Background:High 1-hour plasma glucose (1-h PG) level has been proposed by the International Diabetes Federation to identify high-risk individuals and diagnose type 2 diabetes mellitus (T2DM). In a longitudinal cohort, we examined T2DM risk, β-cell function, and the genetic and lifestyle effects associated with the high 1-h PG. Methods:We analyzed 6,588 participants without baseline T2DM from a community-based prospective cohort in Korea. Participants underwent biennial 2-hour 75-g oral glucose tolerance tests over 14 years. We assessed incident T2DM risk across 1-h PG groups: <155, 155-208, and ≥209 mg/dL. T2DM polygenic risk scores (PRS) were stratified into low (1st quintile), intermediate (2nd-4th quintiles), and high (5th quintile). Lifestyle was evaluated using Life's Essential 8. Results:Compared to the <155 mg/dL group, hazard ratios for T2DM were 3.34 (95% confidence interval [CI], 2.99 to 3.74; P<0.001) for 155-208 mg/dL, and 6.81 (95% CI, 5.81 to 7.98; P<0.001) for ≥209 mg/dL. Both groups had lower baseline disposition index compared to the <155 mg/dL group (57.3% and 72.7%, respectively; both P<0.001). Higher T2DM PRS was associated with elevated baseline 1-h PG (low: 131 mg/dL, intermediate: 141 mg/dL, high: 151 mg/dL) and faster increase in 1-h PG (1.36 vs. 1.85 vs. 2.21 mg/dL/year; all P<0.001). Importantly, healthy lifestyle attenuated the increase in rate across all PRS groups. Conclusion:High 1-h PG predicts T2DM risk and is associated with β-cell dysfunction. The 1-h PG level is influenced by genetic risk and can be modified with a healthy lifestyle.

OBJECTIVE:Genetic variation in the glucagon-like peptide 1 receptor (GLP1R) has been implicated in type 2 diabetes (T2D) risk and treatment response. We investigated whether GLP1R R131Q, which was previously reported as a T2D-protective variant in genome-wide association studies, alters receptor signaling, β-cell function, and response to glucagon-like peptide 1 receptor agonists (GLP-1RAs). RESEARCH DESIGN AND METHODS:Trajectory of β-cell function was evaluated in a 20-year community-based prospective cohort in Korea (n = 6,373), where participants underwent biennial 2-h 75-g oral glucose tolerance tests, and disposition index was used as surrogate marker. Pharmacogenetic response to GLP-1RAs was assessed in a hospital-based T2D cohort in Korea (n = 177). Hyperglycemic clamp studies (n = 17), human islet experiments (n = 21), and in vitro assays were conducted to characterize GLP1R R131Q effects on receptor signaling and islet function. RESULTS:GLP1R R131Q was associated with slower decline in disposition index in individuals without T2D, with reductions from baseline of 30% in homozygous carriers, 35% in heterozygotes, and 37% in wild-type individuals. In people with T2D, each allele conferred an additional 0.53% or 5.8 mmol/mol reduction in HbA1c after 6 months of GLP-1RA treatment (P = 5.8 × 10-4). Hyperglycemic clamp and human islet experiments demonstrated allele-dependent enhancement of GLP-1RA-stimulated insulin secretion (P = 0.050 and P = 0.037, respectively). In vitro, GLP1R R131Q increased GLP-1RA-stimulated cAMP production with directional observations consistent with pathway bias. CONCLUSIONS:GLP1R R131Q is a gain-of-function variant associated with preservation of β-cell function and enhanced glycemic response to GLP-1RA treatment, supporting further investigation as a candidate pharmacogenetic marker for precision diabetes care.

Thyroid nodules are common in older populations, but the role of trace elements in their development and growth remains unclear. Previous studies have reported inconsistent findings regarding the association between trace elements and thyroid nodules. This study investigated the associations between urinary concentrations of various trace elements and the prevalence and incidence of thyroid nodules in older women, a population at higher risk for thyroid disorders. Cross-sectional and longitudinal analyses were conducted using data from 653 women aged 60 years and older in the Ansung cohort of the Korean Genome and Epidemiology Study (KoGES). Urinary concentrations of 18 elements were analyzed using inductively coupled plasma mass spectrometry (ICPMS), and mercury was analyzed using a Direct Mercury Analyzer (DMA). Logistic regression was used to assess associations between trace element exposure and thyroid nodule prevalence, stratified by nodule size (3.0-4.9 mm, 5.0-9.9 mm, and >= 10.0 mm). Higher urinary concentrations of Mn (OR 2.04; 95% CI, 1.27-3.28), Cu (OR 1.71; 95% CI, 1.08-2.72), and Co (OR 1.48; 95% CI, 0.94-2.31) were significantly associated with larger thyroid nodules (>= 10.0 mm). Zinc (OR 1.33; 95% CI, 0.84-2.11) showed a weaker but positive association with larger nodules, while uranium exposure was notably linked to the development of new nodules during follow-up (OR 7.70; 95% CI, 1.56-38.10 for nodules >= 5.0 mm). The findings suggest that trace elements, particularly Mn, Cu, Co, Zn, and U, may contribute to the formation and growth of thyroid nodules in older women. Future research should investigate the underlying mechanisms and expand to other populations to better understand these associations.

OBJECTIVE:To investigate the natural history of diabetes mellitus (DM) based on metabolic phenotypes of prediabetes in a community-based prospective study. METHODS:Individuals aged 40-69 years without DM were followed for 20 years. Glycemic parameters, including the 75 g oral glucose tolerance test, were assessed at baseline and biennially thereafter. Markov models were used to estimate each glycemic state's annual transition probabilities and average total length of residence. RESULTS:Among the 7,676 participants without DM, 205 had isolated impaired fasting glucose (iIFG), and 1,753 had impaired glucose tolerance (IGT) at baseline. During the 17.5 years of follow-up, 2,313 (30.1%) cases of DM occurred. The annual transition to DM for those with iIFG was 7.7% (95% confidence interval [CI] 6.9, 8.5) and 6.9% (95% CI 6.6, 7.3) for those with IGT. In the normoglycemia ↔ iIFG → DM model, the total length in normoglycemia was 49.4 years (95% CI 47.0, 52.1), and the length in iIFG was 6.3 years (95% CI 5.9, 6.8). In the normoglycemia ↔ IGT → DM model, the total length in normoglycemia was 34.0 years (95% CI 32.4, 35.4), and the length in IGT was 11.9 years (95% CI 11.1, 12.5). CONCLUSIONS:Individuals remained normoglycemic for long periods. However, the progression to DM occurs rapidly once prediabetes develops, regardless of the metabolic phenotype.

Background and ObjectiveTo investigate the difference in lung function according to diabetes status in a community-based prospective study.MethodsIndividuals aged 40-69 years from two community-based cohorts were followed prospectively for 16 years. A spirometer was used to evaluate lung function at baseline, and lung function tests were carried out biennially thereafter. Multivariable linear regression analysis was performed for the cross-sectional and longitudinal analyses based on diabetes status.ResultsAmong the 6483 subjects, 2114 (32.6%) had prediabetes and 671 (10.4%) had diabetes. The prediabetes and diabetes groups had lower baseline % predicted values of forced expiratory volume in 1 s (FEV1) (mean, -1.853; 95% confidence interval [CI] -2.715 to -0.990 for prediabetes and mean, -4.088; 95% CI -5.424 to -2.752 for diabetes) and forced vital capacity (FVC) (mean, -2.087; 95% CI -2.837 to -1.337 for prediabetes and mean, -4.622; 95% CI -5.784 to -3.460 for diabetes) compared to the normoglycemia group after adjusting for relevant covariates. The rate of decline in FEV1% predicted (mean, -0.227; 95% CI -0.366 to -0.089) and FVC % predicted (mean, -0.232; 95% CI -0.347 to -0.117) during follow-up were faster in the diabetes group than in the normoglycemia group. The diabetes group had a lower proportion of normal ventilation (ptrend = 0.048) and higher proportions of restrictive (ptrend = 0.001) and mixed (ptrend = 0.035) ventilatory disorders at the last follow-up.ConclusionDiabetes is associated with a lower baseline lung function and a faster rate of deterioration. This study followed 6483 adults within community-based cohorts for 16 years, and investigated cross-sectional and longitudinal changes in lung function according to diabetes status. Individuals with diabetes or prediabetes had lower baseline lung function as well as faster decline over time, resulting in an increased prevalence of ventilatory disorders.

OBJECTIVE To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS We conducted a multi-ancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, HR 1.23, P=3.6×10-9), rs11444867 (near HS3ST1, HR 1.89, P=9.9×10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P=1.5×10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P=1.0×10-16). CONCLUSIONS The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Background Identifying risk factors for postpartum type 2 diabetes in women with gestational diabetes mellitus (GDM) is crucial for effective interventions. We examined whether changes in insulin sensitivity after delivery affects the risk of type 2 diabetes in women with GDM. Methods This prospective cohort study included 347 women with GDM or gestational impaired glucose tolerance, who attended the follow-up visits at 2 months postpartum and annually thereafter. Changes in insulin sensitivity were calculated using the Matsuda index at GDM diagnosis and at 2 months postpartum (ΔMatsuda index). After excluding women with pregestational diabetes or those followed up only once, we analyzed the risk of postpartum type 2 diabetes based on the ΔMatsuda index tertiles. Results The incidence of type 2 diabetes at the two-month postpartum visit decreased with increasing ΔMatsuda index tertiles (16.4%, 9.5%, and 1.8%, P=0.001). During a 4.1-year follow-up, 26 out of 230 women who attended more than two follow-up visits (11.3%) developed type 2 diabetes. Compared to the lowest tertile, subjects in the highest ΔMatsuda index tertile showed a significantly reduced risk of type 2 diabetes (hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.93; P=0.036) after adjusting for confounders. Conclusion Improvement in insulin sensitivity after delivery is associated with a reduced risk of postpartum type 2 diabetes in women with GDM. Postpartum changes in insulin sensitivity could be a useful prediction for future type 2 diabetes development in women with GDM.

Objective: While most genetic variants of type 2 diabetes (T2D) are suggested to be associated with β-cell dysfunction cross-sectionally, their association with the longitudinal change of β-cell function remains largely unknown. Research Design and Methods: We analyzed data from 6,311 participants without T2D at baseline (age: mean±SD 51.6±8.7) from a community-based prospective cohort in Korea. Participants underwent biennial 2h 75g oral glucose tolerance test (OGTT) during 14 years of follow-up and OGTT-derived disposition index (DI) was used as a marker for β-cell function. Genetic risk was quantified using genome-wide polygenic risk score (PRS) and was stratified into low (1st quintile), intermediate (2nd to 4th) and high genetic risk (5th). Lifestyle was assessed according to Life’s Essential 8. Results: During a mean follow-up of 10.9 years, 374 (29.6%), 851 (22.5%) and 188 (14.9%) participants developed T2D in high, intermediate, and low genetic risk group, respectively. Participants in high genetic risk group, compared to low genetic risk group, had a 25% lower DI at baseline. Furthermore, in longitudinal analysis we observed a 1.83-fold faster decline in log2-transformed DI per year (-0.034 vs -0.019, P=2.1×10-3; per SD increase in T2D PRS, P=1.2×10-4). Healthy lifestyle attenuated the rate of decline in DI across all genetic risk group. Conclusion: Individuals with a higher genetic risk for T2D exhibited not only a lower OGTT-derived β-cell function at baseline but notably a more rapid decline during follow-up. This information could be used to enable a focused precision prevention with lifestyle intervention.

Several toxic metals have been associated with metabolic diseases like obesity and diabetes mellitus (DM) in humans. However, knowledge regarding the influence of many trace elements, especially in combination with essential elements is limited. This study aims to address this research gap by investigating the associations of both non-essential and essential inorganic trace elements in urine with DM and obesity, employing a group of postmenopausal women (n = 851) from the Korean Genome and Epidemiology Study (KoGES) cohort. Urine samples were collected during 2017-2018, and were analyzed for 19 trace elements using inductively coupled plasma-mass spectrometry and an automatic mercury analyzer. Outcomes of interest were metabolic diseases (DM and obesity) and DM-related traits (insulin resistance and β-cell function). After adjustment of covariates, such as age, alcohol consumption, smoking status, educational level, and daily energy intake, urinary Zn, Ni, Tl, and U levels were associated with the prevalence of DM and homeostatic model assessment (HOMA) for insulin resistance (IR) in the postmenopausal women. In the whole mixture model, however, no significant association was observed for the prevalence of DM. Urinary levels of Zn were negatively associated with HOMA of β-cell function (HOMA-β), positively correlated with HbA1c levels, HOMA-IR, and prevalent DM. In addition, urinary Zn, Co, Tl, and Cs were positively associated with obesity (body mass index ≥25 kg/m2). The present observation shows that several individual elements and their mixtures may be associated with the prevalence of DM, IR, or obesity.

Background: There is a noticeable lack of information on the levels of both non-essential and essential trace elements in women aged over 50. The main objective of this study is to investigate trace element concentrations and explore the influence of sociodemographic factors and dietary sources of exposure in this demographic. Methods: We analyzed 19 trace elements, including manganese, cobalt, copper, zinc, molybdenum, chromium, nickel, arsenic, strontium, cadmium, tin, antimony, cesium, barium, tungsten, mercury, thallium, lead, and uranium, using ICP-MS and mercury analyzer. Urine samples were obtained from a cohort of 851 women aged over 50 who participated in the 8th KoGES-Ansung study (2017-2018). Multiple linear models were employed to explore associations between urinary trace element concentrations and sociodemographic factors and dietary sources of exposure. We used K-means clustering to discern patterns of exposure to trace elements and identify contributing factors and sources. Results: Our findings indicate higher concentrations of molybdenum (Mo), arsenic (As), cadmium (Cd), and lead (Pb) in our study population compared to women in previous studies. The study population were clustered into two distinct groups, characterized by lower or higher urinary concentrations. Significant correlations between age and urinary concentrations were observed in Ni. Smoking exhibited positive associations with urinary Cd and As. Associations with dietary sources of trace elements were more distinct in women in the high-exposure group. Urinary antimony (Sb) was positively linked to mushroom and egg intake, As to mushroom and fish, and Hg to egg, dairy products, fish, seaweed, and shellfish. Conclusions: Our study underscores the significant gap in understanding urinary concentrations of trace elements in women aged over 50. With higher concentrations of certain elements compared to previous studies and significant correlations between age, smoking, and specific food sources, it is imperative to address this gap through targeted dietary source-specific risk management.

BACKGROUND:Steatotic liver disease (SLD) has emerged as new nomenclature to increase awareness and reflect the pathophysiology of the disease better. We investigated the risk of advanced fibrosis and cardiovascular disease (CVD) in SLD using data derived from a Korean prospective cohort. METHODS:We defined SLD using the fatty liver index (FLI) and identified advanced fibrosis with the age-adjusted Fibrosis-4 Index. SLD was further subcategorized into metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD). FINDINGS:The Ansung-Ansan cohort of the Korean Genome and Epidemiology study, following 9497 participants from 2002 to 2020, included 3642 (38.3%) with MASLD, 424 (4.5%) with MetALD, and 207 (2.1%) with ALD. During the median follow-up of 17.5 years, CVD risk was higher in those with MASLD (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.12-1.45; P < 0.001), MetALD (HR, 1.88; 95% CI, 1.33-2.65; P < 0.001), and ALD (HR, 1.95; 95% CI, 1.01-3.77; P < 0.001) than in those without SLD, after adjusting for conventional risk factors. Notably, CVD risk was higher in the MetALD than in the MASLD group (P = 0.027). In the MASLD group, the number of cardiometabolic risk factors (CMRFs) correlated positively with CVD risk (HR, 1.34; 95% CI, 1.24-1.45; P < 0.001 for trend). Among the CMRFs, hypertension (HR, 1.94; 95% CI, 1.63-2.31; P < 0.001) was the predominant contributor to CVD. The MASLD (HR, 1.39; 95% CI, 1.25-1.55; P < 0.001), MetALD (HR, 1.75; 95% CI, 1.38-2.23; P < 0.001), and ALD (HR, 2.00; 95% CI, 1.30-3.07; P = 0.002) groups had a higher risk of advanced fibrosis than did the non-SLD group (P < 0.001 for trend). INTERPRETATION:Our study provides new insight into hepatic and cardiovascular outcomes related to SLD subtypes. The risk of CVD increased in the order of no SLD, MASLD, and MetALD. The SLD subcategories, considering CMRFs and alcohol intake, outperformed traditional fatty liver categorizations in predicting CVD risk. The proposed SLD terminology could impact clinical practice, warranting further exploration of the heterogeneity of clinical outcomes among SLD subtypes.

Background: Detecting the risk of postpartum diabetes in women with gestational diabetes mellitus (GDM) is essential for proper intervention. We investigated whether changes in insulin sensitivity after delivery affect the risk of diabetes in Korean women with GDM. Method: In a prospective cohort including women with GDM, we included those who attended the postpartum visit at 2 months and yearly thereafter. The change in insulin sensitivity was defined as ∆Matsuda index, the difference between the initial postpartum visit and during pregnancy. We analyzed the risk of diabetes according to tertiles of ∆Matsuda index. Results: During 3.4 years of follow-up, 60 out of 347 subjects (17.3%) developed diabetes. The incidence of diabetes decreased as the tertile of ∆Matsuda index increased (26.7%, 17.2%, and 7.8%, P = 0.001). Subjects in the second and third tertile of ∆Matsuda index showed lower risk of diabetes compared to the subjects in the first tertile (HR, 0.45; 95% CI, 0.24-0.82; HR, 0.18; 95% CI, 0.07-0.48) after adjusting for age, family history of diabetes, gravida, lactation, fasting glucose, and postpartum BMI. Conclusion: Amelioration of insulin resistance lowers the risk of diabetes in Korean women with GDM. Although the assessment of insulin sensitivity is not standardized, changes in insulin sensitivity may be a useful predictor for diabetes in women with GDM. Disclosure H.Son: None. J.Moon: None. N.H.Cho: None. H.Jang: None.

Objective: Polygenic risk score (PRS) for type 2 diabetes (T2D) has been reported to be associated with beta cell function, but whether it is also associated with the longitudinal change of beta cell function is largely unknown. We aimed to evaluate the association of PRS and the trajectory of beta cell function in a community based prospective cohort. Method: We analyzed 6,323 participants without T2D at baseline from Ansan-Ansung cohort with 75-g 2-hour oral glucose tolerance tests taken biennially for 14 years. Disposition index (DI), derived from insulinogenic index at 60 minutes and Matsuda index, was used as a marker for beta cell function. PRS was calculated using 1.2 million variants from trans-ancestry T2D genome-wide association study using Bayesian regression (PRS-CSx). Participants were stratified into low (1st quintile), intermediate (2nd to 4th quintiles) and high genetic risk (5th quintile). Lifestyle was categorized as unfavorable, intermediate and favorable lifestyle according to Life’s Essential 8. Linear mixed model was applied. Result: During a median follow-up of 13 years, 379 (30.6%), 875 (23.0%) and 171 (13.4%) participants developed T2D in high, intermediate and low genetic risk group, respectively. Participants in high genetic risk group, compared to low genetic risk group, had a 33% lower DI at baseline (53 [95% CI 50, 56] vs 79 [74, 84]; P = 7.9×10-15), and a 1.7-fold faster rate of decline in log2(DI) per year (-0.035 [-0.028, -0.042] vs -0.020 [-0.013, -0.027]; P = 0.0026). Notably, we found significant interaction between the rate of decline in DI and T2D PRS (P = 8.5×10-5). Healthy lifestyle was associated with decreased rate of decline in DI across all genetic risk group. Conclusion: Having a high genetic risk for T2D was associated with not only a lower DI at baseline, but also a faster rate of decline in DI. Genetic information could be used to identify those at risk for rapid decline of beta cell function and emphasize lifestyle modification. Disclosure H.Lee: None. J.Choi: None. H.Son: None. K.Park: None. N.H.Cho: None. S.Kwak: None. Funding Ministry of Health & Welfare, Republic of Korea

Background: Current evidence suggests that diminished muscle mass is associated with an increased risk of diabetes. This study aimed to investigate whether the effect of low muscle mass (LMM) on incident diabetes varied depending on the tracking period using a prospective, longitudinal design. Methods: We recruited 6968 subjects without diabetes, aged 40 to 69 years, from the Korean Genomes and Epidemiology study and followed them to monitor the development of type 2 diabetes mellitus (T2DM). A standard 75-g oral glucose tolerance test was conducted at every 2-year follow-up visit. Skeletal muscle mass was assessed using bioelectrical impedance analysis, and a weight-adjusted skeletal muscle mass was defined as muscle mass index (MMI). We assessed the relationship between LMM, the sex-specific lowest tertile of MMI, and the risk of developing T2DM using Cox regression models. Results: Of 6968 (47.4% men), 1846 progressed diabetes during the 18-year follow-up. LMM was associated with an increased risk of T2DM at 10 years and 10-18 years of follow-up in both genders after adjustment for confoundings. After additional adjustment for waist circumference, men with LMM were at significant risk of incident diabetes during the 10-year follow-up (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.28-1.86) but lost significance in 10-18 years., whereas women with LMM were at significantly increased risk (HR 1.32, 95% CI 1.03-1.69) only in 10-18 years. Over 18 years, LMM in men was consistently associated with an increased risk of diabetes from the initial period (at 2-year follow-up), whereas LMM in women has been shown to increase risk in the late period (from 12-year follow-up). Conclusion: This study showed that LMM is an independent risk factor for T2DM with gender differences over time. LMM was a constant risk factor for diabetes in men, whereas it affected the later onset of diabetes in women. Disclosure E.Kim: None. Y.Cho: None. O.Hong: None. S.Moon: None. J.Han: None. S.Yoo: None. N.H.Cho: None.

Background: Current evidence suggests that diminished muscle mass is associated with an increased risk of diabetes. This study aimed to investigate whether the effect of low muscle mass (LMM) on incident diabetes varied depending on the tracking period using a prospective, longitudinal design. Methods: We recruited 6968 subjects without diabetes, aged 40 to 69 years, from the Korean Genomes and Epidemiology study and followed them to monitor the development of type 2 diabetes mellitus (T2DM). A standard 75-g oral glucose tolerance test was conducted at every 2-year follow-up visit. Skeletal muscle mass was assessed using bioelectrical impedance analysis, and a weight-adjusted skeletal muscle mass was defined as muscle mass index (MMI). We assessed the relationship between LMM, the sex-specific lowest tertile of MMI, and the risk of developing T2DM using Cox regression models. Results: Of 6968 (47.4% men), 1846 progressed diabetes during the 18-year follow-up. LMM was associated with an increased risk of T2DM at 10 years and 10-18 years of follow-up in both genders after adjustment for confoundings. After additional adjustment for waist circumference, men with LMM were at significant risk of incident diabetes during the 10-year follow-up (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.28-1.86) but lost significance in 10-18 years., whereas women with LMM were at significantly increased risk (HR 1.32, 95% CI 1.03-1.69) only in 10-18 years. Over 18 years, LMM in men was consistently associated with an increased risk of diabetes from the initial period (at 2-year follow-up), whereas LMM in women has been shown to increase risk in the late period (from 12-year follow-up). Conclusion: This study showed that LMM is an independent risk factor for T2DM with gender differences over time. LMM was a constant risk factor for diabetes in men, whereas it affected the later onset of diabetes in women. Disclosure E.Kim: None. Y.Cho: None. O.Hong: None. S.Moon: None. J.Han: None. S.Yoo: None. N.H.Cho: None.

Background: While the triglyceride-glucose (TyG) index is a measure of insulin resistance, its association with cardiovascular disease (CVD) has not been well elucidated. We evaluated the TyG index for prediction of CVDs in a prospective large communitybased cohort.Methods: Individuals 40 to 70 years old were prospectively followed for a median 15.6 years. The TyG index was calculated as the Ln [fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2]. CVDs included any acute myocardial infarction, coronary artery disease or cerebrovascular disease. We used a Cox proportional hazards model to estimate CVD risks according to quartiles of the TyG index and plotted the receiver operating characteristics curve for the incident CVD.Results: Among 8,511 subjects (age 51.9±8.8 years; 47.5% males), 931 (10.9%) had incident CVDs during the follow-up. After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, total cholesterol, smoking, alcohol, exercise, and C-reactive protein, subjects in the highest TyG quartile had 36% increased risk of incident CVD compared with the lowest TyG quartile (hazard ratio, 1.36; 95% confidence interval, 1.10 to 1.68). Carotid plaque, assessed by ultrasonography was more frequent in subjects in the higher quartile of TyG index (P for trend=0.049 in men and P for trend <0.001 in women). The TyG index had a higher predictive power for CVDs than the homeostasis model assessment of insulin resistance (HOMA-IR) (area under the curve, 0.578 for TyG and 0.543 for HOMA-IR). Adding TyG index on diabetes or hypertension alone gave sounder predictability for CVDs.Conclusion: The TyG index is independently associated with future CVDs in 16 years of follow-up in large, prospective Korean cohort.

Background Genome-wide association studies (GWAS) on type 2 diabetes mellitus (T2DM) have identified more than 400 distinct genetic loci associated with diabetes and nearly 120 loci for fasting plasma glucose (FPG) and fasting insulin level to date. However, genetic risk factors for the longitudinal deterioration of FPG have not been thoroughly evaluated. We aimed to identify genetic variants associated with longitudinal change of FPG over time. Methods We used two prospective cohorts in Korean population, which included a total of 10,528 individuals without T2DM. GWAS of repeated measure of FPG using linear mixed model was performed to investigate the interaction of genetic variants and time, and meta-analysis was conducted. Genome-wide complex trait analysis was used for heritability calculation. In addition, expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression project. Results A small portion (4%) of the genome-wide single nucleotide polymorphism (SNP) interaction with time explained the total phenotypic variance of longitudinal change in FPG. A total of four known genetic variants of FPG were associated with repeated measure of FPG levels. One SNP (rs11187850) showed a genome-wide significant association for genetic interaction with time. The variant is an eQTL for NOC3 like DNA replication regulator (NOC3L) gene in pancreas and adipose tissue. Furthermore, NOC3L is also differentially expressed in pancreatic β-cells between subjects with or without T2DM. However, this variant was not associated with increased risk of T2DM nor elevated FPG level. Conclusion We identified rs11187850, which is an eQTL of NOC3L, to be associated with longitudinal change of FPG in Korean population.

Background/Aims: We investigated the effect of metabolic dysfunction-associated fatty liver disease (MAFLD) on future mortality and cardiovascular disease (CVD) using a prospective community-based cohort study. Methods: Individuals from two community-based cohorts who were 40 to 70 years old were prospectively followed for 16 years. MAFLD was defined as a high fatty liver index (FLI ≥60) plus one of the following conditions: overweight/obesity (body mass index ≥23 kg/m2), type 2 diabetes mellitus, or ≥2 metabolic risk abnormalities. Nonalcoholic fatty liver disease (NAFLD) was defined as FLI ≥60 without any secondary cause of hepatic steatosis. Results: Among 8,919 subjects (age 52.2±8.9 years, 47.7% of males), 1,509 (16.9%) had MAFLD. During the median follow-up of 15.7 years, MAFLD independently predicted overall mortality after adjustment for confounders (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.05 to 1.69) but NAFLD did not (HR, 1.20; 95% CI, 0.94 to 1.53). MAFLD also predicted CVD after adjustment for age, sex, and body mass index (HR, 1.35; 95% CI, 1.13 to 1.62), which lost its statistical significance by further adjustments. Stratified analysis indicated that metabolic dysfunction contributed to mortality (HR, 1.51; 95% CI, 1.21 to 1.89) and CVD (HR, 1.27; 95% CI, 1.02 to 1.59). Among metabolic dysfunctions used for defining MAFLD, type 2 diabetes mellitus in MAFLD increased the risk of both mortality (HR, 2.07; 95% CI, 1.52 to 2.81) and CVD (HR, 1.42; 95% CI, 1.09 to 1.85). Conclusions: MAFLD independently increased overall mortality. Heterogeneity in mortality and CVD risk of subjects with MAFLD may be determined by the accompanying metabolic dysfunctions.

Purpose: The relative contribution of genetic and clinical factors for bone loss is not well known. This study aimed to investigate the annualized percentage change in total hip bone mineral density (BMD) and the genetic and clinical risk factors for bone loss in a Korean prospective cohort study over a 6-year period. Methods: We included 645 men aged 0.001), and years since menopause ? 3 years (P = 0.003) significantly correlated with hip bone loss in women aged 45?59 years. Hip bone loss in women aged 60 years increased with advancing age (P = 0.012), alcohol consumption (P = 0.028), LM loss (%/year) (P = 0.031), and fat mass loss (%/year) (P < 0.001) and decreased with increasing WC (P = 0.025). LRP5 rs498830 (13 = 0.127, P = 0.007) and TNFSF11 rs7325635 (13 = 0.146, P = 0.001) were the top SNPs related to hip bone loss in men and postmenopausal women, respectively. However, none of the SNPs were associated with hip bone loss after Benjamini-Hochberg adjustment. Conclusion: In this study, decreasing WC and LM were significant risk factors for hip bone loss in both men and women. Those factors were also identified that had sex-specific or age-specific effects on hip bone loss. None of the SNPs were associated with hip bone loss after multiple testing adjustments. The understanding of the modifiable factors contributing to bone loss has been broadened, and this may have implications such as in developing individualized preventive strategy. Further studies are needed to better predict the risk for bone loss in men and women.