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.

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.

The efficacy of canagliflozin in diabetes subgroups stratified by data-driven clustering or a supervised machine learning method: a post hoc analysis of canagliflozin clinical trial data.

AIMS/HYPOTHESIS: Data-driven diabetes subgroups have shown distinct clinical characteristics and disease progression, although there is a lack of evidence that this information can guide clinical decisions. We aimed to investigate whether diabetes subgroups, identified by data-driven clustering or supervised machine learning methods, respond differently to canagliflozin. METHODS: We pooled data from five randomised, double-blinded clinical trials of canagliflozin at an individual level. We applied the coordinates from the All New Diabetics in Scania (ANDIS) study to form four subgroups: mild age-related diabetes (MARD); severe insulin-deficient diabetes (SIDD); mild obesity-related diabetes (MOD) and severe insulin-resistant diabetes (SIRD). Machine learning models for HbA1c lowering (ML-A1C) and albuminuria progression (ML-ACR) were developed. The primary efficacy endpoint was reduction in HbA1c at 52 weeks. Concordance of a model was defined as the difference between predicted HbA1c and actual HbA1c decline less than 3.28 mmol/mol (0.3%). RESULTS: The decline in HbA1c resulting from treatment was different among the four diabetes clusters (pinteraction=0.004). In MOD, canagliflozin showed a robust glucose-lowering effect at week 52, compared with other drugs, with least-squares mean of HbA1c decline [95% CI] being 6.6 mmol/mol (4.1, 9.2) (0.61% [0.38, 0.84]) for sitagliptin, 7.1 mmol/mol (4.7, 9.5) (0.65% [0.43, 0.87]) for glimepiride, and 9.8 mmol/mol (9.0, 10.5) (0.90% [0.83, 0.96]) for canagliflozin. This superiority persisted until 104 weeks. The proportion of individuals who achieved HbA1c <53 mmol/mol (<7.0%) was highest in sitagliptin-treated individuals with MARD but was similar among drugs in individuals with MOD. The ML-A1C model and the cluster algorithm showed a similar concordance rate in predicting HbA1c lowering (31.5% vs 31.4%, p=0.996). Individuals were divided into high-risk and low-risk groups using ML-ACR model according to their predicted progression risk for albuminuria. The effect of canagliflozin vs placebo on albuminuria progression differed significantly between the high-risk (HR 0.67 [95% CI 0.57, 0.80]) and low-risk groups (HR 0.91 [0.75, 1.11]) (pinteraction=0.016). CONCLUSIONS/INTERPRETATION: Data-driven clusters of individuals with diabetes showed different responses to canagliflozin in glucose lowering but not renal outcome prevention. Canagliflozin reduced the risk of albumin progression in high-risk individuals identified by supervised machine learning. Further studies with larger sample sizes for external replication and subtype-specific clinical trials are necessary to determine the clinical utility of these stratification strategies in sodium-glucose cotransporter 2 inhibitor treatment. DATA AVAILABILITY: The application for the clinical trial data source is available on the YODA website ( http://yoda.yale.edu/ ).

Metagenomic analysis reveals crosstalk between gut microbiota and glucose-lowering drugs targeting the gastrointestinal tract in Chinese patients with type 2 diabetes: a 6 month, two-arm randomised trial.

AIMS/HYPOTHESIS: The use of oral glucose-lowering drugs, particularly those designed to target the gut ecosystem, is often observed in association with altered gut microbial composition or functional capacity in individuals with type 2 diabetes. The gut microbiota, in turn, plays crucial roles in the modulation of drug efficacy. We aimed to assess the impacts of acarbose and vildagliptin on human gut microbiota and the relationships between pre-treatment gut microbiota and therapeutic responses. METHODS: This was a randomised, open-labelled, two-arm trial in treatment-naive type 2 diabetes patients conducted in Beijing between December 2016 and December 2017. One hundred participants with overweight/obesity and newly diagnosed type 2 diabetes were recruited from the Pinggu Hospital and randomly assigned to the acarbose (n=50) or vildagliptin (n=50) group using sealed envelopes. The treatment period was 6 months. Blood, faecal samples and visceral fat data from computed tomography images were collected before and after treatments to measure therapeutic outcomes and gut microbiota. Metagenomic datasets from a previous type 2 diabetes cohort receiving acarbose or glipizide for 3 months were downloaded and processed. Statistical analyses were applied to identify the treatment-related changes in clinical variables, gut microbiota and associations. RESULTS: Ninety-two participants were analysed. After 6 months of acarbose (n=44) or vildagliptin (n=48) monotherapy, both groups achieved significant reductions in HbA1c (from 60 to 46 mmol/mol [from 7.65% to 6.40%] in the acarbose group and from 59 to 44 mmol/mol [from 7.55% to 6.20%] in the vildagliptin group) and visceral fat areas (all adjusted p values for pre-post comparisons <0.05). Both arms showed drug-specific and shared changes in relative abundances of multiple gut microbial species and pathways, especially the common reductions in Bacteroidetes species. Three months and 6 months of acarbose-induced changes in microbial composition were highly similar in type 2 diabetes patients from the two independent studies. Vildagliptin treatment significantly enhanced fasting active glucagon-like peptide-1 (GLP-1) levels. Baseline gut microbiota, rather than baseline GLP-1 levels, were strongly associated with GLP-1 response to vildagliptin, and to a lesser extent with GLP-1 response to acarbose. CONCLUSIONS/INTERPRETATION: This study reveals common microbial responses in type 2 diabetes patients treated with two glucose-lowering drugs targeting the gut differently and acceptable performance of baseline gut microbiota in classifying individuals with different GLP-1 responses to vildagliptin. Our findings highlight bidirectional interactions between gut microbiota and glucose-lowering drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02999841 FUNDING: National Key Research and Development Project: 2016YFC1304901.

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.

Clinical evaluation of an automated TSI bridge immunoassay in the diagnosis of Graves' disease and its relationship to the degree of hyperthyroidism.

BACKGROUND: The rapid and accurate detection of thyroid-stimulating hormone (TSH) receptor antibodies has always been an urgent need for the clinical diagnosis and management of Graves' disease (GD). We aimed to evaluate the use of an automated thyroid-stimulating immunoglobulin (TSI) bridge immunoassay in the diagnosis of GD and to analyze the relationship between TSI and the degree of hyperthyroidism. METHODS: A total of 227 new-onset GD patients, 29 Hashimoto thyroiditis, 43 non-autoimmune thyroid diseases and 37 euthyroid controls were consecutively recruited. All participants accepted the measurement of their serum thyroid function and thyroid-associated antibodies, including TSI being measured by an Immulite 2000 bridge immunoassay and TSH receptor autoantibodies (TRAb) being measured by a third-generation Roche electrochemiluminescence immunoassay. The quantitative consistency between the TSI and TRAb detection methods was analyzed by using Passing-Bablok regression and Bland-Altman plots. The diagnostic performance for GD was assessed by receiver operating characteristic (ROC) curve analysis. RESULTS: Among 227 GD patients (174 females and 53 males, with a mean age of 39 years), the quantitative TSI was positively correlated with TRAb (r = 0.8099). According to the cut-off values proposed by the manufacturers (TSI: 0.55 IU/L, TRAb: 1.75 IU/L), the positive rates of TSI and TRAb in new-onset GD patients were 96.92% and 95.15%, respectively. Both TSI and TRAb levels positively correlated with FT4 levels (TSI: r = 0.243, TRAb: r = 0.317; all P < 0.001) and FT3 levels (TSI: r = 0.288, TRAb: r = 0.360; all P < 0.001) in new-onset GD patients. The ROC analysis showed that the optimal TSI cut-off value was 0.577 IU/L for GD diagnosis in this Chinese population, with a sensitivity of 96.92% and a specificity of 97.25%, respectively. The optimal TRAb cut-off value of was 1.38 IU/L, with a sensitivity of 96.92% and a specificity of 99.08%. There were no significant differences between the cut-off values obtained through the ROC analysis and those provided by the manufacturer for both TSI and TRAb when calculating their sensitivity and specificity in diagnosing GD. Among the 8 newly diagnosed GD cases with discordant qualitative antibody results, TSI was more likely than TRAb to match the clinical diagnosis of GD (6 TSI-positive vs. 2 TRAb-positive patients). CONCLUSION: The automated TSI bridge immunoassay was positively correlated with thyroxine levels in new-onset GD patients and was more likely to be consistent with the clinical diagnosis of GD than with that of TRAb. The positive Immulite 2000 TSI cut-off value of 0.577 IU/L for GD diagnosis in the Chinese population were close to the value recommended by the manufacturer.

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.

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.

Factors Associated with Acute Complications among Individuals with Type 1 Diabetes in China: The 3C Study.

Background: To identify the sociodemographic and clinical characteristics related to the occurrence of diabetic ketoacidosis (DKA) and frequent hypoglycemia in children, adolescents and adults with type 1 diabetes in China.Methods: The 3C Study was an epidemiological study that recruited 849 type 1 diabetes patients aged 0-78 years in Beijing and Shantou, China. Separate logistic regression models were used to evaluate the association of sociodemographic and clinical factors with the occurrence of DKA in the past 12 months or frequent hypoglycemia (≥5 episodes) in the past 7 days.Results: Children and adolescents were significantly more likely to have DKA in the past 12 months compared to adults: odds ratio (OR) and (95% confidence interval [CI]), 4.67 (1.90, 11.52) for <13 years and 4.00 (1.59, 10.10) for 13 to <19 years. Underweight participants were also more likely to have DKA relative to normal weight participants: OR (95% CI), 6.87 (2.64, 17.87). Children and participants who did not receive diabetes education in the past 12 months were more likely to have frequent hypoglycemia: OR (95% CI), 2.95 (1.23, 7.06) and 7.67 (1.77, 13.2), respectively. Participants who reported self-monitoring of blood glucose ≤2 times/week (ref: 7 times/week) and participants who had higher HbA1c levels were less likely to have frequent hypoglycemia: OR (95% CI), 0.14 (0.03, 0.64) and 0.78 (0.63, 0.96), respectively. Gender, family income, parent education, health insurance coverage, diabetes duration, and insulin administration method were not significantly associated with DKA or frequent hypoglycemia in this sample.Conclusions: Children, adolescents and underweight individuals with type 1 diabetes in China were more likely to report DKA, and children, individuals without adequate diabetes education, and those with lower HbA1c levels were more likely to have frequent hypoglycemia. These patients should be targeted for preventive interventions.

A new clinical screening strategy and prevalence estimation for glucokinase variant-induced diabetes in an adult Chinese population.

PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association between serum thyrotropin within the euthyroid range and obesity.

The relationship between variations in thyroid function and indices of obesity remains a focus of debate. To explore the associations between thyroid function within the normal range and obesity and to evaluate potential modifying factors, we analyzed a large and well-characterized community cohort in Beijing, China, containing 1,816 men and 1,774 women with serum thyrotropin (TSH) levels within the reference range (0.55-4.78 µIU/mL). Associations between TSH levels and BMI were identified using correlation analysis, ANOVA and Chi-square tests. Logistic regression analyses were used to estimate the impact of serum TSH on obesity before and after adjustment for possible confounding factors. The mean serum TSH was 2.04 ± 0.94 µIU/mL. TSH within the reference range was positively associated with BMI in both genders. Compared with euthyroid adults whose TSH was in the middle quartiles (TSH 1.30-2.60 µIU/mL) of the reference range, the odds of obesity (BMI ≥ 28.0 kg/m2) and severe obesity (BMI ≥ 33.0 kg/m2) was 38% (OR = 1.38, 95% CI 1.17-1.64) and 58% (OR = 1.58, 95% CI 1.12-2.21) more likely, respectively, among those with TSH in the upper quartile. For women, postmenopausal subjects with lower TSH levels had a lower risk of severe obesity (OR = 0.42, 95% CI 0.20-0.91) than those in the middle TSH quartile. Positive associations were found between serum TSH within the euthyroid range and obesity, and menopause showed a significant influence on the relationship between TSH level and severe obesity.

DPP-4 inhibitors and risk of infections: a meta-analysis of randomized controlled trials.

BACKGROUND: To evaluate the risk of infections in the treatment of type 2 diabetes patients with dipeptidyl-peptidase 4 (DPP-4) inhibitors. METHODS: A literature search was conducted through electronic databases. The inclusion criteria included study duration of no less than 12 weeks developed in type 2 diabetes patients, the use of a randomized control group receiving a DPP-4 inhibitor and the availability of outcome data for infections. Out of 2181 studies, 74 studies were finally included. RESULTS: The risk of overall infection for DPP-4 inhibitors treatment was comparable to placebo (odds ratio (OR) = 0.97, 95% confidence interval (CI), 0.91 to 1.04, p = 0.40), metformin treatment (OR = 1.22, 95% CI, 0.95 to 1.56, p = 0.12), sulphonylurea treatment (OR = 1.09, 0.93 to 1.29, p = 0.29), thiazolidinedione treatment (OR = 0.86, 95% CI, 0.65 to 1.14, p = 0.29) and alpha glucosidase inhibitor treatment (OR = 1.03, 95% CI, 0.33 to 3.22, p = 0.96). When compared different DPP-4 inhibitors with placebo treatment, risks of infections were comparable for alogliptin, linagliptin, sitagliptin, saxagliptin and vildagliptin. Compared with placebo or active comparator treatment, risks of infection in different systems for DPP-4 inhibitors were all comparable. CONCLUSIONS: The overall risk of infections of DPP-4 inhibitor was not increased compared with control groups.

Impact of variants of the EXT2 gene on Type 2 diabetes and its related traits in the Chinese han population.

PURPOSE/AIM OF THE STUDY: Exostosin 2 (EXT2) is involved in early pancreatic development and the regulation of insulin synthesis. In this study, we aim to evaluate the contribution of EXT2 to the genetic pathogenesis of type 2 diabetes and its related traits in the Chinese population. MATERIALS AND METHODS: A case-control study in a Chinese Han population was conducted that included 4766 patients with type 2 diabetes and 4596 control subjects from 14 different regions of China. Three single nucleotide polymorphism (SNP), rs3740878, rs11037909 and rs1113132, in the EXT2 gene were genotyped using the Illumina GoldenGate Genotyping assay. RESULTS: After adjusting for sex, age and body mass index, logistic regression analysis revealed that the EXT2 gene had no association with type 2 diabetes using an additive genetic model [rs3740878 (Odds Ratio (OR) = 0.996, 95% confidence interval (CI) 0.928-1.069, p = 0.910), rs11037909 (OR = 1.003, 95%CI 0.933-1.078, p = 0.931), and rs1113132 (OR = 0.993, 95% CI 0.925-1.065, p = 0.842)]. None of these SNPs were associated with beta cell function as determined using the baseline disposition index, early phase insulin secretion and Oral Glucose Tolerance Test (OGTT) total disposition index. CONCLUSIONS: Our study suggests that the EXT2 gene might not have a major role in the development of type 2 diabetes in the Chinese population.

Search for genetic determinants of sulfonylurea efficacy in type 2 diabetic patients from China.

AIMS/HYPOTHESIS: The aim of this study was to investigate whether genetic variance can influence the efficacy of glibenclamide in patients with type 2 diabetes. METHODS: A total of 747 patients with type 2 diabetes was enrolled from the Xiaoke Pills Clinical Trial, which is a double-blind, randomised controlled trial. All the patients had been treated with glibenclamide for 48 weeks, with strict drug dose adjustment and data collection. Treatment failure was confirmed when patients reached the criteria for terminating their participation in the study (fasting blood glucose level ≥ 7.0 mmol/l on two consecutive tests 4 weeks after reaching the pre-set maximal dose or maximal tolerated dose). Using this cohort, we tested 44 single-nucleotide polymorphisms (SNPs) in 27 gene regions. The genes in our study were involved in the metabolism of sulfonylureas, islet beta cell function, insulin resistance and beta cell growth and differentiation. A logistic regression model was used to evaluate the relationship between genetic variants and treatment failure over a period of 48 weeks. RESULTS: We found that no SNP reached the significance level of p < 0.00125 if Bonferroni correction was performed for multiple testing in the logistic regression model used in this pharmacogenetic study. Participants with the minor allele C of rs10811661 in CDKN2A/CDKN2B showed a significantly greater reduction in fasting blood glucose (TT vs TC vs CC: 9.3% (0-20.0%) vs 9.2% (0.9-20.5%) vs 12.7% (5.2-24.4%), p = 0.008) after the initial 4 weeks of treatment independent of age, sex and BMI. There was a significant difference in beta cell function among carriers of different genotypes of rs10811661. CONCLUSIONS/INTERPRETATION: Our study demonstrated that the CDKN2A/CDKN2B gene may be nominally associated with the efficacy of glibenclamide, and that CDKN2A/CDKN2B is associated with beta cell function.

CDK1 switches mitotic arrest to apoptosis by phosphorylating Bcl-2/Bax family proteins during treatment with microtubule interfering agents.

Microtubule interfering agents (MIAs), that can stabilise or depolymerise microtubules, are an important class of cancer chemotherapeutic drugs. They can lead to mitotic arrest and subsequent apoptosis. We demonstrate that cell cycle-dependent kinase 1 (CDK1) is important in switching cells from mitotic arrest to apoptosis during MIAs treatment. Overexpression of non-degradable cyclin B1 sustained CDK1 activation and mitotic arrest, followed by caspase-3 dependent apoptosis. CDK1 is responsible for the phosphorylation of several pro- and anti-apoptotic Bcl-2 family proteins during MIAs treatment. CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis. Blockage of CDK1 activity with a specific pharmacological inhibitor suppresses Mcl-1 phosphorylation, degradation and its anti-apoptotic function. Therefore, the death of cancer cells under MIAs treatment was caused by imbalance between CDK1-induced alterations in the pro-apoptotic and anti-apoptotic functions of phosphorylated Bcl-2 family proteins.

Hypoglycemic Response to Dorzagliatin in a Patient With GCK-MODY.

OBJECTIVE: Metformin, insulin, and insulin secretagogues do not alter HbA1c levels in glucokinase maturity-onset diabetes of the young (GCK-MODY). However, the efficacy of the new hypoglycemic drugs on GCK-MODY remains unclear. RESEARCH DESIGN AND METHODS: We describe a case of GCK-MODY with unchanged blood glucose under different therapies during an 8 years' follow-up. His HbA1c and biochemical indices under different hypoglycemic treatments were recorded. RESULTS: Oral glucose-lowering drugs, including thiazolidinediones, dipeptidyl peptidase 4 inhibitor, α-glucosidase inhibitor, and sodium-glucose cotransporter 2 inhibitor that had not been evaluated previously, did not improve the HbA1c level in this patient. However, the glucokinase activator dorzagliatin effectively and safely lowered his HbA1c level. CONCLUSIONS: Dorzagliatin was effective and safe in this patient with GCK-MODY, providing potential application prospects for precise treatment of GCK-MODY with dorzagliatin.

Primary aldosteronism and obstructive sleep apnea: A meta-analysis of prevalence and metabolic characteristics.

BACKGROUND: Primary aldosteronism (PA) and obstructive sleep apnea (OSA) are both causes for resistant hypertension and contribute to adverse cardiovascular outcome. However, the association of these two disorders remains to be investigated. We conducted this meta-analysis to estimate the prevalence and metabolic characteristics of the coexistence of PA and OSA. METHODS: The databases of MEDLINE, EMBASE and Cochrane Reviews were searched for studies investigating the prevalence or clinical characteristics of PA and OSA until Jan 2023. Single proportions of PA and OSA were meta-analyzed for pooled prevalence and 95% confidence intervals (CIs). Odds ratios (ORs) and 95% CIs were calculated for the comparison of the prevalence. Mean differences (MDs) and 95% CIs were calculated for comparisons of the characteristics between patients with both OSA and PA and control groups. RESULTS: A total of 16 studies were included. The pooled prevalence of PA was 27% (95% CI = 24-29%) in all patients with OSA (n = 3498). The prevalence of PA in patients with OSA was significantly higher than that in the patients without OSA (OR = 2.03, 95% CI = 1.30, 3.16, p = 0.002). The pooled prevalence (95% CI) of OSA was 46% (39-54%) in patients with PA (n = 2335). Compared with the hypertensive patients without PA, the prevalence of OSA in the patients with PA was significantly higher (OR = 2.01, 95% CI = 1.37, 2.95, p < 0.001). Compared with the patients of control groups, the patients with both PA and OSA had higher blood pressure and body mass index (BMI). CONCLUSION: Screening for the coexistence of PA and OSA was warranted.

Predictive value of postprandial C-peptide for utilizing multiple daily injection therapy in type 2 diabetes.

PURPOSE: Multiple daily injection (MDI) insulin therapy is an effective method of glycemic control and appropriate assignment to MDI therapy could minimize the risks of hypoglycemia and weight gain. The aim of the present study was to identify factors associated with indication for MDI therapy in type 2 diabetes (T2DM). METHODS: We recruited 360 participants with T2DM that were admitted to the Endocrinology Department of Peking University People's Hospital between August 2017 and July 2018. They first underwent intensive insulin therapy, then were switched to an optimized, simpler insulin treatment that aimed to maintain fasting blood glucose between 4.4 and 7.2 mmol/L, without episodes of hypoglycemia. The baseline characteristics of groups administering either MDI or basal/premix insulin were compared and multivariable logistic regression analysis was used to determine the odds ratios (ORs) for factors associated with MDI therapy. Receiver operating characteristic (ROC) curves were then used to identify independent predictors of MDI insulin regimen efficacy. RESULTS: The mean age of the participants was 57.6 ± 12.9 years, and diabetes duration was 14.2 ± 8.2 years. Two hundred and sixty-seven participants administered basal/premix insulin and 93 underwent MDI therapy, of whom 61.8% and 46.2% were male, respectively (p = 0.01). The duration of diabetes was significantly longer in the MDI group (13.1 ± 7.7 years vs. 17.3 ± 8.7 years; p < 0.01). Fasting plasma glucose (FPG) was higher in the MDI group than in the basal/premix group (8.3 [6.7, 11.3] mmol/L vs. 7.2 [5.7, 9.3] mmol/L; p < 0.01), while the postprandial C-peptide concentration (PCP) was significantly lower in the MDI group (2.6 [1.8, 3.5] ng/mL) compared to the basal/premix group (3.6 [2.5, 6.2] ng/mL, p < 0.01. Multivariable logistic regression analysis suggested that diabetes duration and FPG were positively associated with MDI therapy: OR (95% confidence interval [CI]) 1.06 (1.02, 1.10) and 1.12 (1.02, 1.24), respectively. In addition, PCP was negatively associated with MDI therapy (0.72 [0.60, 0.86]). ROC analysis suggested that a PCP of < 3.1 ng/mL predicted MDI therapy with 59.6% sensitivity and 72.1% specificity. CONCLUSION: The results of our study suggest that longer diabetes duration, higher FPG, and lower PCP were associated with necessity for MDI insulin regimen. These findings should assist with the personalization of insulin treatment.

Adrenal limb thickness is associated with metabolism profiles in patients with diabetes: A cross-sectional study.

BACKGROUND: The association between adrenal size and metabolic profiles in patients with diabetes mellitus (DM) is unclear. This study was conducted to determine whether the adrenal thickness measured by computed tomography (CT) is correlated with the metabolic profiles of patients with DM. METHODS: This was a cross-sectional study including 588 Chinese hospitalized patients with DM without comorbidities or medications known to affect adrenal morphology or hormone secretion. Adrenal limb thickness was measured on unenhanced chest CT. Participants were stratified into tertiles according to their total adrenal limb thickness. Linear and logistic regression models were used to estimate the correlations. RESULTS: After adjustment for sex and age, the adrenal thickness was positively associated with body mass index (BMI), waist circumference (WC), urinary albumin/creatinine ratio, and 24-h urinary free cortisol (UFC) and negatively correlated with high-density lipoprotein cholesterol. The sequential equation model (SEM) suggested UFC partially mediated the effect of adrenal limb thickness on WC by 12%. Adrenal thickness, but not UFC, was associated with a higher risk of existing hypertension (odds ratio [OR] = 3.78, 95% confidence interval [CI] 1.58, 9.02) and hyperlipidemia (OR = 2.76, 95% CI 1.03, 7.38), independent of age, gender, BMI, and WC. CONCLUSIONS: The adrenal thickness is independently associated with BMI, WC, cortisol levels, urinary albumin/creatinine ratio, hypertension, and dyslipidemia but not glycemic parameters in patients with diabetes. Our study encourages further studies to investigate the role of adrenal physiology in patients with diabetes.