Publications by authors named "Guang Ning"

593 Publications

Impact of diabetes on subclinical atherosclerosis and major cardiovascular events in individuals with and without non-alcoholic fatty liver disease.

Diabetes Res Clin Pract 2021 May 26:108873. Epub 2021 May 26.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:

Aims: To investigate the impact of diabetes on subclinical atherosclerosis and cardiovascular disease (CVD) in individuals with and without non-alcoholic fatty liver disease (NAFLD).

Methods: The prospective cohort study included 8,451 Chinese adults free of baseline CVD in 2010. NAFLD was diagnosed based on hepatic ultrasonography. Fibrosis-4 index as a non-invasive marker was used to evaluate the degree of fibrosis. Subclinical atherosclerosis was evaluated by carotid intima-media thickness, brachial-ankle pulse wave velocity, ankle-brachial index, and carotid plaque. At follow-up during 2014-2016, the composite of incident fatal or nonfatal CVD were ascertained.

Results: Of the 8,451 participants, 2,557 (30.3%) had NAFLD at baseline. Diabetes was associated with arterial stiffness and carotid plaque in participants with NAFLD (P < 0.001). Similar associations were observed in participants without NAFLD. During a mean 4.6 years of follow-up, 432 incident CVD events occurred. The multivariable-adjusted hazard ratio (HR) for CVD events associated with diabetes was 1.27 (95% CI 0.90-1.81) in participants with NAFLD and 1.73 (95% CI 1.32-2.26) in those without NAFLD (P for interaction = 0.21). Among participants with NAFLD who had pre-existing diabetes, those with ≥ 5 years of diabetes duration had an adjusted HR of 2.02 (95% CI 1.12-3.62) for CVD as compared to those with < 2 years of duration. When categorizing participants with NAFLD by fibrosis severity, diabetes conferred an increased risk of CVD in those with potential advanced fibrosis.

Conclusions: Among participants with NAFLD, diabetes was associated with prevalent atherosclerosis, and a long duration of diabetes was associated with an increased risk of developing CVD. The effects of diabetes on cardiovascular outcomes did not appreciably differ by NAFLD status.
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http://dx.doi.org/10.1016/j.diabres.2021.108873DOI Listing
May 2021

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Levels and Cardiometabolic Risk Factors: A Population-Based Cohort Study.

Front Cardiovasc Med 2021 10;8:664583. Epub 2021 May 10.

Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

To evaluate the prospective association of circulating PCSK9 levels with the cardiometabolic risk profiles (high LDL-cholesterol, high triglycerides, low HDL-cholesterol, hypertension, type 2 diabetes, and metabolic syndrome). A population-based prospective study was conducted among 7,104 Chinese individuals (age 56.2 ± 7.5 years; 32.0% men). Circulating PCSK9 levels were measured using ELISA. Circulating PCSK9 levels were higher in women than men (286.7 ± 90.1 vs. 276.1 ± 86.4 ng/ml, < 0.001). And circulating PCSK9 was positively correlated with LDL-cholesterol, total cholesterol, and triglycerides both in men and women (all < 0.001). The positive correlation between PCSK9 and waist circumference, fasting glucose, insulin resistance, systolic blood pressure, diastolic blood pressure and C-reactive protein (all < 0.01) was observed in women only. According to Cox regression analysis, circulating PCSK9 was positively associated with incidence of high LDL-cholesterol both in men (HR 1.33, 95% CI 1.09-1.65, < 0.001) and women (HR 1.36, 95% CI 1.12-1.69, < 0.001). Moreover, PCSK9 was significantly associated with incident high triglycerides (HR 1.31, 95% CI 1.13-1.72, < 0.001), hypertension (HR 1.28, 95% CI 1.08-1.53, = 0.011), type 2 diabetes (HR 1.34, 95% CI 1.09-1.76, = 0.005), and metabolic syndrome (HR 1.30, 95% CI 1.11-1.65, = 0.009) per SD change in women only. No statistically significant association was observed between circulating PCSK9 and incidence of low HDL-cholesterol ( > 0.1). Elevated circulating PCSK9 was significantly associated with cardiometabolic risk factors and independently contributed to the prediction of cardiometabolic risks in women.
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http://dx.doi.org/10.3389/fcvm.2021.664583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141620PMC
May 2021

Genetic susceptibility, family history of diabetes, and healthy lifestyle factors in relation to diabetes: a gene-environment interaction analysis in Chinese adults.

J Diabetes Investig 2021 May 16. Epub 2021 May 16.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Aims/introduction: To analyze the associations and interactions of the genetic susceptibility and family history of diabetes with lifestyle factors in relation to diabetes among Chinese adults.

Materials And Methods: We constructed a genetic risk score of 34 single nucleotide polymorphisms in 11596 participants from Songnan and Youyi communities, Baoshan District, Shanghai, China. We determined a healthy lifestyle by a normal body mass index (<24 kg/m ), adequate fruit and vegetable intake (≥4.5 cups/day), never smoked or quit smoking >1 year prior, sufficient physical activity (≥600 metabolic equivalent minutes per week), and a sleep duration of ≥6 to ≤8 hours/day. Logistic regression models were used to examine the associations and interactions between heritability and lifestyle on diabetes.

Results: A healthier lifestyle was associated with a lower prevalence of diabetes within any heritable risk groups categorized by the genetic risk score and family history of diabetes. In the combined communities, the odds ratio (95% confidence interval) for diabetes associated with each additional healthy lifestyle factor was 0.83 (0.77-0.89) among participants with a low genetic risk score and 0.86 (0.81-0.91) among participants with a high genetic risk score (P =0.66). Similar interaction patterns of family history (P =0.15) and the combination of family history and the genetic risk score with healthy lifestyle (P =0.55) on diabetes were observed.

Conclusions: A healthier lifestyle was associated with a significantly lower prevalence of diabetes regardless of heritable risk groups, highlighting the importance of adhering to a healthy lifestyle for diabetes prevention among the entire population.
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http://dx.doi.org/10.1111/jdi.13577DOI Listing
May 2021

Cerebral perfusion alterations in type 2 diabetes mellitus - a systematic review.

Front Neuroendocrinol 2021 May 3;62:100916. Epub 2021 May 3.

Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, China; National Clinical Research Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:

Type 2 diabetes mellitus (T2DM) is related to abnormal brain structure and function, increasing the risk of cognitive impairment and dementia. We systematically reviewed the published literature focusing on cerebral perfusion in patients with T2DM. Although no significant difference was found in global cerebral blood flow (CBF) between the T2DM group and the healthy control group, the regional cerebral perfusion in T2DM was significantly reduced in multiple locations, including the occipital lobe, domains involved in the default mode network and the cerebellum. The decline in regional CBF was associated with a wide range of cognitive disorders in T2DM, including learning, memory, attention, and executive processing, as well as visual function. In addition, diabetes-related biochemical indicators, such as glycated hemoglobin and insulin resistance, were negatively correlated with regional CBF. In general, these functional perfusion imaging studies indicate that decreased CBF in T2DM may be a potential cause of cognitive impairment.
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http://dx.doi.org/10.1016/j.yfrne.2021.100916DOI Listing
May 2021

Reversal of functional brain activity related to gut microbiome and hormones after VSG surgery in patients with obesity.

J Clin Endocrinol Metab 2021 May 5. Epub 2021 May 5.

Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of Chinese Health Commission, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.

Background: Vertical sleeve gastrectomy (VSG) is becoming a prioritized surgical intervention for obese individuals; however, the brain circuits that mediate its effective control of food intake and predict surgical outcome remain largely unclear.

Methods: In this observational cohort study, 80 patients with obesity were screened. 36 patients together with 26 normal-weight subjects were enrolled and evaluated using the 21-item Three-Factor Eating Questionnaire (TFEQ), MRI scanning, plasma intestinal hormone analysis and fecal sample sequencing. 32 cases underwent VSG treatment and 19 subjects completed an average of four-month follow-up evaluation. Data-driven regional homogeneity (ReHo) coupled with seed-based connectivity analysis were used to quantify VSG-related brain activity. Longitudinal alterations of body weight, eating behavior, brain activity, gastrointestinal hormones and gut microbiota were detected and subjected to repeated measures correlation analysis.

Results: VSG induced significant functional changes in the right putamen (PUT.R) and left supplementary motor area, both of which correlated with weight loss and TFEQ scores. Moreover, postprandial levels of active glucagon-like peptide-1 (aGLP-1) and Ghrelin were associated with ReHo of PUT.R; meanwhile, relative abundance of Clostridia increased by VSG was associated with improvements in aGLP-1 secretion, PUT.R activity and weight loss. Importantly, VSG normalized excessive functional connectivities with PUT.R, among which baseline connectivity between PUT.R and right orbitofrontal cortex was related to postoperative weight loss.

Conclusions: VSG causes correlated alterations of gut-brain axis, including Clostridia, postprandial aGLP-1, PUT.R activity and eating habits. Preoperative connectivity of PUT.R may represent a potential predictive marker of surgical outcome in patients with obesity.
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http://dx.doi.org/10.1210/clinem/dgab297DOI Listing
May 2021

The progression and regression of metabolic dysfunction-associated fatty liver disease are associated with the development of subclinical atherosclerosis: A prospective analysis.

Metabolism 2021 Apr 23;120:154779. Epub 2021 Apr 23.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address:

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed and diagnosed based on modified criteria. However, evidence for the risks of developing subclinical atherosclerosis with MAFLD transitions according to its new definition has never been reported.

Methods: Using data from a community-based cohort, 6232 participants aged 40 years or older were included and were followed up for a median of 4.3 years during 2010-2015. Participants were categorized into four groups (stable non-MAFLD, MAFLD regressed to non-MAFLD, non-MAFLD progressed to MAFLD, and stable MAFLD). Subclinical atherosclerosis was defined as elevated carotid intima-media thickness (CIMT), elevated brachial-ankle pulse wave velocity (ba-PWV), or microalbuminuria.

Results: Compared with the stable non-MAFLD category, participants who progressed to MAFLD at follow-up visit had a 1.356-fold increased risk of developing elevated CIMT [odds ratio (OR) = 1.356; 95% confidence interval (CI) = 1.134-1.620], and a 1.458-fold increased risk of incident microalbuminuria (OR = 1.458; 95% CI = 1.034-2.056) after adjustment for confounders, respectively. In addition, participants with stable MAFLD showed 17.6%, 32.4%, and 35.4% increased risks of developing elevated CIMT, elevated ba-PWV and microalbuminuria, respectively. Compared with the stable MAFLD category, participants with MAFLD and low probability of fibrosis at baseline who regressed to non-MAFLD at follow-up visit had a 29.4% decreased risk of developing elevated CIMT (OR = 0.706; 95% CI = 0.507-0.984), a 43.1% decreased risk of developing elevated ba-PWV (OR = 0.569; 95% CI = 0.340-0.950), but was not significantly associated with incident microalbuminuria (OR = 0.709; 95% CI = 0.386-1.301). The decreased risks attributed to MAFLD regression were more evident in participants without diabetes or dyslipidemia, as well as in those with 0-1 metabolic risk abnormalities, respectively.

Conclusions: MAFLD was significantly associated with higher risks of developing subclinical atherosclerosis. Moreover, the regression of MAFLD might modify the risks of developing subclinical atherosclerosis, especially among those with low probability of fibrosis or less metabolic risk abnormalities. Since 40% of baseline participants with missing data on MAFLD measurement at follow-up were excluded, the conclusions should be speculated with caution.
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http://dx.doi.org/10.1016/j.metabol.2021.154779DOI Listing
April 2021

Targeted gene panel sequencing for molecular diagnosis of congenital adrenal hyperplasia.

J Steroid Biochem Mol Biol 2021 Apr 14;211:105899. Epub 2021 Apr 14.

Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai, 200025, PR China. Electronic address:

Context: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic diseases caused by genetic deficiency in nine genes encoding steroidogenesis enzymes and cofactors.

Objective: To establish a targeted next-generation sequencing (NGS) assay for all nine CAH candidate genes.

Methods: We developed a customized targeted NGS assay of CAH candidate genes (CYP21A2, CYP17A1, CYP11B1, StAR, CYP11A1, POR, HSD3B2, H6PD, CYP11B2) and apply this assay plus MLPA of CYP21A2 in a total of 469 patients with CAH like signs and symptoms.

Results: We totally identified 125 variants with seven variant types in eight genes. Variant types included missense variant (46.8 %), splicing variant (21.5 %), small indel (12.5 %), large structure variation (11.8 %), nonsense variant (4.1 %), UTR variant (2.9 %), synonymous variant (0.3 %). Successful genotyping, defined as biallelic pathogenic or likely pathogenic variants, was achieved in 98.5 % (336/341) of cases, including biallelic variants in CYP21A2 (n = 254), CYP17A1 (n = 45), CYP11B1 (n = 23), StAR (n = 7), HSD3B2 (n = 4), POR (n = 1), CYP11A1 (n = 1) and CYP11B2 (n = 1) gene. Importantly, the assay found one patient with CYP11B1 deficiency, one patient with non-classic POR deficiency and two patients with non-classic CYP17A1 deficiency while clinically diagnosed differently.

Conclusions: Our NGS-based assay plus MLPA of CYP21A2 is a useful tool to genotype all subtypes of CAH. The test successfully achieved genotype in 98.5 % of patients with clinically determined CAH. It also efficiently facilitated the diagnosis of CAH in patients with rare subtypes as well as non-classic phenotypes.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105899DOI Listing
April 2021

The 2017 ACC/AHA stage 1 hypertension is associated with arterial stiffness: a prospective analysis.

Aging (Albany NY) 2021 03 26;13(7):10075-10086. Epub 2021 Mar 26.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Objective: To examine the association between stage 1 hypertension defined by the 2017 American College of Cardiology and American Heart Association (ACC/AHA) guideline and risk of developing arterial stiffness.

Methods: During 2010-2015, 4595 adults aged ≥40 years without cardiovascular disease were followed up for a median of 4.3 years. BP levels at baseline were categorized into normal, elevated, stage 1 hypertension, and stage 2 hypertension. The development of arterial stiffness was defined as a normal brachial-ankle pulse wave velocity (ba-PWV) at baseline and an increased ba-PWV at follow-up.

Results: Compared with participants with normal BP, participants with stage 1 hypertension had a 1.48-fold increased risk of developing arterial stiffness [odds ratio (OR) =2.48; 95% confidence interval (CI) =1.59-3.85] after adjustment for cardiovascular risk factors. The association was more evident in adults aged 40-59 years (OR =4.08; 95% CI =2.06-8.08) than that in those aged ≥60 years (OR =1.47; 95% CI =0.81-2.67). A systolic BP 130~139 mmHg was significantly associated with arterial stiffness independent of diastolic BP (OR =2.90; 95% CI =1.86-4.52). Stage 1 hypertension either at baseline or at follow-up was associated with increased risks compared with normal BP at both baseline and follow-up.

Conclusions: The 2017 ACC/AHA stage 1 hypertension was significantly associated with higher risks of arterial stiffness.
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http://dx.doi.org/10.18632/aging.202764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064197PMC
March 2021

Cardiovascular Risk Based on ASCVD and KDIGO Categories in Chinese Adults: A Nationwide, Population-Based, Prospective Cohort Study.

J Am Soc Nephrol 2021 Mar 4. Epub 2021 Mar 4.

Department of Endocrine and Metabolic Diseases, Karamay Municipal People's Hospital, Xinjiang, China.

Background: The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline used eGFR and urinary albumin-creatinine ratio (ACR) to categorize risks for CKD prognosis. The utility of KDIGO's stratification of major CVD risks and predictive ability beyond traditional CVD risk prediction scores are unknown.

Methods: To evaluate CVD risks on the basis of ACR and eGFR (individually, together, and in combination using the KDIGO risk categories) and with the atherosclerotic cardiovascular disease (ASCVD) score, we studied 115,366 participants in the China Cardiometabolic Disease and Cancer Cohort study. Participants (aged ≥40 years and without a history of cardiovascular disease) were examined prospectively for major CVD events, including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death.

Results: During 415,111 person-years of follow-up, 2866 major CVD events occurred. Incidence rates and multivariable-adjusted hazard ratios of CVD events increased significantly across the KDIGO risk categories in ASCVD risk strata (all values for log-rank test and most values for trend in Cox regression analysis <0.01). Increases in statistic for CVD risk prediction were 0.01 (0.01 to 0.02) in the overall study population and 0.03 (0.01 to 0.04) in participants with diabetes, after adding eGFR and log(ACR) to a model including the ASCVD risk score. In addition, adding eGFR and log(ACR) to a model with the ASCVD score resulted in significantly improved reclassification of CVD risks (net reclassification improvements, 4.78%; 95% confidence interval, 3.03% to 6.41%).

Conclusions: Urinary ACR and eGFR (individually, together, and in combination using KDIGO risk categories) may be important nontraditional risk factors in stratifying and predicting major CVD events in the Chinese population.
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http://dx.doi.org/10.1681/ASN.2020060856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017537PMC
March 2021

Construction and validation of a metabolic risk model predicting prognosis of colon cancer.

Sci Rep 2021 Mar 25;11(1):6837. Epub 2021 Mar 25.

Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province, China.

Metabolic genes have played a significant role in tumor development and prognosis. In this study, we constructed a metabolic risk model to predict the prognosis of colon cancer based on The Cancer Genome Atlas (TCGA) and validated the model by Gene Expression Omnibus (GEO). We extracted 753 metabolic genes and identified 139 differentially expressed genes (DEGs) from TCGA database. Then we conducted univariate cox regression analysis and Least Absolute Shrinkage and Selection Operator Cox regression analysis to identify prognosis-related genes and construct the metabolic risk model. An eleven-gene prognostic model was constructed after 1000 resamples. The gene signature has been proved to have an excellent ability to predict prognosis by Kaplan-Meier analysis, time-dependent receiver operating characteristic, risk score, univariate and multivariate cox regression analysis based on TCGA. Then we validated the model by Kaplan-Meier analysis and risk score based on GEO database. Finally, we performed a weighted gene co-expression network analysis and protein-protein interaction network on DEGs, and Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology enrichment analyses were conducted. The results of functional analyses showed that most significantly enriched pathways focused on metabolism, especially glucose and lipid metabolism pathways.
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http://dx.doi.org/10.1038/s41598-021-86286-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994414PMC
March 2021

Neck circumference as an independent predictor for NAFLD among postmenopausal women with normal body mass index.

Nutr Metab (Lond) 2021 Mar 17;18(1):30. Epub 2021 Mar 17.

Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Neck circumference, a proxy for upper-body subcutaneous fat, is a unique and pathogenic fat depot that confers additional metabolic risk. The purpose of present study was to determine whether neck circumference associates with nonalcoholic fatty liver disease (NAFLD) in postmenopausal women with normal body mass index.

Methods: A cross-sectional survey (n = 2492) and a 3.1-year follow-up investigation (n = 1354) were conducted among Chinese postmenopausal women with normal BMI (18.5 to < 25 kg/m). Neck circumference was measured horizontally at the lower margin of the laryngeal prominence.

Results: In the cross-sectional analysis, large neck circumference was associated with the presence of NAFLD (odds ratio 2.28; 95% CI 1.74-2.98; highest tertile versus lowest tertile) after adjustment for confounding factors. Among 1354 subjects without the NAFLD at baseline, 429 (31.7%) incident NAFLD cases occurred at 3.1 years. Neck circumference was positively associated with triglycerides, homeostasis model assessment of insulin resistance, C-reactive protein, and negatively associated with high-density lipoprotein cholesterol and adiponectin. Individuals with large baseline neck circumference had a significantly higher risk of NAFLD than those with small neck circumference. The multivariable adjusted hazard ratio was 1.42 (95% CI 1.15-1.97; p for trend = 0.004) for the highest versus the lowest tertile of neck circumference, and was 1.22 (95% CI 1.10-1.41; p = 0.006) per 1-standard deviation increment in neck circumference.

Conclusions: Among postmenopausal women with normal BMI, relatively large neck circumference levels are associated with an increased risk of NAFLD.
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http://dx.doi.org/10.1186/s12986-021-00562-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967966PMC
March 2021

Associations between parity, pregnancy loss, and breastfeeding duration and risk of maternal type 2 diabetes: An observational cohort study.

J Diabetes 2021 Mar 12. Epub 2021 Mar 12.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Parity, pregnancy loss, and breastfeeding duration were found to be associated with diabetes. However, the results are inconsistent. Also, no epidemiological studies have examined the association of these reproductive factors with diabetes in the same large population. We aim to investigate the associations between parity, pregnancy loss, breastfeeding duration, and the risk of maternal diabetes in middle-aged and elderly Chinese females.

Methods: We included 131 174 females aged ≥40 years from the REACTION study (Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study). Multivariable linear regression and logistic regression were used to assess the association between parity, pregnancy loss, and breastfeeding duration and type 2 diabetes.

Results: The number of parities and breastfeeding duration were positively related to fasting plasma glucose, 2-hour postload glucose, glycosylated hemoglobin, and homeostatic model assessment of insulin resistance. Compared with those with one birth, nulliparous women or women with 2 or ≥3 births had a significantly increased risk of diabetes. The odds ratios (OR) and 95% confidence intervals (CI) were 1.27 (1.10-1.48), 1.17 (1.12-1.22), and 1.28 (1.21-1.35), respectively. Compared with women without pregnancy loss, those who underwent 2 (OR 1.09; 95% CI, 1.04-1.14) or ≥3 pregnancy losses (OR 1.11; 95% CI, 1.04-1.18) had an increased risk of diabetes. Moreover, women with a breastfeeding duration ≥0 to 6 months (OR 0.82; 95% CI, 0.75-0.90) and ≥6 to 12 months (OR 0.94; 95% CI, 0.89-0.99) had a significantly lower risk of diabetes.

Conclusions: Nulliparous women or women with multiparity or more than one pregnancy loss have an increased risk of diabetes in later life, while women who breastfeed more than 0 to 12 months have a lower risk of diabetes.
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http://dx.doi.org/10.1111/1753-0407.13176DOI Listing
March 2021

Association of early adulthood weight and subsequent weight change with cardiovascular diseases: Findings from REACTION study.

Int J Cardiol 2021 06 3;332:209-215. Epub 2021 Mar 3.

The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Background: Excessive adiposity in adulthood is positively associated with the risk of cardiovascular disease (CVD). However, it is less studied how the risk is separately explained by early adulthood weight and later weight change, especially in Asian ancestries.

Methods: This study included 121160 participants in a large population-based cohort in China. Body weight at 20 and 40 years of age wase self-reported. Information on CVD history was obtained through standard questionnaires.

Results: The odds ratios (ORs) were 1.20 (95% CI, 1.10-1.31) for coronary heart disease (CHD), 1.74 (95% CI, 1.36-2.22) for myocardial infarction (MI), 1.14 (95% CI, 0.99-1.32) for stroke and 1.21 (95% CI, 1.12-1.31) for total CVD among individuals with early overweight, and became more prominent for early obesity. Meanwhile, A moderate weight gain of 2.5 kg between early adulthood and midlife significantly increased the risk of CHD (OR: 1.18, 95% CI: 1.05-1.32), stroke (OR: 1.19, 95% CI: 1.03-1.38) and total CVD (OR: 1.15, 95% CI: 1.04-1.27), and the risk escalated with higher amounts of weight gain. Conversely, a weight loss of 2.5 kg conferred lower risk of CVD compared with a stable weight. In further cross-analysis, participants with early adulthood overweight or obesity and significant weight gain afterwards exhibited the greatest risk of CVD.

Conclusions: High early adulthood BMI and subsequent weight gain had both independent and combined effect on the risk of CVD after midlife. Therefore, weight management should start before early adulthood, and emphasized throughout adulthood for CVD prevention.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.086DOI Listing
June 2021

Urinary albumin-to-creatinine ratio levels are associated with subclinical atherosclerosis and predict CVD events and all-cause deaths: a prospective analysis.

BMJ Open 2021 03 3;11(3):e040890. Epub 2021 Mar 3.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

Objective: We aimed to examine the associations of urinary albumin-to-creatinine ratio (ACR) levels with risks of subclinical atherosclerosis, cardiovascular events and all-cause deaths.

Methods: Data from a large population-based cohort were used, which included 9580 participants aged ≥40 years free from cardiovascular diseases. Carotid intima-media thickness, brachial-ankle pulse wave velocity and ankle-brachial index were measured at baseline to assess subclinical atherosclerosis. After a median of 4.53 years' follow-up, 486 cardiovascular events and 230 all-cause deaths were recorded.

Results: The urinary ACR levels were categorised into three groups. Compared with the normal group (0≤ACR <7.82 mg/g), people with low-grade albuminuria (7.82≤ACR <30 mg/g) and albuminuria (ACR ≥30 mg/g) had higher levels of subclinical atherosclerosis. In prospective analysis, people with low-grade albuminuria was not significantly associated with cardiovascular events (HR=1.18; 95% CI 0.95 to 1.46], whereas people with albuminuria had a 50% higher risk of cardiovascular events (HR=1.50; 95% CI 1.11 to 2.03). People with low-grade albuminuria and albuminuria had 43% (HR=1.43; 95% CI 1.05 to 1.93) and 87% (HR=1.87; 95% CI 1.24 to 2.81) higher risks of all-cause deaths during follow-up, respectively. In stratified analysis, the association of higher ACR with risks of cardiovascular events and all-cause deaths was stronger among individuals with concomitant subclinical atherosclerosis, the presence of diabetes and more cardiovascular risk factors, respectively.

Conclusions: ACR levels were positively associated with subclinical atherosclerosis and predicted the risks of cardiovascular events and all-cause deaths. Evaluation of ACR levels should be integrated into risk stratification and prevention of cardiovascular events and all-cause deaths, especially among those with pre-existing subclinical atherosclerosis and cardiometabolic abnormalities.
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http://dx.doi.org/10.1136/bmjopen-2020-040890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931767PMC
March 2021

Fat mass to fat-free mass ratio and the risk of non-alcoholic fatty liver disease and fibrosis in non-obese and obese individuals.

Nutr Metab (Lond) 2021 Feb 19;18(1):21. Epub 2021 Feb 19.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China.

Context: Body composition may explain partially why non-obese individuals still at the risk of developing non-alcoholic fatty liver disease (NAFLD). The ratio of fat mass to fat-free mass (FM/FFM) has been proposed to assess the combined effect of different body compositions.

Objective: We aimed to investigate the associations of FM/FFM ratio with the risk of developing NAFLD and fibrosis and to identify the potential mediators according to obesity status.

Methods: This cohort study comprised 3419 adults age ≥ 40 years and free of NAFLD at baseline. Body composition was measured by bioelectrical impedance analysis. NAFLD was ascertained by ultrasonography and fibrosis was assessed by non-invasive score systems.

Results: For each 1 standard deviation increment in FM/FFM ratio, the odds ratio for the risk of NAFLD was 1.55 (95% confidence interval [CI] 1.23-1.95) in non-obese men, 1.33 (95% CI 1.08-1.65) in obese men, 1.42 (95% CI 1.44-1.67) in non-obese women, and 1.29 (95% CI 1.12-1.50) in obese women. Similar associations were also found between FM/FFM ratio and NAFLD with fibrosis. Mediation analysis showed that insulin resistance, triglycerides, high-density lipoprotein cholesterol, white blood cells, and total cholesterol mediated the association of FM/FFM ratio with NAFLD risk in specific sex and obesity subgroups.

Conclusions: The FM/FFM ratio significantly associated with the NAFLD and fibrosis risk in both non-obese and obese individuals. Different factors may mediate the association between body composition and NAFLD risk according to different obesity status.
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http://dx.doi.org/10.1186/s12986-021-00551-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893940PMC
February 2021

Triglycerides to high-density lipoprotein cholesterol ratio is superior to triglycerides and other lipid ratios as an indicator of increased urinary albumin-to-creatinine ratio in the general population of China: a cross-sectional study.

Lipids Health Dis 2021 Feb 15;20(1):13. Epub 2021 Feb 15.

Medical School of Chinese PLA, Beijing, China.

Background: Dyslipidemia contributes to the pathogenesis of renal dysfunction. Previous research demonstrated that triglycerides (TG), instead of other individual lipid indexes, has a significant link with elevated urinary albumin-to-creatinine ratio (UACR). However, it is unclear whether lipid ratios are superior indicators of increased UACR compared with TG. This research is to determine whether there are close relationships of lipid ratios with UACR in a general population.

Methods: 35,751 participants from seven centers across China were enrolled. UACR equal or higher than 30 mg/g was recognized as increased albuminuria. The associations of TG, low-density lipoprotein cholesterol (LDL-C)/ high-density lipoprotein cholesterol (HDL-C), TG/HDL-C and non-high-density lipoprotein cholesterol (non-HDL-C)/HDL-C with increased UACR were evaluated by linear and logistic regression analyses in females and males separately.

Results: There were 3692 (14.8%) female subjects, and 1307 (12.0%) male subjects characterized as having increased UACR. There were significantly differences in TG/HDL-C and non-HDL-C/HDL-C between the normal UACR group and the increased UACR group, while LDL-C/HDL-C was not. Furthermore, linear regression analysis was implemented and showed that TG and TG/HDL-C were both positively related to UACR even after a variety of potential confounders were adjusted regardless of sexes, while the correlation between non-HDL-C/HDL-C and elevated UACR were only significant in females. Further analyses utilizing logistic regression demonstrated that compared with non-HDL-C/HDL-C and TG, TG/HDL-C showed the strongest association with increased UACR (quartile 1 of TG/HDL-C as a reference; OR [95% CI] of quartile 4: 1.28 [1.13-1.44] in women, 1.24 [1.02-1.50] in men) after fully adjusting for potential confounding factors. Stratified analyses revealed that in males who were overweight and in females who were overweight or over 55 years or had prediabetes or prehypertension, TG/HDL-C had significant associations with abnormal UACR.

Conclusions: Compared with TG and other routine lipid ratios, TG/HDL-C is a superior indicator for increased UACR.
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http://dx.doi.org/10.1186/s12944-021-01442-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883433PMC
February 2021

Chinese adults are more susceptible to effects of overall obesity and fat distribution on cardiometabolic risk factors.

J Clin Endocrinol Metab 2021 Feb 11. Epub 2021 Feb 11.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Context: The body mass index (BMI) and waist circumference (WC) as diagnostic tools of obesity do not reflect the same level of fat mass and whether obesity leads to various effects on cardiometabolic risk factors among different racial/ethnic population is unknown.

Objective: The study aims to address the multicollinearity between BMI and WC by using the residual model approach, and to assess and compare the effects of obesity metrics on cardiometabolic risk factors among different races/ethnicities.

Design, Setting And Participants: Data from a nationally representative sample of Mainland Chinese adults collected in 2010, and data from the National Health and Nutrition Evaluation Survey (NHANES) 2005-2016 were used. By conducting a regression analysis between WC and BMI, the variation of BMI was removed from WC measures and residual of WC was obtained. The associations between obesity metrics and cardiometabolic risk factors were compared among different races/ethnicities by sex.

Results: The residual WC was significantly associated with all the cardiometabolic risk factors in Mainland Chinese, and most of the factors in Non-Hispanic White and Non-Hispanic Black adults, but not in the other races/ethnicities. The standardized regression coefficients of the associations between obesity metrics and cardiometabolic factors showed that the obesity metrics had greater impact on systolic blood pressure, diastolic blood pressure and triglyceride in Chinese adults than those of other racial/ethnic groups.

Conclusions: Chinese adults are more susceptible to the effects of overall obesity and fat distribution on cardiometabolic risk factors than the other racial/ethnic population.
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http://dx.doi.org/10.1210/clinem/dgab049DOI Listing
February 2021

Inverted U-Shaped Associations between Glycemic Indices and Serum Uric Acid Levels in the General Chinese Population: Findings from the China Cardiometabolic Disease and Cancer Cohort (4C) Study.

Biomed Environ Sci 2021 Jan;34(1):9-18

Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, Shandong, China.

Objective: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population.

Methods: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models.

Results: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices).

Conclusion: An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.
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http://dx.doi.org/10.3967/bes2021.003DOI Listing
January 2021

Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson's disease.

Microbiome 2021 01 31;9(1):34. Epub 2021 Jan 31.

Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai, 200025, China.

Background: Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota.

Results: The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice.

Conclusions: Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.
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http://dx.doi.org/10.1186/s40168-020-00988-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849090PMC
January 2021

Visit-to-visit blood pressure variability is associated with arterial stiffness in Chinese adults: A prospective analysis.

J Clin Hypertens (Greenwich) 2021 Apr 9;23(4):802-812. Epub 2021 Jan 9.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Blood pressure (BP) variability may have its effect on the development of vascular disease. The authors aimed to examine the association between the visit-to-visit variability (VVV) of BP and arterial stiffness in Chinese adults. The authors included 1407 participants from a prospective cohort study of community residents who were ≥40 years, without a history of myocardial infarction or stroke, and with data at the baseline, the second and the third visits in 2008, 2009, and 2013. The VVV of BP was defined as the standard deviation (SD), the coefficient of variation (CV), the average successive variability (ASV), and the variability independent of the mean (VIM) in BP levels at the 3 visits. Arterial stiffness was measured by brachial-ankle pulse wave velocity (ba-PWV) at the 2nd and the 3rd visits. Levels of ba-PWV change and the occurrence of an elevated ba-PWV increased significantly in the highest tertile of VVV measures of systolic BP (SBP) and pulse pressure (PP) compared with the lowest tertile, respectively. The multivariable regression analysis revealed that VVV measures of SBP and PP were significantly associated with levels of ba-PWV change and the risks of developing an elevated ba-PWV. The odds ratios (ORs) and 95% confidence intervals (CIs) for the risk were 2.12 (1.57-3.12) and 1.92 (1.38-2.68) in participants with the highest versus the lowest tertile of SBP-SD and PP-SD, respectively. No significant association was found for diastolic BP variability measures. The increased long-term variabilities of SBP and PP were associated with an increased risk of arterial stiffness.
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http://dx.doi.org/10.1111/jch.14166DOI Listing
April 2021

Association between obesity and urinary albumin-creatinine ratio in the middle-aged and elderly population of Southern and Northern China: a cross-sectional study.

BMJ Open 2021 01 5;11(1):e040214. Epub 2021 Jan 5.

Department of Endocrinology, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China

Objective: The relationship between obesity and albuminuria has not been clarified. This study aimed to investigate the correlation between obesity and the urinary albumin-creatinine ratio (UACR) in Southern and Northern China.

Design: A descriptive, cross-sectional study.

Setting: Eight regional centres in REACTION (China's Risk Evaluation of cAncers in Chinese diabeTic Individuals, a lONgitudinal study), including Dalian, Lanzhou, Zhengzhou, Guangzhou, Guangxi, Luzhou, Shanghai and Wuhan.

Participants: A total of 41 085 patients who were not diagnosed with chronic kidney disease (CKD) and had good compliance were selected according to the inclusion criteria. Patients who were diagnosed with CKD, who had other kidney diseases that could lead to increased urinary protein excretion, who were using angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers and whose important data were missing were excluded.

Results: Participants with both, central and peripheral obesity, had a higher risk of elevated UACR, even after adjusting for multiple factors (OR: 1.14, 95% CI: 1.07 to 1.12, p<0.001), and the risk of high UACR in the South was more prominent than that in the North (OR : 1.22, 95% CI: 1.11 to 1.34; OR : 1.13, 95% CI: 1.04 to 1.22, p<0.001). The risk was also elevated in the male population, hypertensive individuals, glycosylated haemoglobin (HbA1c)≥6.5% and age ≥60 years in the South. Besides the above groups, diabetes was also a risk factor for the Northern population.

Conclusions: In China, people with both central and peripheral obesity are prone to a high UACR, and the southern population has a higher risk than northern population. Factors such as male sex, hypertension, HbA1c≥6.5% and an age ≥60 years are also risk factors for CKD.
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http://dx.doi.org/10.1136/bmjopen-2020-040214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786798PMC
January 2021

Fruit intake, genetic risk and type 2 diabetes: a population-based gene-diet interaction analysis.

Eur J Nutr 2021 Jan 5. Epub 2021 Jan 5.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China.

Purpose: Whether the association between fruit and type 2 diabetes (T2D) is modified by the genetic predisposition of T2D was yet elucidated. The current study is meant to examine the gene-dietary fruit intake interactions in the risk of T2D and related glycemic traits.

Methods: We performed a cross-sectional study in 11,657 participants aged ≥ 40 years from a community-based population in Shanghai, China. Fruit intake information was collected by a validated food frequency questionnaire by asking the frequency of consumption of typical food items over the previous 12 months. T2D-genetic risk score (GRS) was constructed by 34 well established T2D common variants in East Asians. The risk of T2D, fasting, 2 h-postprandial plasma glucose, and glycated hemoglobin A1c associated with T2D-GRS and each individual single nucleotide polymorphisms (SNPs) were tested.

Results: The risk of T2D associated with each 1-point of T2D-GRS was gradually decreased from the lower fruit intake level (< 1 times/week) [the odds ratio (OR) and 95% confidence interval (CI) was 1.10 (1.07-1.13)], to higher levels (1-3 and > 3 times/week) [the corresponding ORs and 95% CIs were 1.08 (1.05-1.10) and 1.07 (1.05-1.08); P for interaction = 0.04]. Analyses for associations with fasting, 2 h-postprandial plasma glucose and glycated hemoglobin A1c demonstrated consistent tendencies (all P for interaction ≤ 0.03). The inverse associations of fruit intake with risk of T2D and glucose traits were more prominent in the higher T2D-GRS tertile.

Conclusions: Fruit intakes interact with the genetic predisposition of T2D on the risk of diabetes and related glucose metabolic traits. Fruit intake alleviates the association between genetic predisposition of T2D and the risk of diabetes; the association of fruit intake with a lower risk of diabetes was more prominent in population with a stronger genetic predisposition of T2D.
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http://dx.doi.org/10.1007/s00394-020-02449-0DOI Listing
January 2021

Type 2 diabetes RCTs in mainland China: insights from a systematic review.

Lancet Diabetes Endocrinol 2021 02 23;9(2):64-66. Epub 2020 Dec 23.

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People's Republic of China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30404-6DOI Listing
February 2021

Association of Serum Bile Acids Profile and Pathway Dysregulation With the Risk of Developing Diabetes Among Normoglycemic Chinese Adults: Findings From the 4C Study.

Diabetes Care 2021 Feb 18;44(2):499-510. Epub 2020 Dec 18.

The First Hospital of Jilin University, Changchun, China

Objective: Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults.

Research Design And Methods: We tested 23 serum BA species in subjects with incident diabetes ( = 1,707) and control subjects ( = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression.

Results: In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83-0.96) for cholic acid, 0.90 (0.84-0.97) for chenodeoxycholic acid, and 0.90 (0.83-0.96) for deoxycholic acid ( < 0.05 and false discovery rate <0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset.

Conclusions: These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.
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http://dx.doi.org/10.2337/dc20-0884DOI Listing
February 2021

Association of circulating proprotein convertase subtilisin/kexin type 9 levels and the risk of incident type 2 diabetes in subjects with prediabetes: a population-based cohort study.

Cardiovasc Diabetol 2020 12 10;19(1):209. Epub 2020 Dec 10.

Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism by targeting the low-density lipoprotein receptor. Recent studies have shown that circulating PCSK9 is associated with glucose homeostasis and insulin resistance. The aim of this study was to examine the association of circulating PCSK9 levels and risk for the development of type 2 diabetes in individuals with prediabetes.

Methods: A population-based prospective study was conducted among 4205 Chinese subjects with prediabetes (average age 56.1 ± 7.5 years). Incident type 2 diabetes was diagnosed according to 2010 American Diabetes Association criteria. Circulating PCSK9 levels were measured using a commercially available enzyme-linked immunosorbent assay (ELISA). The association of circulating PCSK9 levels with the risk of incident type 2 diabetes was assessed by Cox regression analysis.

Results: During a median follow-up period of 3.1 years, 568 subjects developed type 2 diabetes. Baseline circulating PCSK9 levels were significantly higher in female subjects developing incident type 2 diabetes than in those not developing incident type 2 diabetes (p < 0.001). In female subjects, the risk of incident type 2 diabetes was significantly higher in the highest PCSK9 quartile group (hazard ratio 2.16; 95% confidence interval 1.16-4.04) than in the lowest quartile group after adjustments for age, body mass index, waist circumference, C-reactive protein, γ-glutamyltransferase, triglycerides, low-density lipoprotein cholesterol, systolic blood pressure, and homeostatic model assessment of insulin resistance score. No significant association was observed between PCSK9 and incident type 2 diabetes in male subjects.

Conclusion: Elevated circulating PCSK9 levels are associated with an increased incidence of type 2 diabetes in female subjects with prediabetes.
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http://dx.doi.org/10.1186/s12933-020-01185-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726879PMC
December 2020

Clinical and molecular characterization of thirty Chinese patients with congenital lipoid adrenal hyperplasia.

J Steroid Biochem Mol Biol 2021 02 20;206:105788. Epub 2020 Nov 20.

Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200025, China. Electronic address:

Congenital lipoid adrenal hyperplasia (LCAH), as the most severe form of congenital adrenal hyperplasia (CAH), is caused by mutations in the steroidogenic acute regulatory protein (STAR). Affected patients were typically characterized by adrenal insufficiency in the first year of life and present with female external genitalia regardless of karyotype. Non-classic LCAH patients usually present from 2 to 4 years old with glucocorticoid deficiency and mild mineralocorticoid deficiency, even develop naturally masculinized external genitalia at birth when they have 46,XY karyotype. We described thirty patients from unrelated Chinese families, including three non-classic LCAH ones. Four novel mutations were reported, including c.556A > G, c.179-15G > T, c.695delG and c.306 + 3_c.306 + 6delAAGT. The c.772C > T is the most common STAR mutation in Chinese population, suggesting a possibility of founder effect. Enzymatic activity assay combined with clinical characteristics showed a good genotype-phenotype correlation in this study. Residual STAR activity more than 20 % may be correlated with non-classic LCAH phenotype. We support the perspective that onset age may be affected by multiple factors and masculinization should be the main weighting factor for diagnosis of non-classic LCAH. Compared with 46,XX LCAH patients, less 46,XY ones were found in our report. A less comprehensive inspection and an easy diagnosis due to classical phenotype both would reduce the possibility of 46,XY LCAH patients to be referred to specialists or geneticists.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105788DOI Listing
February 2021

Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese.

Diabetes Ther 2021 Jan 20;12(1):289-300. Epub 2020 Nov 20.

Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China.

Introduction: East Asians are more susceptible to early-onset diabetes than Europeans and exhibit reduced insulin secretion at earlier stages. PAX4 plays a critical role in the development of β-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans. Therefore, we aim to investigate the diabetes-associated genes, including PAX4 R192H/S, in East Asians with early-onset diabetes.

Methods: Exome variants of 80 Chinese early-onset diabetes patients (onset age < 35 years) after the exclusion of type 1 diabetes (T1D) were detected by a customized gene panel covering 32 known diabetes-associated genes. Then, 229 subjects with early-onset diabetes (T1D excluded) and 1679 controls from the Chinese population were genotyped to validate the association of PAX4 R192H/S with early-onset diabetes and related phenotypes.

Results: The gene panel detected 11 monogenic diabetes patients with five novel mutations among the 80 early-onset diabetes patients. Asian-specifically enriched PAX4 R192H and R192S were associated with early-onset diabetes (R192H: OR 1.88, 95% CI 1.37-2.60, P = 8.41 × 10; R192S: OR 1.71, 95% CI 1.17-2.51, P = 0.005). In early-onset diabetes patients, PAX4 R192H carriers had higher haemoglobin A1c (HbA1c) levels (P = 0.030) and lower 2 h C-peptide levels in the oral glucose tolerance test (OGTT) (P = 0.040); R192S carriers had lower fasting C-peptide (FCP) (P = 0.011) and 2 h C-peptide levels (P = 0.033) in OGTT than non-variant carriers.

Conclusions: The ethnic-specific enrichment of PAX4 R192H/S predisposing East Asians to early-onset diabetes with decreased C-peptide levels may be one explanation of the discrepancy of diabetes between East Asians and Europeans.

Clinical Trial Registration: ClinicalTrials.gov (NCT01938365).
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http://dx.doi.org/10.1007/s13300-020-00960-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843779PMC
January 2021

Association between nonalcoholic fatty liver and increased low-level albuminuria in postmenopausal women in China: A cross-sectional study.

J Diabetes 2021 Jun 6;13(6):494-505. Epub 2020 Dec 6.

School of Medicine, Nankai University, Tianjin, China.

Background: Several studies have suggested that nonalcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD). The excretion of low-level albuminuria (LLA) elevates as the prevalence of CVD increases. However, few studies have explored the association between NAFLD and LLA.

Methods: This cross-sectional study included 31 147 Chinese adults (7664 men and 23 483 women). The "normal" level of albuminuria as determined by the urinary albumin to creatinine ratio (UACR) was below 30 mg/g. LLA was defined as a higher level within the "normal" albuminuria range (5.54 mg/g < LLA≤29.9 mg/g). The participants with NAFLD were defined as having a fatty liver index (FLI) ≥ 60. The FLI was calculated using the Bedogni equation.

Results: A positive association was found between UACR and FLI through multivariate linear regression analyses (nonstandardized β ± SE: .047 ± 0.004, P <.001). The logistic regression analyses revealed that NAFLD had adjusted odds ratios (ORs) showing a significant relationship with LLA in models 1 to 4 (all subjects: OR, 1.207; 95% CI, 1.098-1.326; women: OR, 1.43; 95% CI, 1.26-1.63; all P <.001); however, we did not find significant adjusted ORs among the men. In the stratified analyses, the relationship between NAFLD and LLA was significant among postmenopausal women with a body mass index ≥24 but <28 kg/m , fasting plasma glucose ≥5.6 but <7.0 mmol/L, or postprandial plasma glucose ≥7.8 but <11.1 mmol/L and those aged below 60 years without moderate-intensity exercise.

Conclusions: A noteworthy association between NAFLD and LLA was found among postmenopausal women who had borderline blood glucose values, were overweight, and did not engage in moderate-intensity physical activity.
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http://dx.doi.org/10.1111/1753-0407.13134DOI Listing
June 2021

Serum Dickkopf-3 Level Is Inversely Associated with Significant Coronary Stenosis in an Asymptomatic Chinese Cohort.

Int Heart J 2020 Nov 13;61(6):1107-1113. Epub 2020 Nov 13.

Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.

Dickkopp-3 (DKK3) has been identified to play a protection role against atherosclerosis. However, little is known about the relationship between serum DKK3 levels and subclinical coronary atherosclerosis. We aimed to investigate the association of serum DKK3 with coronary stenosis in an asymptomatic Chinese population. A total of 550 Chinese adults aged 40-60 years and without symptoms or histories of cardiovascular diseases were randomly selected to undergo coronary computed tomography angiography. We defined ≥ 50% luminal narrowing as significant coronary stenosis and measured serum DKK3 levels by an enzyme-linked immunosorbent assay (ELISA). Fifty-nine participants had significant coronary stenosis and 223 had < 50% coronary stenosis. Proportions of significant coronary stenosis were 13.7%, 11.4%, and 7.1% in DKK3 tertiles 1-3, respectively (P = 0.0427). In the univariable multinomial logistic regression model, a decreasing DKK3 tertile was associated with significant coronary stenosis with borderline significance (OR: 1.40; 95% confidence intervals (CI): 0.98-1.99, P = 0.0642). In the multivariable regression model, participants in the lowest DKK3 tertile were associated with a 1.42-fold increased risk of significant coronary stenosis than those in the highest DKK3 tertile (OR: 2.42; 95% CI: 1.10-5.33; P = 0.0279) after adjustment for conventional cardiovascular risk factors. In addition, associations between DKK3 and significant coronary stenosis were consistent among subgroups. However, no significant association was found between serum DKK3 levels and < 50% coronary stenosis. Therefore, we have added to the existing evidence that serum DKK3 is inversely associated with the risk of significant coronary stenosis in asymptomatic middle-aged Chinese.
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http://dx.doi.org/10.1536/ihj.20-094DOI Listing
November 2020