Phenotypic features, prevalence of KCNJ11-MODY in Chinese patients with early-onset diabetes and a literature review.

OBJECTIVE: Gain-of-function (GOF) variants of KCNJ11 cause neonate diabetes and maturity-onset diabetes of the young (KCNJ11-MODY), while loss-of-function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11-MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early-onset type 2 diabetes (EOD). DESIGN, PATIENTS AND MEASUREMENTS: We performed next-generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11-MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11-MODY. RESULTS: We identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11-MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C-peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed. CONCLUSIONS: Some rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11-MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11-MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.

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.

Differential effect of interventions in patients with prediabetes stratified by a machine learning-based diabetes progression prediction model.

AIM: To investigate whether stratifying participants with prediabetes according to their diabetes progression risks (PR) could affect their responses to interventions. METHODS: We developed a machine learning-based model to predict the 1-year diabetes PR (ML-PR) with the least predictors. The model was developed and internally validated in participants with prediabetes in the Pinggu Study (a prospective population-based survey in suburban Beijing; n = 622). Patients from the Beijing Prediabetes Reversion Program cohort (a multicentre randomized control trial to evaluate the efficacy of lifestyle and/or pioglitazone on prediabetes reversion; n = 1936) were stratified to low-, medium- and high-risk groups using ML-PR. Different effect of four interventions within subgroups on prediabetes reversal and diabetes progression was assessed. RESULTS: Using least predictors including fasting plasma glucose, 2-h postprandial glucose after 75 g glucose administration, glycated haemoglobin, high-density lipoprotein cholesterol and triglycerides, and the ML algorithm XGBoost, ML-PR successfully predicted the 1-year progression of participants with prediabetes in the Pinggu study [internal area under the curve of the receiver operating characteristic curve 0.80 (0.72-0.89)] and Beijing Prediabetes Reversion Program [external area under the curve of the receiver operating characteristic curve 0.80 (0.74-0.86)]. In the high-risk group pioglitazone plus intensive lifestyle therapy significantly reduced diabetes progression by about 50% at year l and the end of the trial in the high-risk group compared with conventional lifestyle therapy with placebo. In the medium- or low-risk group, intensified lifestyle therapy, pioglitazone or their combination did not show any benefit on diabetes progression and prediabetes reversion. CONCLUSIONS: This study suggests personalized treatment for prediabetes according to their PR is necessary. ML-PR model with simple clinical variables may facilitate personal treatment strategies in participants with prediabetes.

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.

Association Between Non-Alcoholic Fatty Liver Disease and Diabetes-Related Microvascular Complications: A Retrospective Cross-Sectional Study of Hospitalized Patients.

OBJECTIVE: Owing to limited research, the effect of nonalcoholic fatty liver disease (NAFLD) on type 2 diabetes outcomes remains unclear. This study aimed to investigate the association between NAFLD and microvascular complications in hospitalized patients with type 2 diabetes. METHODS: We included 1982 patients with type 2 diabetes. NAFLD was defined as hepatic steatosis detected by ultrasound without secondary causes of fat accumulation. The diagnosis of diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic neuropathy was based on clinical medical records. Risk for advanced liver fibrosis was categorized as "low risk," "indeterminate risk," and "high risk," based on the NAFLD fibrosis score (NAFLD-FS). Logistic regression was used to test the association between NAFLD, risk for advanced fibrosis, and the presence of DR, DKD, and diabetic neuropathy. RESULTS: The prevalence of NAFLD was 61.3%. The presence of DR and DKD was inversely associated with NAFLD, after adjusting for covariates. The presence of DR and DKD was higher in the "indeterminate risk" and "high risk" groups than in the "low risk" group, after adjusting for the same covariates. Only the presence of DKD significantly increased with high NAFLD-FS. CONCLUSION: The presence of DR and DKD was inversely associated with NAFLD among hospitalized patients with type 2 diabetes. DKD was closely associated with high NAFLD-FS among patients with NAFLD.

Hb broomhill [α1 or α2 114(GH2) pro > ala;HBA1 or HBA2:c.343C > G]: a rare Hb variant found in a diabetic chinese individual.

We report a clinically silent hemoglobin (Hb) variant, Hb Broomhill [α1 or α2 114(GH2) Pro > Ala;HBA1 or HBA2:c.343C > G] in a diabetic Chinese man. The Hb fractions of the subject were analyzed using various chromatographic and electrophoretic techniques. The glycated hemoglobin (HbA1c) levels measured using cation-exchange high-performance liquid chromatography (CE-HPLC) and the boronate affinity method showed nearly identical results. Analysis of the chromatogram of the CE-HPLC revealed an abnormal shoulder peak that appeared towards the end of the elution profile. Though the capillary electrophoresis method did not interpret the results, a manual examination revealed an abnormal shoulder on the HbA0 peak. Similarly, the electropherogram of the capillary zone electrophoresis also had an abnormal shoulder on the HbA peak. A missense mutation specific to the Hb Broomhill variant was found using Sanger sequencing.

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.

Independent markers of nonalcoholic fatty liver disease in a gentrifying population-based Chinese cohort.

BACKGROUND: Prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in developing countries, but its causes are not known. We aimed to ascertain the prevalence and determinants of NAFLD in a new largely unmedicated population-based cohort from the rapidly gentrifying region of Pinggu, China. METHODS: We randomized cluster sampled 4002 Pinggu residents aged 26 to 76 years. Data from 1238 men and 1928 women without significant alcohol drinking or hepatitis virus B or C infection were analysed. NAFLD was defined using a liver-spleen ratio (L/S ratio) ≤1.1 on unenhanced abdominal computed tomography (CT) scanning. RESULTS: Of men and women, 26.5% and 20.1%, respectively, had NAFLD. NAFLD prevalence was highest in younger men and older women. In multivariate logistic regression models, higher body mass index, waist circumference, serum triglyceride, alanine transaminase, and haemoglobin A1c independently increased the odds of NAFLD in both men and women separately. Higher annual household income and systolic blood pressure for men and higher serum uric acid and red meat intake and lower physical activity levels for women also independently associated with higher odds of NAFLD. Individuals with L/S ratio ≤1.1 had linearly increasing rates of obesity, diabetes, and metabolic syndrome that paralleled fatty liver increase. CONCLUSIONS: NAFLD is common in a gentrifying Chinese population particularly in younger men of high socioeconomic status and older women with sedentary behaviour who eat red meat. Demographic factors add independent risk of NAFLD above traditional metabolic risk factors. A CT L/S ratio of ≤1.1 identifies individuals at high risk of metabolic disease.

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.

Susceptibility loci for metabolic syndrome and metabolic components identified in Han Chinese: a multi-stage genome-wide association study.

Metabolic syndrome (MetS), a cluster of metabolic disturbances that increase the risk for cardiovascular disease and diabetes, was because of genetic susceptibility and environmental risk factors. To identify the genetic variants associated with MetS and metabolic components, we conducted a genome-wide association study followed by replications in totally 12,720 participants from the north, north-eastern and eastern China. In combined analyses, independent of the top known signal at rs651821 on APOA5, we newly identified a secondary triglyceride-associated signal at rs180326 on BUD13 (Pcombined = 2.4 × 10-8 ). Notably, by an integrated analysis of the genotypes and the serum levels of APOA5, BUD13 and triglyceride, we observed that BUD13 was another potential mediator, besides APOA5, of the association between rs651821 and serum triglyceride. rs671 (ALDH2), an east Asian-specific common variant, was found to be associated with MetS (Pcombined = 9.7 × 10-22 ) in Han Chinese. The effects of rs671 on metabolic components were more prominent in drinkers than in non-drinkers. The replicated loci provided information on the genetic basis and mechanisms of MetS and metabolic components in Han Chinese.

Association between frequency of self-monitoring of blood glucose and glycemic control in patients with type 2 diabetes.

AIM: To determine the association between the frequency of self-monitoring of blood glucose (SMBG) and glycemic control in patients with type 2 diabetes. METHODS: The retrospective study analyzed data from 3,630 patients with type 2 diabetes who were enrolled between August 2020 and July 2021. 2456 non-insulin-treated patients were divided into SMBG ≤ 6 times/week and > 6 times/week groups. 1174 insulin-treated patients were divided into SMBG ≤ 9 times/week and > 9 times/week groups. Propensity score matching was used to generate groups with well-balanced covariates. Primary outcomes were changes in fasting blood glucose (FBG) and postprandial blood glucose (PBG) from baseline to 6 months. RESULTS: In the non-insulin-treated group, a comparison in FBG and PBG reduction between the SMBG > 6 times/week and ≤ 6 times/week groups was statistically significant (-0.59 vs. -0.18 mmol/l, P < 0.001; -0.91 vs. -0.36 mmol/l, P < 0.001). In the insulin-treated group, there was no statistically significant reduction in FBG or PBG, patients with baseline FBG > 8 or 9 mmol/l and SMBG > 9 times/week had a significant FBG reduction than the ≤ 9 times/week group. CONCLUSION: Frequent SMBG was associated with better glycemic control in non-insulin-treated patients. Insulin-treated patients with poor glycemic control may benefit from frequent SMBG.

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.

Clinical and genetic characteristics of CEL-MODY (MODY8): a literature review and screening in Chinese individuals diagnosed with early-onset type 2 diabetes.

OBJECTIVE: CEL-related maturity-onset diabetes of the young (CEL-MODY, MODY8) is a special type of monogenetic diabetes caused by mutations in the carboxyl-ester lipase (CEL) gene. This study aimed to summarize the genetic and clinical characteristics of CEL-MODY patients and to determine the prevalence of the disease among Chinese patients with early-onset type 2 diabetes (EOD). METHODS: We systematically reviewed the literature associated with CEL-MODY in PubMed, Embase, Web of Science, China National Knowledge Infrastructure and Wanfang Data to analyze the features of patients with CEL-MODY. We screened and evaluated rare variants of the CEL gene in a cohort of 679 Chinese patients with EOD to estimate the prevalence of CEL-MODY in China. RESULTS: In total, 21 individuals reported in previous studies were diagnosed with CEL-MODY based on the combination of diabetes and pancreatic exocrine dysfunction as well as frameshift mutations in exon 11 of the CEL gene. CEL-MODY patients were nonobese and presented with exocrine pancreatic affection (e.g., chronic pancreatitis, low fecal elastase levels, pancreas atrophy and lipomatosis) followed by insulin-dependent diabetes. No carriers of CEL missense mutations were reported with exocrine pancreatic dysfunction. Sequencing of CEL in Chinese EOD patients led to the identification of the variant p.Val736Cysfs*22 in two patients. However, these patients could not be diagnosed with CEL-MODY because there were no signs that the exocrine pancreas was afflicted. CONCLUSION: CEL-MODY is a very rare disease caused by frameshift mutations affecting the proximal VNTR segments of the CEL gene. Signs of exocrine pancreatic dysfunction provide diagnostic clues for CEL-MODY, and genetic testing is vital for proper diagnosis. Further research in larger cohorts is needed to investigate the characteristics and prevalence of CEL-MODY in the Chinese population.

Association between remnant cholesterol level and severity of chronic kidney disease in patients with type 2 diabetes.

BACKGROUND: Studies on whether remnant cholesterol (RC) affects the progression of chronic kidney disease (CKD) remain insufficient. This study aimed to determine whether RC level was associated with the severity of CKD in patients with type 2 diabetes mellitus (T2DM). METHODS: In total, 3383 individuals diagnosed with T2DM were enrolled in this cross-sectional study from China. The severity of CKD was defined as no, moderate, severe, and very severe CKD based on the urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. Because RC was non-normally distributed, it was log-transformed and categorized into quantiles. Multivariate logistic regression and multivariate ordinal logistic regression analysis were performed to investigate whether RC was independently associated with CKD and its severity. RESULTS: The median RC level was 25.9 mg/dL. The number of patients with no, moderate, severe, and very severe CKD was 2587 (76.5 %), 520 (15.4 %), 189 (5.6 %), and 87 (2.5 %), respectively. After adjusting for confounding factors, the prevalence of CKD increased 1.67-fold when the log-transformed RC level was elevated by one unit (OR [95 % CI], 1.67 [1.43-1.95]). The likelihood of CKD severity increasing by one degree was 1.76-fold for each one-unit increase in log-transformed RC level (OR [95 % CI], 1.76 [1.52-2.05]). When RC was incorporated as a categorical variable, it still correlated with CKD severity compared with quantile 1 (Q1) (Q2, 1.30 [1.01-1.68]; Q3, 1.60 [1.23-2.07]; Q4, 2.39 [1.86-3.09]). The association remained regardless of whether the patient's traditional lipid profiles achieved the target range. CONCLUSION: RC level was associated with CKD severity even when traditional lipid profiles were within the target range in patients with T2DM.

How does obesity affect mortality through blood pressure and blood glucose in Chinese and US citizens? Insights from a causal mediation analysis of two large cohorts.

Background: Obesity, which has reached the scale of a global pandemic, is a leading cause of premature death. It is unclear to what extent its effect on mortality was driven by blood pressure or glucose levels in people of different ethnicities. Methods: We conducted a causal mediation analysis to estimate the mediation effect of blood pressure and glucose between body mass index (BMI) or waist-hip ratio (WHR) on mortality based on data from the China Kadoorie Biobank (CKB) (n = 458 385) and US National Health and Nutrition Examination Survey (NHANES) (1999-2008, n = 20 726). Results: The WHR's effect on mortality was mediated by blood pressure and glucose in the CKB data set by 38.7% (95% confidence interval (CI) = 34.1, 43.2) and 36.4% (95% CI = 31.6, 42.8), whereas in NHANES by 6.0% (95% CI = 2.3, 8.3) and 11.2% (95% CI = 4.7, 22.7), respectively. For associations between BMI and mortality in subjects with overweight or obesity, the mediator proportion of blood glucose and pressure was 49.4% (95% CI = 40.1, 62.5) and 16.9% (95% CI = 13.6, 22.9) in CKB and 9.10% (95% CI = 2.2, 25.9) and 16.7% (95% CI = 7.3, 49.0) in NHANES, respectively. We stratified the patients by their blood glucose, blood pressure level, or both into four groups. The effect of WHR on mortality was comparable across subgroups in either cohort. The associations between BMI and mortality were stronger in patients with higher blood pressure in CKB (P = 0.011) and blood glucose in NHANES (P = 0.035) in patients with overweight and obesity. Conclusions: The relationship between WHR and mortality in the CKB data set was potentially caused by blood pressure and glucose to a much greater extent than in the NHANES one. The effect of BMI influenced by blood pressure was significantly higher among Chinese individuals with overweight and obesity. These results implicate a different intervention strategy is required for blood pressure and blood glucose in China and US to prevent obesity and obesity-related premature death.

Sensitivity to thyroid hormone and risk of components of metabolic syndrome in a Chinese euthyroid population.

INTRODUCTION: To evaluate the association of sensitivity to thyroid hormone with metabolic syndrome (MetS) and its components in a Chinese euthyroid population. METHODS: A total of 3573 participants from Pinggu Metabolic Disease Study were analyzed. Serum-free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) area of abdominal, and lumbar skeletal muscle area (SMA) were measured. Central thyroid hormone resistance was calculated by the Thyroid Feedback Quantile-based Index (TFQI) and Chinese-referenced Parametric TFQI (PTFQI), Thyrotroph T4 Resistance Index (TT4RI) and TSH Index (TSHI). Peripheral thyroid hormone resistance was assessed by FT3/FT4 ratio. RESULTS: Higher values of TSHI (odds ratio [OR] = 1.167, 95% confidence interval [CI]: 1.079-1.262, p < .001), TT4RI (OR = 1.115, 95% CI: 1.031-1.206, p = .006), TFQI (OR = 1.196, 95% CI: 1.106-1.294, p < .001), PTFQI (OR = 1.194, 95% CI: 1.104-1.292, p < .001), and lower values of FT3/FT4 ratio (OR = 0.914, 95% CI: 0.845-0.990, p = .026) were associated with MetS. Increased levels of TFQI and PTFQI were associated with abdominal obesity, hypertriglyceridemia, and hypertension. Increased levels of TSHI and TT4RI were associated with hypertriglyceridemia, abdominal obesity, low high-density lipoprotein cholesterol. Reduced levels of FT3/FT4 ratio were associated with hyperglycemia, hypertension, and hypertriglyceridemia. The levels of TSHI, TFQI, and PTFQI were negatively related to SMA and positively related to VAT, SAT, and TAT (all p < .05). CONCLUSIONS: Reduced thyroid hormone sensitivity was associated with MetS and its components. Impaired thyroid hormone sensitivity might affect the distribution of adipose tissue and muscle.