nonalcoholic fatty liver disease (NAFLD) remain to be identified. Aims To identify potential DNA methylation biomarkers for NAFLD. Methods Genome-wide DNA methylation profiling was performed to identify differentially methylated CpG sites in peripheral blood leukocytes. Differentially methylated regions were validated using the MassCLEAVE assay. The expression levels of candidate genes were explored by Gene Expression Omnibus database. Results The hypomethylation of PRKCE CpG 4.5 and CpG 18.19 was associated with nonalcoholic fatty liver (NAFL), the odds ratio (OR) and 95% confidence interval (CI) were 0.129 (0.026–0.639) and 0.231 (0.069–0.768). The methylation level of CpG 1.2 and average methylation level of SEC14L3 were correlated with NAFL, with OR (95% CI) being 0.283 (0.093–0.865) and 0.264 (0.087–0.799). PRKCE CpG 4.5 and cg17802464 of SEC14L3 were correlated with body mass index, waist circumference, total triglyceride, high-density lipoprotein cholesterol, alanine aminotransferase and aspartate aminotransferase. All selected datasets showed high expression levels of PRKCE and SEC14L3 in patients with NAFLD. Conclusions Our findings suggest that the hypomethylation of PRKCE and SEC14L3 promoters represent attractive biomarkers for NAFLD. Further studies are warranted to validate these biomarkers as molecular tools for diagnosis of NAFLD and therapeutic targets.

Objective. To assess the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and the risk of cardiovascular events in patients with systemic inflammatory conditions. Methods. Eligible cohort studies or randomized controlled trials (RCTs) from inception to January 2021 were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for cardiovascular outcomes were calculated in the fixed- and random-effects model accordingly. Associated factors with risks of cardiovascular events were also studied in sensitivity analyses and metaregression analyses. Results. Compared with non-bDMARD users, the risks of myocardial infarction (MI) ( OR = 0.74 , 95% CI, 0.63 to 0.87), heart failure ( OR = 0.84 , 95% CI, 0.74 to 0.95), cardiovascular (CV) death ( OR = 0.62 , 95% CI, 0.40 to 0.95), all-cause mortality ( OR = 0.64 , 95% CI, 0.58 to 0.70), and 3P-MACE (composite endpoint of MI, stroke, and CV death) ( OR = 0.69 , 95% CI, 0.53 to 0.89) were significantly reduced in bDMARD users, which were mainly driven by the risk reduction in patients with rheumatoid arthritis (RA). TNF-α inhibitors exhibited consistent benefits in reducing the risks of MI, heart failure, CV death, all-cause mortality, and 3P-MACE. Moreover, the risks of heart failure, CV death, all-cause mortality, and 3P-MACE were significantly reduced in bDMARD users with follow-up over one year. Conclusions. The use of bDMARDs might be associated with the reduced risks of CV events, especially in patients with RA. The CV events might be less frequent in bDMARD users with TNF-α inhibitors or follow-up over one year. More investigations are needed to validate conclusions.

To evaluate the reductions of C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C) in different lipid-lowering drugs, and to assess the relationships between the reductions of CRP, LDL-C, and cardiovascular (CV) events.We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to September 1, 2021. Randomized controlled trials (RCTs) comparing statins, proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9-mAbs), or ezetimibe against placebo with a treatment duration of at least 4 weeks and data on the effects of cholesterol-lowering interventions on LDL-C and CRP were included in this meta-analysis. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated.Compared with placebo treatment, statins and ezetimibe treatments resulted in a significant decrease in LDL-C level (statins: WMD -47.94 mg/dL, 95% CI -51.21 to -44.67 mg/dL; ezetimibe: WMD -22.84 mg/dL, 95% CI -26.76 to -18.92 mg/dL) and CRP level (statins: WMD -0.67 mg/L, 95% CI -0.90 to -0.45 mg/dL; ezetimibe: -0.64 mg/L, 95% CI -1.07 to -0.21 mg/dL). Compared with placebo treatment, treatment with PCSK9-mAbs resulted in significant decrease in LDL-C level (WMD -54.24 mg/dL, 95% CI -59.77 to -48.70 mg/dL), while the concentration of CRP did not decrease significantly. Meta-regression analysis showed no significant association between change in CRP level and change in LDL-C level. Subgroup comparisons suggested that treatment with PCSK9-mAbs showed a greater reduction in LDL-C level when compared with the statins group and ezetimibe group, while the risks of CV death, myocardial infarction (MI), and stroke showed no significant differences.Based on the current study, our results suggested that statins, ezetimibe, and PCSK9-mAbs are effective in reducing LDL-C levels. Treatment with statins and ezetimibe also demonstrated a significant effect on CRP. The traditional lipid-lowering strategy including statin and ezetimibe showed similar benefit on CV outcomes compared with the PCSK9-mAbs treatment.

To evaluate the association between dipeptidyl peptidase 4 inhibitor (DPP-4i) and the incidence of neoplasm in patients with type 2 diabetes (T2D).Pubmed, Medline, Embase, the Cochrane Central Register of Controlled Trials andGenerally, DPP-4i was associated with a decreased incidence of overall neoplasm events in patients with T2D when compared with non-DPP-4i agents (OR = 0.91, 95%CI, 0.8 to 0.97). Moreover, the incidence of rectal neoplasm, especially rectal malignant neoplasm, and the incidence of skin neoplasm were significantly decreased in DPP-4i users. The overall neoplasm events were less frequent in DPP-4i users who were elderly, or male, or obese, or Caucasian, or with over 10 years of diabetes, or with follow-up duration over 52 weeks.DPP-4i was associated with decreased risks of overall neoplasm, rectal neoplasm, rectal malignant neoplasm and skin neoplasm in patients with T2D. The overall neoplasm events were less frequent in patient with DPP-4i treatment who were elderly, male, obese, Caucasian, with long diabetes durations and with long follow-up durations. Further investigations are still required.CRD42021273627.

The urinary C-peptide/creatinine ratio (UCPCR) is low in patients with type 1 diabetes mellitus, but it has not been well characterized in patients with type 2 diabetes mellitus (T2DM). We aimed to measure the UCPCRs in patients with T2DM and explore the relationships among UCPCR, insulin resistance (IR), and chronic vascular complications of diabetes.A cross-sectional study was performed of 1299 Chinese hospitalized patients with T2DM. Binary logistic regression was used to evaluate the relationships between the chronic vascular complications of diabetes and UCPCR. K-means analysis was used to allocate participants to subgroups with five to six variables (age at diagnosis, body mass index [BMI], glycosylated hemoglobin, homoeostasis model assessment 2-estimated beta-cell function (HOMA2-B), and HOMA2-insulin resistance (HOMA2-IR), with or without UCPCR).UCPCR positively correlated with HOMA2-IR (r = 0.448, P .001). After adjustment for sex, age, duration of diabetes, and other cardiovascular risk factors, UCPCR was positively associated with diabetic kidney disease (DKD) (odds ratio [OR] = 1.198, 95% CI 1.019-1.408, P = .029) and coronary heart disease (CHD) (OR = 1.312, 95% CI 1.079-1.594, P = .006). When UCPCR was added, cluster analysis using the six variables identified five subgroups of T2DM, characterized by differing age at diagnosis, BMI, beta-cell function, IR, and prevalence of vascular complications.UCPCR is positively associated with IR, DKD, and CHD and represents a promising biomarker that could refine the classification of T2DM.背景: 1型糖尿病患者尿C肽/肌酐比值水平低。但尿C肽/肌酐比值在2型糖尿病患者中并没有被充分评估, 本研究拟测定2型糖尿病患者的尿C肽/肌酐比值水平, 探讨尿C肽/肌酐比值与胰岛素抵抗及糖尿病慢性血管并发症的相关性, 并评估尿C肽/肌酐比值改善2型糖尿病精准分型的可能性。 方法: 本研究共纳入北京大学人民医院内分泌科住院2型糖尿病患者1299名。采集所有患者的临床资料, 测定其空腹尿C肽/肌酐比, 通过二元Logistic回归分析尿C肽/肌酐比值与糖尿病血管并发症的相关性。并分别用传统的五个变量[诊断年龄, 体重指数, 糖化血红蛋白, 改良稳态模型计算的β细胞功能指数(HOMA2-B)及胰岛素抵抗指数(HOMR2-IR)]和加入尿C肽/肌酐比值后的六个变量, 通过相同的k-means聚类算法对2型糖尿病患者进行聚类分组, 比较不同亚组的临床特点。 结果: 尿C肽/肌酐比值与HOMA2-IR水平 (r=0.448, P0.001)正相关。在调整了性别, 年龄, 病程及其他心血管疾病危险因素后, 尿C肽/肌酐比值水平与糖尿病肾病 [比值比(OR) =1.198, 95%CI (1.019, 1.408), P=0.029]及冠状动脉粥样硬化性心脏病的发生风险呈正相关 [OR=1.312, 95%CI (1.079, 1.594), P=0.006]。在五个传统临床变量基础上, 加入尿C肽/肌酐比值后再进行聚类分型, 可以清晰地将患者分为五组:两组具有早发糖尿病特征[早发胰岛素缺乏型糖尿病(n=350)和早发胰岛素抵抗型糖尿病(n=176)], 两组具有晚发糖尿病特征[晚发胰岛素缺乏型糖尿病(n=318)和晚发胰岛素抵抗型糖尿病(n=133)]及轻型糖尿病(n=299)。各组间诊断年龄, 体重指数, 胰岛β细胞功能, 胰岛素抵抗水平以及糖尿病血管并发症比例显著不同。 结论: 尿C肽/肌酐比值与胰岛素抵抗水平及糖尿病肾病, 冠状动脉粥样硬化性心脏病发生风险正相关。在传统临床变量基础上引入尿C肽/肌酐比值, 可以改善2型糖尿病的精准分型。.

Background Pseudohypoaldosteronism type II (PHAII), also called Gordon syndrome, is a rare hereditary disease caused by variants in the WNK1, WNK4, KLHL3 and CUL3 genes. The combination of PHAII with hyperthyroidism and secondary hyperparathyroidism has not been reported previously. Case presentation A 54-year-old female with recently diagnosed Graves’ disease presented hyperkalemia, hypertension, hypercalciuria, elevated levels of parathyroid hormone (PTH) and normal renal function. PHAII was established based on the finding of a homozygous variant (c.328 A > G, T110A) in the KLHL3 gene. Low-dose thiazide diuretics normalized her potassium, calcium and PTH. Conclusions PHAII caused by a KLHL3 variant can affect adults later in life. This diagnosis should be considered in patients with hypertension, consistent hyperkalemia, and normal eGFR and can be corrected by thiazides. The patient also had hyperthyroidism and secondary hyperparathyroidism. The latter was also corrected by thiazide treatment. The hyperthyroidism was assumed to be unrelated to PHAII.

AIM We aimed to use data-driven glucose pattern analysis to unveil the correlation between the metrics reflecting glucose fluctuation and beta-cell function, and to identify the possible role of this metric in diabetes classification. MATERIALS AND METHODS In total, 78 participants with type 1 diabetes and 59 with type 2 diabetes were enrolled in this study. All participants wore a flash glucose monitoring system, and glucose data were collected. A detrended fluctuation function (DFF) was utilized to extract glucose fluctuation information from flash glucose monitoring data and a DFF-based glucose fluctuation metric was proposed. RESULTS For the entire study population, a significant negative correlation between the DFF-based glucose fluctuation metric and fasting C-peptide was observed (r = -0.667; P

BackgroundThe placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine.MethodsLiterature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, andClinicalTrials.govfor studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373.ResultsSignificantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = − 0.12%, 95% CI, − 0.16 to − 0.07%) and weight reduction (ES = − 0.40 kg, 95% CI, − 0.50 to − 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = − 0.22%, 95% CI, − 0.32 to − 0.11%) versus oral types (ES = − 0.09%, 95% CI, − 0.14 to − 0.04%) in T2DM (P = 0.03). Older age (β = − 0.01, 95% CI, − 0.02 to − 0.01,P β = − 0.02, 95% CI, − 0.03 to − 0.21 × 10−2,P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03,P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10−2, 0.01,P β = − 0.02, 95% CI, − 0.04 to − 0.26 × 10−2,P = 0.02), and higher baseline HbA1c (β = − 0.09, 95% CI, − 0.16 to − 0.01,P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10,P ConclusionThe placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.

Current knowledge about the ovarian reserve in patients with type 1 diabetes is inconsistent and based on studies with small sample size. This meta-analysis aimed to produce a comprehensive evaluation on the ovarian reserve of type 1 diabetes female patients and to analyze the associated factors with the ovarian reserve.Systematic searches were conducted for studies published from the inception to December 2021. Original human observational studies either with case-control, cross-sectional, or longitudinal design evaluating ovarian reserve markers between type 1 diabetes patients and healthy controls were included. Levels of anti-müllerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol (E2) were extracted.It was indicated that women with type 1 diabetes were associated with decreased levels of AMH compared with healthy controls (weighted mean difference [WMD] -0.70 ng/ml, 95% confidence intervals [CI] -1.05 to -0.34 ng/ml, P = 0.0001). Subgroup analyses stratified by age showed that adult patients with type 1 diabetes were associated with decreased levels of AMH (WMD -0.70 ng/ml, 95% CI -1.06 to -0.34 ng/ml, P = 0.0001) and FSH (WMD -1.07 IU/L, 95% CI -1.75 to -0.39 IU/L, P = 0.002) compared with healthy controls. Meta-regression analysis showed no significant correlation between AMH, FSH, and clinical factors, while level of E2 was negatively correlated with daily insulin doses and glycosylated hemoglobin A1c (HbA1c) values.According to this meta-analysis, type 1 diabetes might be associated with decreased AMH levels. Further studies using different markers and fertility outcomes focus on the ovarian reserve of women with type 1 diabetes are urgently needed.

IntroductionBody composition is closely related to metabolic health status. Visceral adipose tissue (VAT) dysfunction contributes to metabolic syndrome. However, results regarding subcutaneous adipose tissue (SAT) and skeletal muscle are controversial. We aimed to determine the association of indices of body composition with abnormal metabolic phenotype in China.MethodsA total of 3, 954 subjects (age 50.2 ± 11.7 years) with body mass index (BMI) more than 18.5 kg/m2 from Pinggu Metabolic Disease Study were analyzed. Quantitative computed tomography (QCT) was performed to measure total adipose tissue (TAT), VAT, SAT area, and lumbar skeletal muscle area (SMA). Participants were divided into six groups on the basis of BMI category (normal weight/overweight/obesity) and metabolic status (healthy/unhealthy), as defined by the presence or absence of components of the metabolic syndrome by Chinese Diabetes Society criteria.Results63.4%, 39.5%, and 23.3% participants were classified as metabolically healthy phenotype in individuals with normal weight, overweight and obese, respectively. Individuals in the highest TAT, VAT, and VAT/TAT ratio category had higher risk of being metabolically unhealthy than individuals in the lowest group (all ppp=0.008) in individuals with obese after adjustment for age, sex and BMI. However, skeletal muscle index (SMI) showed no significant association with the metabolically healthy status in different BMI categories (p>0.05). The VAT and VAT/TAT ratio were better diagnostic values of indicators to differentiate metabolically unhealthy subjects from controls compared with other indicators, such as TAT, SAT, SMI, SMA/TAT ratio.ConclusionsHigher visceral adipose tissue was closely associated with metabolically unhealthy phenotype in Chinese adults. Subcutaneous adipose tissue might be a protective factor for metabolic health status only in obese individuals.

ObjectivePrevious evidence suggested that sodium–glucose cotransporter 2 inhibitor (SGLT2i)-mediated urinary glucose excretion (UGE) appeared to be reduced with a decrease in glomerular filtration rate. Thus, we conducted a systematic review and meta‐analysis to compare SGLT2i-mediated UGE among individuals with different levels of renal function.MethodsWe conducted systematic searches in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to May 2021. Clinical studies of SGLT2i with reports of UGE changes in predefined different levels of renal function were included. The results were expressed as pooled effect sizes with 95% confidence interval (CI). A random-effects model was used to calculate the pooled effect sizes.ResultsIn total, eight eligible studies were included. Significant differences were observed in the post-treatment UGE level among subgroups stratified by renal function (P <0.001 for subgroup difference), which were gradually decreased along with the severity of impaired renal function. Consistently, changes in UGE before and after SGLT2i treatment were also decreased along with the severity of impaired renal function [67.52 g/day (95%CI: 55.58 to 79.47 g/day) for individuals with normal renal function, 52.41 g/day (95%CI: 38.83 to 65.99 g/day) for individuals with mild renal function impairment, 35.11 g/day (95%CI: 19.79 to 50.43 g/day) for individuals with moderate renal function impairment, and 13.53 g/day (95%CI: 7.20 to 19.86 g/day) for individuals with severe renal function impairment; P <0.001 for subgroup differences].ConclusionsSGLT2i-mediated UGE was renal function dependent, which was decreased with the extent of renal function impairment.

To investigate the effect of biologic therapy on risk of fracture in selected rheumatic and autoimmune diseases.The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2021. Randomized clinical trials (RCTs) comparing biological disease-modifying antirheumatic drugs (bDMARDs) with non-bDMARDs or placebo in patients with five selected rheumatic and autoimmune diseases were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95 % confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture.A total of 100 RCTs involving 51,413 participants fulfilled the inclusion criteria. In patients with psoriasis (Ps), and psoriatic arthritis (PsA), compared with placebo or non-bDMARDs therapy, the risk of major osteoporotic fracture (OR, 0.34 [95 %Cl, 0.15-0.76], p = 0.009), hip fracture (OR, 0.22 [95 %Cl, 0.05-0.89], p = 0.03), and osteoporotic non-vertebral fracture (OR, 0.26 [95 %Cl, 0.10-0.62], p = 0.003) were significantly decreased with the use of bDMARDs. In patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), the risk of fracture were not changed with biologic treatment.The existing evidence from RCTs indicated the use of bDMARDs was associated with a low risk of major osteoporotic fracture, hip fracture, and osteoporotic non-vertebral fracture in patients with Ps and PsA. There are still urgent needs for studies regarding the actions of biologic therapies on the risk of bone fractures in systemic inflammatory diseases.

To assess the association between the use of sodium–glucose cotransporter 2 inhibitor (SGLT2i) and the incidence of diabetic retinopathy (DR). PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov were searched from inception to October 2021. Randomized controlled trials (RCTs) with reports of incidence of DR and other eye disorders between SGLT2i and non-SGLT2i users with type 2 diabetes mellitus were included. In general, the incidences of DR were comparable between SGLT2i and non-SGLT2i users (OR = 0.80, 95%CI 0.61 to 1.06, P = 0.12). However, compared with non-SGLT2i users, the incidence of DR was significantly reduced in SGLT2i users with diabetes duration less than 10 years (OR = 0.32, 95%CI 0.13 to 0.76, P = 0.01). Weight reduction in SGLT2i users was associated with a decreased risk of retinal detachment. Moreover, longer study duration was associated with lower incidence of cataract and retinal vasculopathy in SGLT2i users. In general, the use of SGLT2i was not associated with the incidence of DR. However, a reduced risk of DR was observed in SGLT2i users with diabetes duration less than 10 years. An early initiation of SGLT2i might be more likely to provide with ocular benefits.

Sorbin and SH3-domain-containing-1 (SORBS1) play important roles in insulin signalling and cytoskeleton regulation. Variants of the SORBS1 gene have been inconsistently reported to be associated with type 2 diabetes or diabetic kidney disease (DKD).Two independent case-control studies based on two randomized sampling cohorts (cohort 1, n = 3345; cohort 2, n = 2282) were used to confirm the association between rs2281939 of SORBS1 and impaired glucose regulation (IGR). An additional hospital-based cohort (cohort 3, n = 2135) and cohort 1 were used to investigate the association between rs2281939 and DKD. The phenotype of rare variants of SORBS1 was explored in 453 patients with early onset type 2 diabetes (diagnosed before 40 years of age, EOD).The G allele was associated with type 2 diabetes (additive model: OR = 1.25, 95% CI [1.03-1.52], p = 0.022) in cohort 1, and IGR in cohort 2 (additive model: OR = 1.22, 95% CI [1.05-1.43], p = 0.01). We found that the G allele was also associated with HDL-c levels in women in both cohort 1 (p = 0.03) and 2 (p = 0.029) in the dominant model. The rare variant carriers also had lower HDL-c and LDL-c levels than non-carriers in patients with EOD. No association between rs2281939 or rare variants and DKD was observed.The variants in the SORBS1 gene were associated with IGR and HDL-c levels but not with DKD in the Chinese Han population.

PurposeThe effect of physical activity on glycemic variability remains controversial. This meta-analysis aimed to assess the overall effect of physical activity treatment on glycemic variability in patients with diabetes.MethodsPubMed/MEDLINE, Embase, and Cochrane databases were searched for clinical trials that conducted in patients with type 1 diabetes mellitus and type 2 diabetes mellitus with reports of the mean amplitude of glycemic excursion (MAGE), time in range (TIR), time above range (TAR), or time below range (TBR). Eligible trials were analyzed by fixed-effect model, random effect model, and meta-regression analysis accordingly.ResultsIn total, thirteen trials were included. Compared with the control group, physical activity intervention was significantly associated with increased TIR (WMDs, 4.17%; 95% CI, 1.11 to 7.23%, PConclusionPhysical activity was associated with significantly decreased glycemic variability in patients with diabetes. Patients with higher BMI might benefit more from physical activity therapy in terms of a lower MAGE. Hypoglycemia associated with physical activity treatment still warranted caution, especially in patients with intensive glycemic control.Systematic Review RegistrationPROSPERO [CRD42021259807].

Cardiovascular (CV) disease is the leading cause of morbidity and mortality in adults with type 2 diabetes (T2D). The aim of this study was to determine the CV risk in Chinese patients with T2D based on the 2019 European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD) guidelines on diabetes, pre-diabetes, and CV diseases.A total of 25,411 patients with T2D, who participated in the study of China Cardiometabolic Registries 3B study, were included in our analysis. We assessed the proportions of patients in each CV risk category according to 2019 ESC/EASD guidelines.Based on the 2019 ESC/EASD guidelines, 16,663 (65.6%), 1895 (7.5%), and 152 (0.6%) of patients were included in "very high risk," "high risk," and "moderate risk" categories, respectively. The proportions of patients in each category varied based on age, sex, body mass index, and duration. While 58.7% (9786/16,663) of elderly patients were classified to "very high risk" group, 89.6% (3732/4165) of patients with obesity were divided into "very high risk" group. Almost all patients with a duration of diabetes10 years had "very high risk" or "high risk." However, 6701 (26.4%) of Chinese T2D patients, who had shorter duration, and one or two risk factors, could not be included in any category (the "unclear risk" category).In China, most patients with T2D have "very high" or "high" CV risk based on 2019 ESC/EASD guidelines. However, the risk of patients in "unclear risk" group needs to be further classified.

ObjectivesPPARγ variants cause lipodystrophy, insulin resistance, and diabetes. This study aimed to determine the relationship between PPARγ genotypes and phenotypes and to explore the pathogenesis of diabetes beyond this relationship.MethodsPPARγ2 exons in 1,002 Chinese patients with early-onset type 2 diabetes (diagnosed before 40 years of age) were sequenced. The functions of variants were evaluated by in vitro assays. Additionally, a review of the literature was performed to obtain all reported cases with rare PPARγ2 variants to evaluate the characteristics of variants in different functional domains.ResultsSix (0.6%) patients had PPARγ2 variant-induced diabetes (PPARG-DM) in the early-onset type 2 diabetes group, including three with the p.Tyr95Cys variant in activation function 1 domain (AF1), of which five patients (83%) had diabetic kidney disease (DKD). Functional experiments showed that p.Tyr95Cys suppresses 3T3-L1 preadipocyte differentiation. A total of 64 cases with damaging rare variants were reported previously. Patients with rare PPARγ2 variants in AF1 of PPARγ2 had a lower risk of lipodystrophy and a higher rate of obesity than those with variants in other domains, as confirmed in patients identified in this study.ConclusionThe prevalence of PPARG-DM is similar in Caucasian and Chinese populations, and DKD was often observed in these patients. Patients with variants in the AF1 of PPARγ2 had milder clinical phenotypes and lack typical lipodystrophy features than those with variants in other domains. Our findings emphasize the importance of screening such patients via genetic testing and suggest that thiazolidinediones might be a good choice for these patients.

Aim. To investigate the metabolic profiles of newly diagnosed type 2 diabetes (NEW2D) in Chinese older adults (≥65 years) and assess the proportion of patients who achieved the targeted goals of blood glucose, blood pressure, and blood lipid. Methods. NEW2D study was an observational, longitudinal, prospective cohort study involving patients who were diagnosed with type 2 diabetes (T2D) within the past 6 months and had a follow-up of 12 months. Participants were divided into younger NEW2D group (aged 20-65 years old) and older NEW2D group (aged ≥65 years old) according to age of diabetes onset. The baseline metabolic profiles were compared and the proportion of patients achieving adequate control of blood glucose, blood pressure, and blood lipids in reference to target goals were assessed during treatment. Results. The older NEW2D (n=1362) had a lower BMI, HbA1c%, diastolic blood pressure, triglyceride, low-density lipoprotein cholesterol (LDL-C), and total cholesterol, higher systolic blood pressure, and high-density lipoprotein cholesterol levels at baseline. 47.8%, 66.7%, and 39.4% reached the target of HbA1c<7.0%, BP<140/90 mmHg, and LDL−C<2.6 mmol/L, respectively. After 12 months, the proportion achieving above three targets increased to 70.2%, 76.1%, and 47.5%, respectively. The proportions of patients achieving three combined therapeutic targets doubled from 13.5% to 26.7%. Conclusion. The older NEW2D patients have special metabolic profiles compared with younger patients. The control of cardiovascular disease risk factors was suboptimal in older adults with type 2 diabetes.

Aims/Introduction Data of nationwide glycemic control and hypoglycemic treatment patterns in newly diagnosed type 2 diabetes patients in China are absent. The aim of this study was to assess the evolution of treatment patterns for newly diagnosed type 2 diabetes patients and the clinical outcomes during 12‐month follow up. Materials and Methods This is an observational prospective cohort study with 12 months of follow up. Patients with a diagnosis of type 2 diabetes for, This is a prospective, nationwide multicenter, observational cohort study with 12‐month follow up, a study of the China Cardiometabolic Registry, with the aim to evaluate treatment patterns and the clinical outcomes for newly diagnosed type 2 diabetes patients in China, and to assess the associated factors with treatment changes during the 12‐month follow‐up period (CCMR‐NEW2D study).

To estimate the prevalence of glucokinase variant-induced diabetes (GCK-DM) in a general population and to establish a clinical strategy for identifying GCK-DM from type 2 diabetes (T2DM). A population-based study of diabetes in a rural region of Beijing, China, was conducted using two-stage stratified random cluster sampling. The glucokinase exons were sequenced in patients with diabetes. A total of 3345 subjects, including 545 patients with diabetes, participated in this study. Seven patients with GCK-DM were identified. The estimated prevalence rates of GCK-DM were 0.21% and 1.3% in the whole population and the diabetic patients, respectively. In the newly diagnosed diabetic patients (New-DM), a triglyceride cutoff ≤1.43 mmol/L (126.55 mg/dl) could discriminate GCK-DM from T2DM with 100% sensitivity and 68.4% specificity. Its effectiveness was confirmed in an additional 134 early-onset young patients with T2DM and mild hyperglycemia. A clinical criterion based on triglyceride and mild hyperglycemia could differentiate GCK-DM from T2DM in New-DM and was shown to be effective in identifying GCK-DM from 559 early-onset young patients with T2DM in the hospital. The prevalence of GCK-DM is approximately 1.3% in the Chinese population with diabetes, and the new clinical screening strategy is helpful for identifying GCK-DM.

OBJECTIVE Individualized treatment of patients with diabetes requires detailed evaluation of risk factor dynamics at the population level. This study evaluated the persistent glycemic and cardiovascular (CV) risk factor burden over 2 years after treatment intensification (TI). RESEARCH DESIGN AND METHODS From U.S. Centricity Electronic Medical Records, 276,884 patients with incident type 2 diabetes who intensified metformin were selected. Systolic blood pressure (SBP) ≥130/140 mmHg and LDL ≥70/100 mg/dL were defined as uncontrolled for those with/without a history of CV disease at TI. Triglycerides ≥150 mg/dL and HbA1c ≥7.5% (58 mmol/mol) were defined as uncontrolled. Longitudinal measures over 2 years after TI were used to define risk factor burden. RESULTS With 3.7 years’ mean follow-up, patients were 59 years; 70% were obese; 22% had a history of CV disease; 60, 30, 50, and 48% had uncontrolled HbA1c, SBP, LDL, and triglycerides, respectively, at TI; and 81% and 69% were receiving antihypertensive and lipid-modifying therapies, respectively. The proportion of patients with consistently uncontrolled HbA1c increased from 31% in 2005 to 41% in 2014. Among those on lipid-modifying drugs, 41% and 37% had consistently high LDL and triglycerides over 2 years, respectively. Being on antihypertensive therapies, 29% had consistently uncontrolled SBP. Among patients receiving cardioprotective therapies, 63% failed to achieve control in HbA1c + LDL, 57% in HbA1c + SBP, 55% in LDL + SBP, and 63% in HbA1c + triglycerides over 2 years after TI. CONCLUSIONS Among patients on multiple therapies for risk factor control, more than one-third had uncontrolled HbA1c, lipid, and SBP levels, and more than one-half had two CV risk factors that were simultaneously uncontrolled after TI.

mPGES-1 is a terminal rate-limiting enzyme responsible for inflammation-induced PGE2 production. The inhibition of mPGES-1 has been considered as a safe and effective target for the treatment of inflammation and cancer. However, a specific, efficient, and simple method for high-throughput screening of mPGES-1 inhibitors is still lacking. In this study, we developed a fluorescence imaging strategy to monitor the expression of mPGES-1 via CRISPR/Cas9 knock-in system. Immunofluorescence colocalisation, Sanger sequencing, RNAi, and IL-1β treatment all confirmed the successful construction of mPGES-1 reporter cells. The fluorescence signal intensity of the reporter cells treated with four conventional mPGES-1 inhibitors was considerably attenuated via flow cytometry and fluorescent microplate reader, demonstrating that the reporter cells can be used as an efficient and convenient means for screening and optimising mPGES-1 inhibitors. Moreover, it provides a new technical support for the development of targeted small molecule compounds for anti-inflammatory and tumour therapy.

Few studies have investigated the dose–response relationship between exercise and weight control. This study aimed to assess the effects of different types of supervised exercise training on weight control and other metabolic outcomes in patients with type 2 diabetes mellitus and explore the dose–response relationship between exercise volume/duration and these outcomes. PubMed/MEDLINE, Embase, and Cochrane databases were searched for studies between January 1980 and June 2019. Randomized control trials in type 2 diabetes mellitus patients with supervised exercise training versus control treatment were included. The primary outcome was changes in body weight (kg). The secondary outcomes included changes in waist circumference (cm) and total body fat percentage (%). Forty-two randomized control trials, including 3,625 patients with type 2 diabetes mellitus were included. Overall, exercise treatment was associated with significant reduction in body weight (weighted mean differences, −1.10 kg; 95% CI [−1.58, −0.62], p p p p = .02) and a significant difference between combined exercise and resistance exercise (p

Background Non-alcohol fatty liver disease (NAFLD) is the most common liver disease and an unhealthy lifestyle can lead to an increased risk of NAFLD. The present study aims to evaluate the association of meat consumption with NAFLD risk and liver-related biochemical indexes in middle-aged and elderly Chinese. Methods A cross-sectional study was conducted in individuals who were 45 years or older and underwent a physical examination from April 2015 to August 2017 in Southeast China. To evaluate associations between meat intake and NAFLD risk, inverse probability of treatment weighting and subgroup analyses were performed with logistic regressions. Spearman’s rank correlation was carried out to examine the relationship between meat consumptions and liver-related biochemical indexes. Results High consumptions of red meat (28.44–49.74 and > 71.00 g/day) (ORadjusted = 1.948; P ORadjusted = 1.714; P = 0.002) was positively associated with NAFLD risk on inverse probability of treatment weighting analysis, adjusting for smoking, tea intake, weekly hours of physical activity and presence of hypertension, dyslipidemia and diabetes. Exposure–response relationship analysis presented that red meat intake was positively associated with NAFLD risk. Significant associations of red meat intakes with serum levels of γ-glutamyl transferase, alanine transaminase, aspartate aminotransferase, total triglyceride and high-density lipoprotein cholesterol were found (rs = 0.176; P rs = 0.128; P rs = 0.060; P = 0.016; rs = 0.085; P = 0.001; rs = − 0.074; P = 0.003). Conclusions These findings suggest that the reduction of meat consumption may decrease NAFLD risk and should warrant further investigations.

BackgroundTo exam the associations between the use of sodium glucose co-transporter 2 inhibitor (SGLT2i) and the risk of lower limb complications, and to analyze the associated factors.MethodsPubmed, Medline, Embase, the Cochrane Center Register of Controlled Trials for Studies andClinicaltrial.govwere searched from the inception to November 2020. Randomized controlled trials of SGLT2i conducted in population containing diabetic patients with reports of amputation, peripheral arterial disease (PAD) and diabetic foot (DF) events were included. Random-effect model, fixed-effect model and meta-regression analysis were accordingly used.ResultThe numbers of SGLT2i users versus non-SGLT2i users in the analyses of amputation, PAD and DF were 40,925/33,414, 36,446/28,685 and 31,907/25,570 respectively. Compared with non-SGLT2i users, the risks of amputation and PAD were slightly increased in patients with canagliflozin treatment (amputation: OR = 1.60, 95% CI 1.04 to 2.46; PAD: OR = 1.53, 95 % CI 1.14 to 2.05). Meta-regression analyses indicated that greater weight reduction in SGLT2i users was significantly associated with the increased risks of amputation (β = − 0.461, 95% CI − 0.726 to − 0.197), PAD (β = − 0.359, 95% CI − 0.545 to − 0.172) and DF (β = − 0.476, 95% CI − 0.836 to − 0.116). Lower baseline diastolic blood pressure (β = − 0.528, 95% CI − 0.852 to − 0.205), more systolic blood pressure reduction (β = − 0.207, 95% CI − 0.390 to − 0.023) and more diastolic blood pressure reduction (β = − 0.312, 95% CI − 0.610 to − 0.015) were significantly associated with the increased risks of amputation, PAD and DF respectively in patients with SGLT2i treatment.ConclusionsThe risks of amputation and PAD were slightly increased in patients with canagliflozin treatment. Reductions in body weight and blood pressure were associated with lower limb complications in patients with SGLT2i treatment.

ObjectiveWhether hypoglycemic treatments with weight-alternating effects influence the incidence of neoplasm in type 2 diasbetes (T2D) remains uncertain. Therefore, we performed a meta-analysis to assess the association between the weight alteration and incidence of neoplasm in patients with T2D.Research Design and MethodsSystematic searches were conducted for studies published between the inception of 1950s and September 2019. Randomized controlled trials conducted in T2D patients with at least 48-week follow-up, significant weight change difference between treatment arms and reports of neoplasm events were included. Fixed-effects model and meta-regression analysis were accordingly used.ResultsIn all, 46 studies were included. Analysis indicated weight reduction was not associated with a decreased incidence of neoplasm (OR = 1.01, 95% CI, 0.96 to 1.07, I2 = 17%) and weight elevation was not associated with an increased incidence of neoplasm (OR = 0.91, 95% CI, 0.76 to 1.09, I2 = 0%). Meta-regression analysis showed a slower weight reduction rate (β = −5.983, 95% CI, −11.412 to 0.553, P = 0.03) instead of weight change difference (β = −0.030, 95% CI, −0.068 to 0.007, P = 0.115) was significantly associated with reduced risk of neoplasm in patients with T2D. Moreover, a decreased incidence of prostate, bladder, and uterine neoplasm was observed in T2D patients with weight reduction difference while an increased incidence of thyroid neoplasm was found in glucagon-like peptide-1 receptor analog (GLP-1RA) users with weight reduction difference.ConclusionsAdditional weight change achieved by current hypoglycemic agents or strategies in short and medium periods was not associated with incidence of most neoplasm in patients with T2D. However, a decreased incidence of prostate, bladder, and uterine neoplasm was shown in T2D patients with weight reduction difference while an increased risk of thyroid neoplasm was observed in T2D patients on GLP-1RA treatments with weight reduction difference. A more sustained and persistent weight reduction process may confer reduced risk of neoplasm in patients with T2D.

Drug-induced liver injury (DILI) is a common adverse drug reaction leading to the interruption of tuberculosis (TB) therapy. We aimed to identify whether the hepatitis B virus (HBV) infection would increase the risk of DILI during first-line TB treatment. A meta-analysis of cohort studies searched in PubMed, Web of Science and China National Knowledge Infrastructure was conducted. Effect sizes were reported as risk ratios (RRs) and 95% confidence intervals (CIs) and calculated by R software. Sixteen studies with 3960 TB patients were eligible for analysis. The risk of DILI appeared to be higher in TB patients co-infected with HBV (RR 2.66; 95% CI 2.13–3.32) than those without HBV infection. Moreover, patients with positive hepatitis B e antigen (HBeAg) were more likely to develop DILI (RR 3.42; 95% CI 1.95–5.98) compared to those with negative HBeAg (RR 2.30; 95% CI 1.66–3.18). Co-infection with HBV was not associated with a higher rate of anti-TB DILI in latent TB patients (RR 4.48; 95% CI 0.80–24.99). The effect of HBV infection on aggravating anti-TB DILI was independent of study participants, whether they were newly diagnosed with TB or not. Besides, TB and HBV co-infection patients had a longer duration of recovery from DILI compared to non-co-infected patients (SMD 2.26; 95% CI 1.87–2.66). To conclude, the results demonstrate that HBV infection would increase the risk of DILI during TB therapy, especially in patients with positive HBeAg, and close liver function monitoring is needed for TB and HBV co-infection patients.

ABCC8 variants cause neonatal diabetes, maturity onset diabetes of the young (MODY), and hyperinsulinemic hypoglycemia because of activating or inactivating variants. In this study we used targeted exon sequencing to investigate genetic variants of ABCC8 and phenotypic features in Chinese patients with early onset diabetes (EOD).A cross-sectional study of 543 Chinese patients with EOD was recruited and the exons of them were conducted targeted sequencing. The pathogenicity of ABCC8 variants was defined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline. The phenotypes of patients owing to ABCC8 variants (ABCC8-MODY) were characterized.Among the 543 participants, eight (1.5%) patients with ABCC8-MODY were identified. They harbored eight missense ABCC8 variants (p.R306C, p.E1326K, and p.R1379H, previously reported; p.R298C, p.F1176C, p.R1221W, p.K1358R, and p.I1404V) classified as likely pathogenic. Two family members with ABCC8-MODY were also confirmed. The average diagnosed age of the 10 patients was 26.8 ± 12.9 years. The majority of them had unsatisfactory glucose control, 80% of them had diabetic kidney disease, and neurological features were not observed.Using targeted exon sequencing followed by pathogenicity analysis, we could be able to make genetic diagnoses for eight (1.5%) patients with ABCC8-MODY. The phenotype was variable with higher risk of diabetic microvascular complications. Genetic diagnosis is conducive for facilitating the personalized treatment of ABCC8-MODY.背景: ABCC8基因激活或失活变异可导致新生儿糖尿病、青年起病的成年型糖尿病(MODY)和高胰岛素血症低血糖。本研究中，我们利用靶向外显子测序方法在中国早发糖尿病(EOD)患者中检测ABCC8基因变异，分析ABCC8基因变异的临床特征。 方法: 我们纳入了543例中国EOD患者，详细收集临床资料，采用外显子靶向测序技术对ABCC8基因进行检测。根据“美国医学遗传学和基因组学会和分子病理学协会指南”分析ABCC8基因变异的致病性，并分析ABCC8基因变异(ABCC8-MODY)导致糖尿病患者的临床特征。 结果: 在543例患者中，遗传学确诊ABCC8-MODY患者8例(1.5%)。他们分别携带8个ABCC8基因错义突变(p.R306C、p.E1326K、 p.R1379H、p.R298C、p.F1176C、p.R1221W、p.K1358R、p.I1404V)，且均为可能致病性变异。同时发现2例家族成员为ABCC8-MODY。以上10例患者平均诊断年龄为26.8±12.9岁。大部分患者的血糖控制并不理想，80%患者有糖尿病肾病，未观察到神经肌肉合并症。 结论: 利用靶向外显子测序结合致病性分析，遗传学确诊8例(1.5%) ABCC8-MODY患者。此类患者的临床表型多样，糖尿病微血管并发症的发生风险较高。采用遗传学诊断有利于ABCC8-MODY的个体化治疗。.

Aims This meta-analysis aimed to evaluate the risk of developing bullous pemphigoid (BP) and other skin-related adverse events (AEs) in patients with type 2 diabetes (T2DM) undergoing dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment in randomized controlled trials (RCTs). Methods In this meta-analysis, the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases were searched for RCTs, which involve patients with T2DM reporting skin-related AEs. RCTs that comparatively evaluated the effects of DPP-4i treatment and placebo on patients with T2DM and reported skin-related AEs were included in the analysis. The odds ratio (OR) and 95% confidence interval (CI) were calculated using the Peto's methods. The GRADE approach was used to rate the quality of evidence. Results 46 randomized placebo-controlled trials, including 3 trials with reports of BP (n=38,011), that reported skin-related AEs were included (n=59,332). Compared to the placebo group, the risk of developing BP was significantly higher in the DPP-4i treatment group (OR=7.38, 95% CI 2.00-27.25, I2 =0%, P=0.003; quality rating: very low). Additionally, DPP-4i treatment was associated with an increased overall risk of developing skin-related AEs (OR=1.22, 95% CI 1.02-1.46, I2 =32%, P=0.03; quality rating: moderate). Conclusions This meta-analysis suggested that treatment with DPP-4is, including sitagliptin, saxagliptin, and linagliptin, was associated with an increased risk of developing BP. Additionally, the risk of developing skin-related AEs increased when all DPP-4is were combined. Skin lesion, especially BP, should be monitored in patients with diabetes undergoing DPP-4i treatment. Future studies should evaluate the susceptible population and develop strategies for early detection of skin-related AEs. This article is protected by copyright. All rights reserved.

Aim Urinary glucose excretion (UGE) is mainly regulated by the sodium glucose cotransporter (SGLT)-2 in the proximal tubule of kidney. Lower UGE was associated with higher extent of insulin resistance in patients with type 2 diabetes. Animal studies suggested the relation of Fibroblast growth factor 21 (FGF21) and UGE. However, little was known about the association of FGF21 and UGE in human. We conducted a study to investigate the association of serum FGF21 and low UGE in patients with type 2 diabetes. Method A cohort of 2066 hospitalized patients with type 2 diabetes was screened for the fasting urinary glucose concentration and fasting blood glucose in the medical records. 70 patients with high UGE and 61 patients with Low UGE were analyzed. Frozen serum samples were used for the test of FGF21 levels. Results The body mass index (BMI) and serum FGF21 levels were higher in low UGE group. Multivariable logistic regression indicated the association of FGF21 and low UGE after adjusting for age, sex, renal function, fasting plasma glucose, the treatment of insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index. Conclusion Higher serum FGF21 levels were independently associated with low UGE in patients with type 2 diabetes.

Whether the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) would influence the risk of new-onset diabetes remains uncertain. Therefore, we performed a systematic review and meta-analysis to evaluate the association between the use of bDMARDs and the incidence of diabetes in patients with systemic inflammatory conditions. Pubmed, Medline, Embase and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2000 to March 2020. Studies conducted in systemic inflammatory conditions with reports of the incidence of diabetes in subjects treated with bDMARDs were included. With 22 randomized controlled trials and 3 cohort studies included, the overall result indicated that compared with non-bDMARD treatment, the use of bDMARDs was significantly associated with decreased incidence of diabetes in patients with systemic inflammatory conditions (RR = 0.56, 95 % CI, 0.43 to 0.74, P < 0.001, I2 = 69 %), especially in patients with in rheumatoid arthritis (RR = 0.54, 95 % CI, 0.38 to 0.76, P = 0.0005, I2 = 26). Reduced risk of new-onset diabetes was observed in studies with follow-up more than 1 year (RR = 0.73, 95 % CI, 0.54 to 0.99, P = 0.04, I2 = 88). New-onset diabetes was less frequent in patients with TNF-α inhibitor treatment (RR = 0.54, 95 % CI, 0.48 to 0.60, P < 0.001, I2 = 42 %) and abatacept treatment (RR = 0.44, 95 % CI, 0.34 to 0.58, P < 0.001, I2 = 3 %), which might be associated with the inhibition of TNF-α mediated inflammatory responses and dysregulated T cell activation and immune responses respectively. Further investigations are required to validate the glucose metabolism protective effect of bDMARDs and clarify the underlying mechanisms of the crosstalk between bDMARDs and diabetes.

In order to evaluate the efficacy and side effects of the non-insulin antidiabetes medications as an adjunct treatment in type 1 dia betes mellitus (T1DM), we conducted systematic searches in MEDLINE, Embase, and the Cochrane Central Register of Con trolled Trials for randomized controlled trials published between the date of inception and March 2020 to produce a systematic review and meta-analysis. Overall, 57 studies were included. Compared with placebo, antidiabetes agents in adjunct to insulin treatment resulted in significant reduction in glycosylated hemoglobin (weighted mean difference [WMD], -0.30%; 95% confi dence interval [CI], -0.34 to -0.25%; P

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease globally, but there are no optimal methods for its prediction or diagnosis. The present cross-sectional study proposes a non-invasive tool for NAFLD screening. The study included 2,446 individuals, of whom 574 were NAFLD patients. Multivariable logistic regression analysis was used to identify risk factors for NAFLD and incorporate them in a risk prediction nomogram model; the variables included both clinical and lifestyle-related variables. Following stepwise regression, BMI, waist circumference, serum triglyceride, high-density lipoprotein cholesterol, alanine aminotransferase, presence of diabetes and hyperuricemia, tuber and fried food consumption were identified as significant risk factors and used in the model. The final nomogram was found to have good discrimination ability (area under the receiver operating characteristic curve = 0.843 [95% CI: 0.819-0.867]), and reasonable accuracy for the prediction of NAFLD risk. A cut-off score of

Glucokinase (GCK) regulates insulin secretion and hepatic glucose metabolism, and its inactivating variants could cause diabetes. We aimed to evaluate the association of a low-frequency variant of GCK (rs13306393) with type 2 diabetes (T2D), prediabetes, or both (impaired glucose regulation [IGR]) in a Chinese population. An association study was first conducted in a random cluster sampling population (sample 1: 537 T2D, 768 prediabetes, and 1,912 control), and then another independent population (sample 2: 3,896 T2D, 2,301 prediabetes, and 868 control) was used to confirm the findings in sample 1. The A allele of rs13306393 was associated with T2D (odds ratio 3.08 [95% CI 1.77–5.36], P = 0.00007) in sample 1; rs13306393 was also associated with prediabetes (1.67 [1.05–2.65], P = 0.03) in sample 2. In a pooled analysis of the two samples, the A allele increased the risk of T2D (1.57 [1.15–2.15], P = 0.005), prediabetes (1.83 [1.33–2.54], P = 0.0003) or IGR (1.68 [1.26–2.25], P = 0.0004), insulin resistance estimated by HOMA (β = 0.043, P = 0.001), HbA1c (β = 0.029, P = 0.029), and urinary albumin excretion (β = 0.033, P = 0.025), irrespective of age, sex, and BMI. Thus, the Chinese-specific low-frequency variant increased the risk of T2D through reducing insulin sensitivity rather than islet β-cell function, which should be considered in the clinical use of GCK activators in the future.

Previous epidemiologic studies indicate an increased risk of cancer and cancer mortality in patients with type 2 diabetes (T2D). Whether the resolution of hyperglycemia will lead to reduced risk of neoplasm in T2D remains uncertain. Therefore, we performed a meta-analysis to assess the association between glycemic control and incidence of neoplasm in T2D patients. Randomized controlled trials (RCTs) in T2D with significant HbA1c reduction difference between intensive/active and standard/control groups plus follow-up ≥48 weeks were included and analyzed by fixed-effect models, random-effect model, and meta-regression analysis accordingly. Overall, 52 studies were included. Compared with standard/control treatment, intensive/active treatment led to significantly greater HbA1c reduction from baseline (WMD = −0.51%, 95% CI, −0.55 to −0.46%, P

Background Glucagon‐like peptide‐1 receptor agonists ( GLP ‐1 RAs ) and sodium‐glucose cotransporter‐2 inhibitors ( SGLT 2is) have shown their beneficial effects on cardiovascular outcomes and multiple cardiovascular risk factors, including hypertension. However, the mechanism of blood pressure ( BP )–lowering effects of these agents has not been elucidated. This study aims to evaluate the effect of hemoglobin A1c reduction or body weight reduction with GLP ‐1 RA treatment and SGLT 2i treatment on BP changes in patients with type 2 diabetes mellitus. Methods and Results Studies were identified by a search of MEDLINE , EMBASE , and the Cochrane Central Register until June 2019. Meta‐regression analysis was performed to evaluate the association between hemoglobin A1c reduction or body weight reduction and changes of BP . A total of 184 trials were included. Both GLP ‐1 RA and SGLT 2i led to significant reductions in systolic BP (weighted mean difference, −2.856 and −4.331 mm Hg, respectively; P BP (weighted mean difference, −0.898 and −2.279 mm Hg, respectively; P BP reduction or diastolic BP reduction. In GLP ‐1 RA treatment, weight reduction was positively associated with systolic BP reduction and diastolic BP reduction (β=0.821 and β=0.287, respectively; P SGLT 2i treatment, weight loss was significantly associated with systolic BP reduction (β=0.820; P =0.001) but was not associated with diastolic BP reduction. Conclusions Treatment with GLP ‐1 RA and SGLT 2i led to significant reductions in BP in patients with type 2 diabetes mellitus. Weight reduction was significantly and independently associated with BP reductions in GLP ‐1 RA treatment and SGLT 2i treatment.

As initial combination therapy of metformin and dipeptidyl peptidase-4 (DPP-4) inhibitor, the efficacy and safety for the use of high dose of metformin or low dose of metformin and the efficacy and safety for the combination use for Asian and Caucasian patients were not clear.Double-blind randomized controlled trials comparing the efficacy of initial combination therapy of metformin and DPP-4 inhibitors with metformin monotherapy were included. The primary outcome was a result of comparisons between high-dose combination therapy and low-dose combination therapy in terms of efficacy and safety.A total of 11 studies were included. The results indicated that the high-dose combination therapy showed significant decreases in hemoglobin AAs an initial treatment, the high dose of metformin in combination with DPP-4 inhibitors not only provided better glycemic control but also had less effect on weight gain compared with the low-dose combination therapy through the correction of metformin monotherapy. Moreover, initial combination therapy in the Caucasian population showed better glycemic control and less increase in body weight compared with the Asian population.

miR-122, the expression of which is regulated by several transcription factors, such as HNF1A, was recently reported to be associated with type 2 diabetes (T2DM) and hepatocellular carcinoma. HNF1A variants can cause diabetes and might be involved in the development of primary liver neoplasm. Differences in miR-122 expression among different types of diabetes have not been studied. This study aimed to investigate differences in serum miR-122 levels in Chinese patients with different forms of diabetes, including T2DM, type 1 diabetes (T1DM), HNF1A variant-induced diabetes (HNF1A-DM), glucokinase variant-induced diabetes (GCK-DM), and mitochondrial A3243G mutation-induced diabetes (MDM). In total, 12 HNF1A-DM patients, 24 gender-, age-, and body mass index-matched (1 : 2) T2DM patients and 24 healthy subjects were included in this study. In addition, 30 monogenic diabetes (11 GCK-DM and 19 MDM) and 17 T1DM patients were included. Fasted blood biochemistry and miR-122 were measured. The results showed that the HNF1A-DM patients had lower miR-122 levels [0.046 (0.023, 0.121)] than T2DM patients [0.165 (0.036, 0.939), P=0.02] and healthy controls [0.249 (0.049, 1.234), P=0.019]. The area under the curve of the receiver operating characteristic curve for miR-122 to discriminate HNF1A-DM and T2DM was 0.687 (95% CI: 0.52–0.86, P=0.07). There was no difference in serum miR-122 among HNF1A-DM, GCK-DM, MDM, and T1DM patients. Lower serum miR-122 is a unique feature of HNF1A-DM patients and might partially explain the increased risk for liver neoplasm and abnormal lipid metabolism in HNF1A-DM patients.

Background: Placebo was defined as any therapy that is used for its nonspecific psychological and physiologic effect but has no specific pharmacologic impact on the condition being treated. Besides medication therapies, studies have found that the optimal dietary approach as well as physical activity and education are useful to control hyperglycemia in patients with type 2 diabetes (T2DM). The aim of this study was to evaluate the placebo effects of antidiabetic therapies inAsian and Caucasian T2DM patients and make a comparison between the two ethnicities. Methods: A search using the MEDLINE database, EMBASE, and Cochrane Database was performed, from when recording began until December 2016. The main concepts searched in English were sulfonylurea (SU); alpha glucosidase inhibitors (AGI); metformin (MET); thiazolidinediones (TZD); dipeptidyl peptidase-4 inhibitors (DPP-4i); sodium-glucose cotransporter 2 inhibitors (SGLT2i); glucagon-like peptide-1 receptor agonist (GLP-1RA); type 2 diabetes (T2DM); placebo controlled; and randomized controlled trials. Using the Cochrane instrument, we evaluated the adequacy of randomization, allocation concealment procedures, and blinding. Results: This study included 63 studies with a total of 7096 Asian patients involved and 262 studies with a total of 27,477 Caucasian patients involved. In Caucasian population, the use of placebo led to significant reductions of glycosylated hemoglobin (HbA1c), −0.683% (P = 0.008) in SU monotherapy treatment, −0.193% (P = 0.001) in DPP-4i treatment, and −0.230% (P < 0.001) in SGLT2i treatment, respectively. In Asian population, the use of placebo resulted in significant decreases of HbA1c, −0.162% (P = 0.012) in DPP-4i treatment and −0.269% (P = 0.028) in GLP-1RA add-on therapy, respectively. The placebo also significantly reduced body weight. In Caucasian population, placebo use resulted in 0.833 kg (P = 0.006) weight loss by SU treatment and 0.953 kg (P = 0.006) weight loss by GLP-1RA treatment. In Asian population, the placebo led to a weight change of 0.612 kg (P < 0.001) by GLP-1RA analog treatment. The changes of HbA1c and weight due to the placebo effect in other treatments were not significant in both Asian and Caucasian population. Comparisons of the placebo effect on HbA1c change and weight change in each treatment group indicated that no significant difference was found between Asian and Caucasian population. Conclusions: The overall differences of the placebo effect on HbA1c changes as well as on body weight changes were not significant between Asian and Caucasian T2DM patients. The placebo effect on HbA1c changes and weight changes was not associated with baseline age, gender, baseline body mass index, baseline HbA1c, duration of diabetes, or study duration. Key words: Asian; Caucasian; Placebo; Type 2 Diabetes Mellitus

The consistency of cardiovascular risk reduction by antidiabetes medications across racial and ethnic groups remains unclear. The aim of this study was to analyze racial/ethnic patterns in the results of cardiovascular outcomes trials of antidiabetes medications in people with type 2 diabetes.PubMed and Cochrane library databases were searched from the inception dates to December 2020. Cardiovascular outcome trials in type 2 diabetes that randomized participants to antidiabetes medication or control treatment and reported results by race/ethnic groups or region were included.A total of 19 studies were included in this meta-analysis. Among White participants, treatment with antidiabetes medications significantly decreased the risk of composite cardiovascular outcomes when compared with placebo treatment (OR = 0.88, 95% CI 0.83-0.94, p0.05). Among Asian participants, antidiabetes medications also significantly decreased the risk of composite cardiovascular outcomes when compared with control treatment (OR = 0.80, 95% CI 0.74-0.86, p 0.05). A similar pattern was found when analyzing the effects of antidiabetes medications vs. control treatment in other racial/ethnic groups comprising mostly Hispanics and Pacific Islanders (OR = 0.87, 95% CI 0.78-0.98, p0.05). However, among Black participants, treatment with antidiabetes medications resulted in nominal but non-significant decreases in the composite cardiovascular outcomes when compared with control treatment (OR = 0.84, 95% CI 0.62-1.14, p = 0.26).The present meta-analysis showed cardiovascular safety of antidiabetes medications in people with type 2 diabetes from all racial/ethnic groups studied; however, significant composite cardiovascular risk reductions were demonstrated only in White and Asian participants. To determine whether antidiabetes drugs confer consistent cardiovascular benefits in Black and other racial/ethnic participants requires more investigations in the future.

Increased glucagon level was hypothesized to participate in the ketoacidosis associated with sodium-glucose co-transporter 2 inhibitors (SGLT2i) treatment. However, the effect of SGLT2i on glucagon remains controversial. Hence, we conducted this meta-analysis to assess the overall effect of SGLT2i treatment on plasma fasting glucagon level in patients with diabetes. PubMed/MEDLINE, Embase, and Cochrane databases were searched for studies published before August 2020. Clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus with reports of glucagon changes before and after SGLT2i intervention were included. Eligible trials were analyzed by fixed-effect model, random effect model, and meta-regression analysis accordingly. In total, ten trials were included in this meta-analysis. Compared with the non-SGLT2i treatment group, SGLT2i treatment resulted in increased plasma fasting glucagon levels with significance (WMD, 8.35 pg/ml; 95% CI, 2.17–14.54 pg/ml, P＜0.01) in patients with diabetes mellitus. Besides, when compared with non-SGLT2i control group, the insulin level decreased (WMD, −2.78 μU/ml; 95% CI, −5.11 to −0.46 μU/ml, P = 0.02) and ketone body level increased (WMD, 0.17 mmol/l; 95% CI, 0.09–0.25 mmol/l, P＜0.01) in patients with type 2 diabetes. In conclusion, our result indicated SGLT2i intervention would increase the plasma fasting glucagon level in patients with diabetes mellitus. The increase in plasma fasting glucagon level may be associated with reduced insulin level. The increased glucagon-insulin ratio after the use of SGLT2i may make diabetic patients susceptible to ketosis.

Aims/Introduction To evaluate whether there is disparity of the efficacy and all-cause mortality and other adverse effects between Asian and non-Asian patients with sodium–glucose cotransporter 2 (SGLT2) inhibitors treatment. Materials and Methods Randomized clinical trials publicly available before January 2017, comparing SGLT2 inhibitors treatment with a placebo in type 2 diabetes patients were identified. The association between treatment and outcomes was estimated by computing the weighted mean difference for glycated hemoglobin level, blood pressure level, lipid profile levels and bodyweight, and the odds ratios for adverse events. Results A total of 17 trials with Asian patients were included and 39 trials with non-Asian patients were included. Comparison of the glycated hemoglobin decreases corrected by a placebo between Asian and non-Asian patients showed that there was a non-significant difference of 0.05% between groups (P > 0.05). Comparisons of the bodyweight changes and blood pressure changes corrected by a placebo between Asian and non-Asian patients did not show a significant difference between groups (P > 0.05). The risk of all-cause mortality was not increased when compared with a placebo both in Asian and non-Asian populations, and the risk of genital infection in Asian and non-Asian populations were both significant increased. Conclusions Overall, according to the present meta-analysis, comparison of the efficacy in SGLT2 inhibitors treatment between Asian and non-Asian type 2 diabetes patients showed no significant difference in glycated hemoglobin reduction and bodyweight reduction. Furthermore, no disparity was found in the risk of all-cause mortality or hypoglycemia in SGLT2 inhibitors treatment between Asian and non-Asian patients.

BACKGROUND The impact of metformin on body weight is variable in T2DM patients among studies. The reasons for the discrepancies are still unknown. OBJECTIVES We aimed to find out the possible predictive factors of weight change induced by metformin based on an analysis of a phase IV open-labeled trial. MATERIAL AND METHODS We performed a sub-analysis from a prospective, multi-center phase IV open-labeled study in which 371 Chinese newly-diagnosed type 2 diabetes patients received 16 weeks' extended-release metformin monotherapy. The clinical characteristics including weight and laboratory assessments of subjects were collected every 4 weeks. The weight changes from baseline to week 4, 8, 12 and 16 were calculated respectively. The patients were divided into 4 groups by quartile statistics method according to magnitudes of weight change. RESULTS Of 371 enrolled patients, 324 patients had the weight records from baseline to week 16. The weight decreased gradually with each visit (p < 0.001) and the average weight loss was 2 kg after 16 weeks' treatment of metformin. The patients with higher BMI and bigger waist circumference at baseline showed a more pronounced weight loss. However, the magnitudes of weight loss were independently associated with BMI at baseline only. CONCLUSIONS Metformin can lead to weight loss gradually in newly-diagnosed type 2 diabetes patients. The magnitude of weight loss was independently and only associated with baseline BMI.

Aims/Introduction To evaluate the efficacy of weight changes from baseline of the sodium‐glucose cotransporter 2 (SGLT2) inhibitors treatment and glucagon‐like peptide‐1 (GLP‐1) analogs treatment after comparisons with a placebo in type 2 diabetes patients, and the associated factors. Materials and Methods Studies were searched from when recording began, June 2004, until June 2015, and re‐searched in July 2016, and placebo‐controlled randomized trials in type 2 diabetes patients with a study length of ≥12 weeks were included. Results A total of 97 randomized controlled trials were included. Compared with a placebo, treatment with SGLT2 inhibitors was associated with a significantly greater decrease in weight change from baseline (weighted mean differences −2.01 kg, 95% confidence interval −2.18 to −1.83 kg, P < 0.001). Compared with a placebo, changes with GLP ‐1 treatment were also associated with a comparable decrease in weight change from baseline (weighted mean differences −1.59 kg, 95% confidence interval −1.86 to −1.32 kg, P < 0.001). Meta‐regression analysis showed that the baseline age, sex, baseline glycated hemoglobin, diabetes duration or baseline body mass index were not associated with the weight change from baseline in SGLT2 inhibitors or in GLP‐1 treatment corrected by placebo. Comparisons of weight changes from baseline corrected by placebo between SGLT2 inhibitors and GLP‐1 treatment showed that the difference was not significant (P > 0.05). Conclusions According to the present meta‐analysis, treatment with SGLT2 inhibitors and treatment with GLP‐1 analogs led to comparable weight changes from baseline, which are both with significance when compared with placebo treatment.

Context A sodium glucose cotransporter 2 (SGLT2) inhibitor, which increases urinary glucose excretion, was reported to decrease blood glucose levels and deaths among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease. SLC5A2 and HNF1A mutations are associated with renal glycosuria, but their contributions to renal glycosuria in patients with T2DM are not well understood. Objective To assess the clinical features of patients with T2DM and renal glycosuria and those with T2DM and low urinary glucose excretion (LUGE) and identify variants in the exons of SLC5A2 and HNF1A in patients with renal glycosuria and T2DM. Design A total of 2044 Chinese patients with T2DM, including 64 patients with renal glycosuria and 58 patients with LUGE, were tested for their plasma and urine glucose concentrations after fasting. SLC5A2 and HNF1A exons were sequenced. Results Compared with patients with LUGE, those with renal glycosuria were younger (P = 0.008), had lower body mass index (BMI) (P = 0.002) and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) values (P < 0.0001), and were less likely to have hypertension (P = 0.006). HOMA-IR and BMI were negatively associated with renal glycosuria after adjusting for age, sex, hypertension, and insulin therapy. One novel mutation (V359G) of SLC5A2 in 32 patients with renal glycosuria and one known mutation (R131W) of HNF1A in 28 nonobese patients with renal glycosuria were identified. Conclusions These findings suggest that there are subtypes of T2DM characterized by different urinary glucose excretion and cardiovascular risk factors. SLC5A2 and HNF1A mutations partially explain renal glycosuria in patients with T2DM.

Nationwide data on glycemic control, blood pressure (BP) control and lipid control in patients with newly diagnosed type 2 diabetes were vacant in China. The aim of this study was to assess the clinical outcomes for these patients. This is an observational prospective cohort study with 12 months of follow up. Patients with a diagnosis of type 2 diabetes less than 6 months were enrolled. Hemoglobin A1c (HbA1c) levels, BP levels and lipid levels were collected at baseline and the follow-ups. This study was registered at www.clinicaltrials.gov (NCT01525693). A total of 5770 participants from 79 hospitals across six geographic regions of China were recruited. After 12 months of treatment, 68.5% of these patients achieved HbA1c