Overburden of rare ALMS1 deleterious variants in Chinese early-onset type 2 diabetes with severe insulin resistance.

AIMS: Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early-onset type 2 diabetes (age at diagnosis ≤40 years; EOD). MATERIALS AND METHODS: ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre-diabetes and fasting IR. In-silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants. RESULTS: Sixty-two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C-peptide, postprandial C-peptide, and HOMA2-IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin-resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre-diabetes with fasting IR. CONCLUSIONS: ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.

The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Baseline Urine Albumin-to-Creatinine Ratio is Associated With Decline of Estimated Glomerular Filtration Rate in Patients Newly Diagnosed With Type 2 Diabetes Mellitus: An Observational 5-year Cohort Study.

OBJECTIVE: This study aimed to investigate the association between baseline albuminuria and the progression of diabetic kidney disease (DKD) in patients newly diagnosed with type 2 diabetes mellitus (DM). METHODS: A retrospective cohort study was conducted among 604 patients aged ≥18 years who were newly diagnosed with type 2 DM between January 2014 and 31 December 2017 at an outpatient clinic in a tertiary hospital in China. The incidence of albuminuria was determined and the associations between albuminuria at baseline and the progression of DKD estimated by estimated glomerular filtration rate slope were evaluated using binary logistic regression analysis. RESULTS: At diagnosis of type 2 DM, 18.8% of patients had albuminuria, with 17.4% having microalbuminuria and the other 1.4% having macroalbuminuria. During the 5-year follow-up period, patients with albuminuria at the baseline experienced a more rapid decline of estimated glomerular filtration rate over time than patients with normoalbuminuria at baseline (-2.6 vs -1.5 mL/min/1.73 m2 per year, P =.01). Albuminuria at baseline is independently associated with the progression of DKD. CONCLUSIONS: The prevalence of albuminuria is 18.8% in patients newly diagnosed with type 2 diabetes and the occurrence of albuminuria can predict steeper annual decline in kidney function.

Prognostic value of triglyceride glucose index in population at high cardiovascular disease risk.

BACKGROUND: Early identification of populations at high cardiovascular disease (CVD) risk and improvement of risk factors can significantly decrease the probability of CVD development and improve outcomes. Insulin resistance (IR) is a CVD risk factor. The triglyceride glucose (TyG) index is a simple and reliable index for evaluating IR. However, no clinical studies on the prognostic value of the TyG index in a high risk CVD population have been conducted. This study evaluated the relationship between the TyG index and prognosis in a high risk CVD population. METHODS: This study enrolled 35,455 participants aged 35-75 years who were at high CVD risk and visited selected health centers and community service centers between 2017 and 2021. Their general clinical characteristics and baseline blood biochemical indicators were recorded. The TyG index was calculated as ln[fasting triglyceride (mg/dl)× fasting blood glucose (mg/dl)/2]. The endpoints were all-cause death and cardiovascular death during follow-up. Cox proportional hazard models and restricted cubic spline (RCS) analysis were used to evaluate the correlation between the TyG index and endpoints. RESULTS: In the overall study population, the mean age of all participants was 57.9 ± 9.6 years, 40.7% were male, and the mean TyG index was 8.9 ± 0.6. All participants were divided into two groups based on the results of the RCS analysis, with a cut-off value of 9.83. There were 551 all-cause deaths and 180 cardiovascular deaths during a median follow-up time of 3.4 years. In the multivariate Cox proportional hazard model, participants with a TyG index ≥ 9.83 had a higher risk of all-cause death (Hazard ratio [HR] 1.86, 95% Confdence intervals [CI] 1.37-2.51, P<0.001) and cardiovascular death (HR 2.41, 95%CI 1.47-3.96, P = 0.001) than those with a TyG index < 9.83. Subgroup analysis revealed that there was no interaction between the TyG index and variables in all subgroup analyses. CONCLUSIONS: The high TyG index was associated with an increased risk of all-cause death and cardiovascular death in people at high risk of CVD. This finding demonstrates the value of the TyG index in the primary prevention of CVD. TRIAL REGISTRATION: retrospectively registered, the registration number is K2022-01-005 and the date is 2022.01.30.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24 weeks 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. 30 trials assessing PCSK9i among 95, 911 adults were included. There were no significant associations between PCSK9i therapy and the risk of major osteoporotic fracture [OR 1.08 (95% Cl 0.87-1.34), p = 0.49], hip fracture [OR 1.05 (95% Cl 0.73-1.53), p = 0.79], osteoporotic non-vertebral fracture [OR 1.03 (95% Cl 0.80-1.32), p = 0.83], and total fracture [OR 1.03 (95% Cl 0.88-1.19), p = 0.74] over a period of 6-64 months. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term.

The predictive value of the neutrophil/platelet ratio on in-hospital adverse events and long-term prognosis in patients with coronary artery disease after percutaneous coronary intervention and its possible internal mechanism.

The neutrophil-to-platelet ratio (NPR) is considered to be an indicator of inflammatory status. The value of the NPR in predicting in-hospital adverse events (AEs) and long-term prognosis after percutaneous coronary intervention (PCI) in coronary artery disease (CAD) patients has not yet been reported. Meanwhile, the mechanisms behind its predictive value for long-term prognosis remain unreported as well. The study retrospectively enrolled 7284 consecutive patients with CAD undergoing PCI from January 2012 to December 2018. Multivariable logistic regression analysis, multivariable Cox regression analysis, Kaplan‒Meier (KM) curve analysis, restricted cubic spline (RCS) curve analysis, and sensitivity analysis were used in the study. All-cause death was the endpoint of the study. According to the median value of the NPR, the patients were divided into two groups: the high group (NPR ≥ 0.02, n = 3736) and the low group (NPR < 0.02, n = 3548). Multivariate logistic regression analysis demonstrated that a high NPR was a risk factor for in-hospital AEs [odds ratio (OR) = 1.602, 95% CI 1.347-1.909, p = 0.001]. During a mean follow-up period of 3.01 ± 1.49 years, the multivariate Cox regression analysis showed that a high NPR affected the long-term prognosis of patients (HR 1.22, 95% CI 1.03-1.45, p = 0.025) and cardiac death (HR 1.49, 95% CI 1.14-1.95, p = 0.003). The subgroup analysis showed that the NPR was affected by age and sex. The mediation analysis identified that the effect of the NPR on long-term outcomes is partially mediated by serum creatinine (Scr) and triglycerides. The NPR may be a convenient indicator of in-hospital AEs and poor long-term and cardiac outcomes in CAD patients. It might have impacted prognosis through effects on kidney function and lipid metabolism.

Population attributable fractions of modifiable risk factors for microvascular complications of type 2 diabetes in China: An analysis using national cross-sectional data.

AIM: To assess the population attributable fractions (PAFs) for modifiable risk factors for microvascular complications of type 2 diabetes (T2D) in China. MATERIALS AND METHODS: Data collected from the China National HbA1c Surveillance System from 2009 to 2013 were used. The PAFs of four predefined risk factors, including an HbA1c of 7% or higher, blood pressure (BP) of 130/80 mmHg or higher, low-density lipoprotein-cholesterol (LDL-C) of 1.8 mmol/L or higher and body mass index (BMI) of 24 kg/m2 or higher, were calculated for diabetic microvascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN). PAFs were further adjusted for age, sex and duration of diabetes. RESULTS: In total, there were 998 379 participants with T2D from nationwide mainland China included in this analysis. As for DR, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher conferred PAFs of 16.2%, 15.2%, 5.8% and 2.8%, respectively. In the case of DKD, BP of 130/80 mmHg or higher provided a PAF of 25.2%, followed by an HbA1c of 7% or higher (13.9%), BMI of 24 kg/m2 or higher (8.0%) and LDL-C of 1.8 mmol/L or higher (5.6%). As for DSPN, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher contributed to PAFs of 14.2%, 11.7%, 5.9% and 5.8%, respectively. PAFs for diabetic microvascular complications were mildly to moderately reduced after adjusting for participants' age, sex and duration of diabetes. CONCLUSIONS: Suboptimal glycaemic and BP control were the main contributors to diabetic microvascular complications, while the PAFs of unmet LDL-C and BMI control targets were quite limited for diabetic microvascular complications. In addition to glycaemic control, BP control should be especially prioritized in the management of diabetic microvascular complications to further reduce the disease burden.

A variation in SORBS1 is associated with type 2 diabetes and high-density lipoprotein cholesterol in Chinese population.

AIM: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: The variants in the SORBS1 gene were associated with IGR and HDL-c levels but not with DKD in the Chinese Han population.

An Update on Animal Models of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous disorder characterized by bone fragility, multiple fractures, bone deformity, and short stature. In recent years, the application of next generation sequencing has triggered the discovery of many new genetic causes for OI. Until now, more than 25 genetic causes of OI and closely related disorders have been identified. However, the mechanisms of many genes on skeletal fragility in OI are not entirely clear. Animal models of OI could help to understand the cellular, signaling, and metabolic mechanisms contributing to the disease, and how targeting these pathways can provide therapeutic targets. To date, a lot of animal models, mainly mice and zebrafish, have been described with defects in 19 OI-associated genes. In this review, we summarize the known genetic causes and animal models that recapitulate OI with a main focus on engineered mouse and zebrafish models. Additionally, we briefly discuss domestic animals with naturally occurring OI phenotypes. Knowledge of the specific molecular basis of OI will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches.

Association between biologic therapy and fracture incidence in patients with selected rheumatic and autoimmune diseases: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To investigate the effect of biologic therapy on risk of fracture in selected rheumatic and autoimmune diseases. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A novel inflammation-related prognostic biomarker for predicting the disease-free survival of patients with colorectal cancer.

BACKGROUND: To develop and evaluate the prognostic value of a comprehensive inflammatory biomarker for postoperative colorectal cancer (CRC) patients. METHODS: A total of 646 CRC patients were recruited between August 2017 and December 2019 from Fujian Medical University Union Hospital, with follow-up data up to 2021. The least absolute shrinkage and selection operator method (LASSO) was used to select inflammation indicators in order to construct a comprehensive biomarker (named NSAP). The Cox regression model was utilized to analyze the association between the NSAP and the disease-free survival (DFS) of CRC. Predictive performance and clinical utility of prognostic models were evaluated by area under the curve (AUC) and decision curve analyses (DCAs). RESULTS: During a median follow-up of 23 months, 95 clinical outcomes were observed, with a 1-year survival rate is 89.47%. A comprehensive inflammatory biomarker (NSAP) was established based on four blood indicators (including neutrophil-to-lymphocyte ratio (NLR), neutrophil×monocyte-to-lymphocyte ratio (SIRI), albumin-to-globulin ratio (AGR), and platelet-to-lymphocytes ratio (PLR)). Patients with a lower NSAP had significantly associated with better DFS of CRC (HR=0.53, 95%CI 0.32-0.89). Moreover, compared to a previously established model, the traditional TNM staging system or/and tumor markers, the nomogram based on NSAP displayed more excellent predictive ability (0.752 vs 0.597, 0.711 and 0.735, P < 0.05). DCAs also demonstrated that the established nomogram had better utility for decision making. CONCLUSIONS: Our study suggests that NSAP may be a useful comprehensive prognostic biomarker for predicting the DFS of CRC patients. The nomogram based on NSAP can be considered a valuable tool to estimate the prognosis of patients with CRC.

The Effects of Supervised Exercise Training on Weight Control and Other Metabolic Outcomes in Patients With Type 2 Diabetes: A Meta-Analysis.

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 < .01), waist circumference (weighted mean differences, -2.51 cm; 95% CI [-3.25, -1.77], p < .01), and total body fat (weighted mean differences, -1.16%; 95% CI [-1.58%, -0.75%], p < .01). The percentage of total body fat was reduced by all types of exercise, with a significant difference between aerobic exercise and resistance exercise (p = .02) and a significant difference between combined exercise and resistance exercise (p < .01). A higher volume of aerobic exercise and a higher volume of resistance exercise were superior in reducing body weight. In conclusion, supervised exercise training improved metabolic outcomes in general, while different types and volume of exercises have their own merits.

SGLT2 inhibitors and lower limb complications: an updated meta-analysis.

BACKGROUND: To 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. METHODS: Pubmed, Medline, Embase, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were 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. RESULT: The 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 (ß = - 0.461, 95% CI - 0.726 to - 0.197), PAD (ß = - 0.359, 95% CI - 0.545 to - 0.172) and DF (ß = - 0.476, 95% CI - 0.836 to - 0.116). Lower baseline diastolic blood pressure (ß = - 0.528, 95% CI - 0.852 to - 0.205), more systolic blood pressure reduction (ß = - 0.207, 95% CI - 0.390 to - 0.023) and more diastolic blood pressure reduction (ß = - 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. CONCLUSIONS: The 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.

Dipeptidyl peptidase-4 inhibitor treatment and the risk of bullous pemphigoid and skin-related adverse events: A systematic review and meta-analysis of randomized controlled trials.

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: A total of 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 = .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 = .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.

Flash glucose monitoring data analysed by detrended fluctuation function on beta-cell function and diabetes classification.

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 <.001), which was larger than the correlation coefficient between the fasting C-peptide and mean amplitude of plasma glucose excursions (r = -0.639; P < .001), standard deviation (r = -0.649; P <.001), mean blood glucose (r = -0.519; P < .001) and time in range (r = 0.593; P < .001). As glucose data analysed by DFF revealed a clear bimodal distribution among the total participants, we randomly assigned the 137 participants into discovery cohorts (n = 100) and validation cohorts (n = 37) for 10 times to evaluate the consistency and effectiveness of the proposed metric for diabetes classification. The confidence interval for area under the curve according to the receiver operating characteristic analysis in the 10 discovery cohorts achieved (0.846, 0.868) and that for the 10 validation cohorts was (0.799, 0.862). In addition, the confidence intervals for sensitivity and specificity in the discovery cohorts were (75.5%, 83.0%), (81.3%, 88.5%) and (71.8%, 88.3%), (76.5%, 90.3%) in the validation cohorts, indicating the potential capacity of DFF in distinguishing type 1 and type 2 diabetes. CONCLUSIONS: Our study first proposed the possible role of data-driven analysis acquired glucose metric in predicting beta-cell function and diabetes classification, and a large-scale, multicentre study will be needed in the future.

Association of meat consumption with NAFLD risk and liver-related biochemical indexes in older Chinese: a cross-sectional study.

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 < 0.001; 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 < 0.001; rs = 0.128; P < 0.001; 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.

A case report of pseudohypoaldosteronism type II with a homozygous KLHL3 variant accompanied by hyperthyroidism.

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.

The Biological Disease-Modifying Antirheumatic Drugs and the Risk of Cardiovascular Events: A Systematic Review and Meta-Analysis.

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.

Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus.

BACKGROUND: The 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. METHODS: Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for 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. RESULTS: Significantly 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 (ß = - 0.01, 95% CI, - 0.02 to - 0.01, P < 0.01) and longer diabetes duration (ß = - 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 (ß = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (ß = 0.01, 95% CI, 0.22 × 10-2, 0.01, P < 0.01), higher baseline BMI (ß = - 0.02, 95% CI, - 0.04 to - 0.26 × 10-2, P = 0.02), and higher baseline HbA1c (ß = - 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 (ß = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. CONCLUSION: The 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.

The association between the biological disease-modifying anti-rheumatic drugs and the incidence of diabetes: A systematic review and meta-analysis.

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.