Phenotyping obesity through a two-dimensional tree structure reveals cardiometabolic heterogeneity.

Diabetes heterogeneity has been modelled as a continuum in European populations, but its phenotypes and long-term comorbidity risks remain unclear in Chinese individuals. This study aimed to identify distinct phenotypes and evaluate their links to future cardiometabolic risks in a large Chinese cohort. The discriminative dimensionality reduction with trees (DDRTree) algorithm was used to develop a tree structure based on nine clinical variables. Cox proportional hazard models or logistic regression models were used to analyse probabilities of diabetes-related outcomes. This study included 19,612 individuals with newly diagnosed diabetes (36.8% male, mean age 59.01 years [SD 8.63]) from the China Cardiometabolic Disease and Cancer Cohort (4C) study. All nine clinical variables used for establishing DDRTree models were gradient distributed across the tree. By overlaying risks of diabetes-related outcomes, we show how these risks differ by participant phenotype. Participants characterised by hyperglycaemia, obesity and dyslipidaemia showed elevated risks of insulin initiation, hypoglycaemia and chronic kidney diseases, while those with hypertension and high creatinine, total cholesterol and alanine aminotransferase levels were associated with a higher risk of CVD. Notably, social determinants and lifestyle factors further contributed to the observed heterogeneity. These findings characterise the heterogeneity of diabetes phenotypes and complication risks in the Chinese population, suggesting potential implications for personalised diabetes care. Given the observed phenotypic differences, management strategies should consider population-specific characteristics.

BackgroundANGPTL8, an important regulator of lipid metabolism, was recently proven to have additional intracellular and receptor-mediated functions. This study aimed to investigate circulating levels of ANGPTL8 and its potential association with the risk of kidney function decline in a cohort study.MethodsWe analysed 2,311 participants aged 40 years old and older from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Kidney function decline was defined as an estimated glomerular filtration rate (eGFR) less than 60 mL per minute per 1.73 m2 of body surface area, a decrease in eGFR of ≥ 30% from baseline, chronic kidney disease (CKD)-related hospitalization or death, or end-stage renal disease. The association between baseline ANGPTL8 levels and kidney function decline was assessed using multivariable-adjusted Cox proportional hazards models, and inverse possibility of treatment weight (IPTW) was utilized to prevent overfitting.ResultsThere were 136 (5.9%) cases of kidney function decline over a median of 3.8 years of follow-up. We found that serum ANGPTL8 levels at baseline were elevated in individuals with kidney function decline compared to those without kidney function decline during follow-up (718.42 ± 378.17 vs. 522.04 ± 283.07 pg/mL, p < 0.001). Compared with the first quartile, multivariable-adjusted hazard ratio (95% confidence intervals [CIs]) for kidney function decline was 2.59 (95% CI, 1.41–4.77) for the fourth ANGPTL8 quartile. Furthermore, compared with patients in the first ANGPTL8 quartile, those in the fourth ANGPTL8 quartile were more likely to report a higher stage of CKD (relative risk: 1.33; 95% CI, 1.01–1.74). The conclusions of the regression analyses were not altered in the IPTW models. Multivariable-adjusted restricted cubic spline analyses suggested a linear relationship of ANGPTL8 with kidney function decline (p for nonlinear trend = 0.66, p for linear trend < 0.001).ConclusionsParticipants with higher circulating ANGPTL8 levels were at increased risk for kidney function decline, highlighting the importance of future studies addressing the pathophysiological role of ANGPTL8 in CKD.

Dose-response association between sedentary time and incident of diabetes in Chinese middle-aged and older adults: The 4C study

Amino acids, microbiota-related metabolites, and the risk of incident diabetes among normoglycemic Chinese adults: Findings from the 4C study

&lt;b&gt;OBJECTIVE&lt;/b&gt; &lt;p&gt;We aim to investigate the impact of ideal cardiovascular heath metrics (ICVHMs) on the association between famine exposure and adulthood diabetes risk. &lt;/p&gt; &lt;p&gt;&lt;b&gt;RESEARCH DESIGN AND METHODS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;This study included 77 925 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, who were born around the time of the Chinese Great Famine and free of diabetes at baseline. They were divided into 3 famine exposure groups according to the birth year, including non-exposed (1963-1974), fetal-exposed (1959-1962) and childhood exposed (1949-1958). Relative risk regression was used to examine the associations between famine exposure and ICVHMs on diabetes.&lt;/p&gt; &lt;p&gt;&lt;b&gt;RESULTS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;During a mean follow-up of 3.6 years, the cumulative incidence of diabetes was 4.2%, 6.0% and 7.5% in non-exposed, fetal-exposed and childhood-exposed participants, respectively. Compared with non-exposed participants, fetal-exposed but not childhood-exposed participants had increased risks of diabetes with multivariable-adjusted risk ratios (RRs) (95% confidence intervals) (CIs) of 1.17 (1.05-1.31) and 1.12 (0.96-1.30), respectively. Increased diabetes risks were observed in fetal-exposed individuals with non-ideal dietary habits, non-ideal physical activity, BMI ≥24.0 kg/m&lt;sup&gt;2&lt;/sup&gt;, or blood pressure ≥120/80 mmHg, whereas significant interaction was detected only in BMI strata (P for interaction=0.0018). Significant interactions have been detected between number of ICVHMs and famine exposure on the risk of diabetes (P for interaction=0.0005). The increased risk was observed in fetal-exposed participants with 1 or less ICVHMs (RR, 1.59; 95% CI, 1.24-2.04), but not in those with 2 or more ICVHMs. &lt;/p&gt; &lt;p&gt;&lt;b&gt;CONCLUSIONS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;The increased risk of diabetes associated with famine exposure appears to be modified by the presence of ICVHMs. &lt;/p&gt;

&lt;b&gt;OBJECTIVE&lt;/b&gt; &lt;p&gt;Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We aim to examine the association of serum BA profile and co-regulation with the risk of developing type 2 diabetes (T2DM) among normoglycemic Chinese adults.&lt;/p&gt; &lt;p&gt;&lt;b&gt;RESEARCH DESIGN AND METHODS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;We tested 23 serum BA species in subjects with incident diabetes (n=1707) and propensity score (including age, sex, BMI and fasting glucose)–matched controls (n=1707) from the China Cardiometabolic Disease and Cancer Cohort(4C) Study, which was composed of 54807 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. &lt;/p&gt; &lt;p&gt;&lt;b&gt;RESULTS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with the 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 (P&lt;0.05 and FDR&lt;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).&lt;a&gt; In fully adjusted model additionally adjusted for liver enzyme, HDL, 2 hour-postload glucose&lt;/a&gt;, HOMA-IR and waist circumference, the risk estimates are similar. Differential correlation network analysis revealed that perturbations in intra-class (i.e. primary and secondary) and interclass (i.e. unconjugated and conjugated) BAs co-regulation preexisted before diabetes onset.&lt;b&gt;&lt;/b&gt;&lt;/p&gt; &lt;p&gt;&lt;b&gt;CONCLUSIONS&lt;/b&gt;&lt;/p&gt; These findings reveal novel changes in BA exist prior to incident type 2 diabetes and support a potential role of BA metabolism in the pathogenesis of diabetes.

We aim to investigate the impact of ideal cardiovascular health metrics (ICVHMs) on the association between famine exposure and adulthood diabetes risk. This study included 77,925 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study who were born around the time of the Chinese Great Famine and free of diabetes at baseline. They were divided into three famine exposure groups according to the birth year, including nonexposed (1963-1974), fetal exposed (1959-1962), and childhood exposed (1949-1958). Relative risk regression was used to examine the associations between famine exposure and ICVHMs on diabetes. During a mean follow-up of 3.6 years, the cumulative incidence of diabetes was 4.2%, 6.0%, and 7.5% in nonexposed, fetal-exposed, and childhood-exposed participants, respectively. Compared with nonexposed participants, fetal-exposed but not childhood-exposed participants had increased risks of diabetes, with multivariable-adjusted risk ratios (RRs) (95% CIs) of 1.17 (1.05-1.31) and 1.12 (0.96-1.30), respectively. Increased diabetes risks were observed in fetal-exposed individuals with nonideal dietary habits, nonideal physical activity, BMI ≥24.0 kg/m2, or blood pressure ≥120/80 mmHg, whereas significant interaction was detected only in BMI strata (P for interaction = 0.0018). Significant interactions have been detected between number of ICVHMs and famine exposure on the risk of diabetes (P for interaction = 0.0005). The increased risk was observed in fetal-exposed participants with one or fewer ICVHMs (RR 1.59 [95% CI 1.24-2.04]), but not in those with two or more ICVHMs. The increased risk of diabetes associated with famine exposure appears to be modified by the presence of ICVHMs.

&lt;b&gt;OBJECTIVE&lt;/b&gt; &lt;p&gt;Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We aim to examine the association of serum BA profile and co-regulation with the risk of developing type 2 diabetes (T2DM) among normoglycemic Chinese adults.&lt;/p&gt; &lt;p&gt;&lt;b&gt;RESEARCH DESIGN AND METHODS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;We tested 23 serum BA species in subjects with incident diabetes (n=1707) and propensity score (including age, sex, BMI and fasting glucose)–matched controls (n=1707) from the China Cardiometabolic Disease and Cancer Cohort(4C) Study, which was composed of 54807 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. &lt;/p&gt; &lt;p&gt;&lt;b&gt;RESULTS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with the 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 (P&lt;0.05 and FDR&lt;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).&lt;a&gt; In fully adjusted model additionally adjusted for liver enzyme, HDL, 2 hour-postload glucose&lt;/a&gt;, HOMA-IR and waist circumference, the risk estimates are similar. Differential correlation network analysis revealed that perturbations in intra-class (i.e. primary and secondary) and interclass (i.e. unconjugated and conjugated) BAs co-regulation preexisted before diabetes onset.&lt;b&gt;&lt;/b&gt;&lt;/p&gt; &lt;p&gt;&lt;b&gt;CONCLUSIONS&lt;/b&gt;&lt;/p&gt; These findings reveal novel changes in BA exist prior to incident type 2 diabetes and support a potential role of BA metabolism in the pathogenesis of diabetes.

&lt;b&gt;OBJECTIVE&lt;/b&gt; &lt;p&gt;We aim to investigate the impact of ideal cardiovascular heath metrics (ICVHMs) on the association between famine exposure and adulthood diabetes risk. &lt;/p&gt; &lt;p&gt;&lt;b&gt;RESEARCH DESIGN AND METHODS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;This study included 77 925 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, who were born around the time of the Chinese Great Famine and free of diabetes at baseline. They were divided into 3 famine exposure groups according to the birth year, including non-exposed (1963-1974), fetal-exposed (1959-1962) and childhood exposed (1949-1958). Relative risk regression was used to examine the associations between famine exposure and ICVHMs on diabetes.&lt;/p&gt; &lt;p&gt;&lt;b&gt;RESULTS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;During a mean follow-up of 3.6 years, the cumulative incidence of diabetes was 4.2%, 6.0% and 7.5% in non-exposed, fetal-exposed and childhood-exposed participants, respectively. Compared with non-exposed participants, fetal-exposed but not childhood-exposed participants had increased risks of diabetes with multivariable-adjusted risk ratios (RRs) (95% confidence intervals) (CIs) of 1.17 (1.05-1.31) and 1.12 (0.96-1.30), respectively. Increased diabetes risks were observed in fetal-exposed individuals with non-ideal dietary habits, non-ideal physical activity, BMI ≥24.0 kg/m&lt;sup&gt;2&lt;/sup&gt;, or blood pressure ≥120/80 mmHg, whereas significant interaction was detected only in BMI strata (P for interaction=0.0018). Significant interactions have been detected between number of ICVHMs and famine exposure on the risk of diabetes (P for interaction=0.0005). The increased risk was observed in fetal-exposed participants with 1 or less ICVHMs (RR, 1.59; 95% CI, 1.24-2.04), but not in those with 2 or more ICVHMs. &lt;/p&gt; &lt;p&gt;&lt;b&gt;CONCLUSIONS&lt;/b&gt;&lt;/p&gt; &lt;p&gt;The increased risk of diabetes associated with famine exposure appears to be modified by the presence of ICVHMs. &lt;/p&gt;

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. We tested 23 serum BA species in subjects with incident diabetes (n = 1,707) and control subjects (n = 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. 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 (P < 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. These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.

Ischemic stroke (IS) is a leading cause of death and disability, imposing a significant economic burden globally. Research has demonstrated that insulin resistance (IR) plays a key role in the development of atherosclerosis, platelet dysfunction, and a hypercoagulable state, all of which contribute to the pathogenesis and progression of IS. The triglyceride-glucose (TyG) index serves as a practical tool for assessing insulin sensitivity, with previous studies exploring its correlation with IS. However, the relationship between the novel TyG-body mass index (TyG-BMI), which combines TyG with body mass index (BMI) as a measure of general obesity, and IS remains unclear. Therefore, this study employs a prospective design to assess the predictive value of TyG-BMI for the 10-year risk of IS in individuals without intervention. The study population was derived from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, predominantly comprising participants from Luzhou City, Sichuan Province, and primarily targeting individuals aged 40 and above. Comprehensive data collection was conducted using both questionnaires and specialized medical equipment, covering physical measurements, blood pressure, and relevant biochemical markers. Participants with a history of stroke were excluded from the study. Based on the initial data, participants were divided into four groups according to the TyG-BMI quartiles. Spearman correlation analysis was used to examine the relationship between TyG-BMI and clinical and laboratory parameters. The Log-rank test was applied to analyze differences in the cumulative incidence of IS among the four groups. The Cox proportional hazards model was used to analyze the relationship between TyG-BMI and the 10-year incidence of new IS. Additionally, the ROC curve was employed to assess the predictive value of TyG-BMI for the 10-year incidence of new IS in the middle-aged and elderly population. This study included 9,406 participants, consisting of 3,139 males (33.4%) and 6,267 females (66.6%). During the non-interventional follow-up period of 10 years, 483 deaths were recorded, resulting in a mortality rate of 5.1%. In addition, 527 new cases of IS were reported, yielding an incidence rate of 5.6%. The Log-rank test revealed a significant increase in the cumulative incidence of IS across increasing TyG-BMI quartiles (p < 0.01). Furthermore, Cox regression analysis identified a significant correlation between TyG-BMI levels, as a risk factor, and the occurrence of IS. After adjusting for other risk factors, the risk of developing new IS in the Q2 group was 1.449 times that of the Q1 group (p = 0.012), while the risk in the Q3 group was 1.438 times that of the Q1 group (p = 0.014), and the risk in the Q4 group was 1.434 times that of the Q1 group (p = 0.020). ROC curve analysis showed that, in the overall study population, TyG-BMI demonstrated a predictive value for new IS over 10 years (AUC = 0.566, 95% CI = 0.542-0.590, p < 0.001), with a cutoff value of 204.1307, sensitivity of 64.3%, and specificity of 47.8%. In male participants, TyG-BMI showed a predictive value for new IS over 10 years (AUC = 0.537, 95% CI = 0.501-0.574, p = 0.067), with a cutoff value of 195.1996, sensitivity of 73.8%, and specificity of 37.0%. In female participants, TyG-BMI demonstrated a predictive value for new IS over 10 years (AUC = 0.583, 95% CI = 0.551-0.615, p < 0.001), with a cutoff value of 204.295, sensitivity of 65.8%, and specificity of 48.7%. This study revealed a significant association between TyG-BMI and the 10-year incidence of new-onset IS among middle-aged and elderly individuals, indicating that TyG-BMI may serve as a valuable predictive marker for assessing IS risk in this population.

BackgroundWe aimed to evaluate the association between depression and major cardiovascular events and test whether the relationship between depression and cardiovascular events is influenced by lifestyle or metabolic risk factors.MethodsThe China Cardiometabolic Disease and Cancer Cohort (4C) Study was a nationwide, multicenter, prospective cohort study. About 92,869 participants without cardiovascular disease or cancer at baseline were included. Depression status was evaluated by the Patient Health Questionnaire-9 (PHQ-9). Lifestyle information was collected by the questionnaire, and metabolic risk factors including waist circumference, blood pressure, lipid profiles, and plasma glucose were measured. Major cardiovascular events including cardiovascular death, myocardial infarction, stroke, and hospitalized or treated heart failure events were validated based on medical records.ResultsDuring an average of 3.8 years of follow-up, we detected 2,076 cardiovascular events and showed that participants with depressive symptoms had an increased risk for cardiovascular events after adjustments [hazard ratio (HR): 1.29; 95% confidence index (CI): 1.08–1.53]. Stratified on metabolic risk status, the relationship between depression and cardiovascular events tended to be stronger according to the increasing numbers of metabolic risk factors, with HR (95% CI) of 0.98 (0.72–1.35) in the category with 0–2 metabolic risk factors, 1.36 (0.996–1.87) and 1.47 (1.13–1.92) for those with 3, and 4–5 metabolic risk factors, respectively, indicating an interaction effect (P = 0.039).ConclusionDepression was independently associated with an increased risk of major cardiovascular events. The effect was particularly prominent among populations at higher metabolic risk.

To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.

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

Elucidating the heterogeneity of prediabetes through subphenotyping with a two-dimensional tree structure