Trajectory of lung function in diabetic adults: A 16-year follow-up study of community-based prospective cohorts.

BACKGROUND AND OBJECTIVE: To investigate the difference in lung function according to diabetes status in a community-based prospective study. METHODS: Individuals 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. RESULTS: Among 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. CONCLUSION: Diabetes is associated with a lower baseline lung function and a faster rate of deterioration.

Steatotic liver disease predicts cardiovascular disease and advanced liver fibrosis: A community-dwelling cohort study with 20-year follow-up.

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.

Triglyceride-Glucose Index Predicts Future Atherosclerotic Cardiovascular Diseases: A 16-Year Follow-up in a Prospective, Community-Dwelling Cohort Study.

BACKGRUOUND: 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.

Genome-Wide Association Study on Longitudinal Change in Fasting Plasma Glucose in Korean Population.

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 ß-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.

Metabolic Dysfunction-Associated Fatty Liver Disease Predicts Long-term Mortality and Cardiovascular Disease.

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.

Liver Fibrosis Indices for the Prediction of Mortality in Korean Subjects: A 16-Year Prospective Cohort Study.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) and its progression to liver fibrosis are related to higher mortality. OBJECTIVE: We investigated whether noninvasive indices of NAFLD and liver fibrosis could predict mortality in a Korean prospective cohort study. METHODS: We followed 4163 subjects from the Korean Genome and Epidemiology Study biannually over 16 years. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) of NAFLD or liver fibrosis indices in the total group of subjects and subgroups according to body mass index (BMI) and glucose metabolism status. RESULTS: The mean age (± SD) of the subjects was 55.7 ± 8.7 years and 39.2% were men. During a median follow-up period of 15.6 years, 643 subjects (15.4%) died. The Fibrosis-4 (FIB-4), NAFLD fibrosis score (NFS), and aspartate aminotransferase to platelet ratio index were consistently higher in deceased subjects regardless of baseline glucose metabolism status. The FIB-4 and NFS displayed acceptable discrimination power for mortality, with area under the receiver operating characteristic curve values of 0.686 and 0.666, respectively. The adjusted HRs for FIB-4 and NFS were 1.41 (95% CI, 1.18-1.68) and 1.43 (95% CI, 1.21-1.68), respectively. Both FIB-4 and NFS were significantly associated with liver-specific mortality but not cardiovascular mortality. The association between mortality with fibrosis indices were more prominent in subjects with a lower BMI (<25 kg/m2). CONCLUSION: Noninvasive indices of liver fibrosis might be a significant predictor of all-cause and liver-specific mortality in Korean subjects.

Integrative analysis of genetic and clinical risk factors for bone loss in a Korean population.

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 ≥50 years and 683 postmenopausal women who had repeated BMD testing between 2007 and 2014. The association between covariates and annualized percentage change in hip BMD was analyzed through the multivariate linear regression analysis. A total of 2614 single-nucleotide polymorphisms (SNPs) from 23 known BMD-related candidate genes and genome-wise association study were investigated. RESULTS: Hip bone loss increased more rapidly in women than in men with advancing age. Hip bone loss in men increased with lean mass (LM) loss (%/year) (P < 0.001) and current smoking (P = 0.024) and decreased with increasing waist circumference (WC) (P < 0.001), alcohol consumption (P = 0.049), and increase in red blood cell counts (P = 0.031). Decreasing WC (P = 0.009), LM loss (%/year) (P < 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 (ß = 0.127, P = 0.007) and TNFSF11 rs7325635 (ß = 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.

Development of a clinical risk score for incident diabetes: A 10-year prospective cohort study.

AIMS/INTRODUCTION: We developed a self-assessable Korean Diabetes Risk score using the data of the Korean Genome and Epidemiology Study. MATERIALS AND METHODS: A total of 8,740 participants without diabetes at baseline were followed up biannually over a period of 10 years. We included variables that were significantly different between participants who developed diabetes mellitus and those who did not in the development cohort at baseline. We assigned a maximum score of 100 to the selected variable in each gender group. Next, the 10-year probability of incident diabetes was calculated and validated in the validation cohort. Finally, we compared the predictive power of Korean Diabetes Risk score with models including fasting plasma glucose or glycated hemoglobin and other cohort models of Atherosclerosis Risk in Communities and Korea National Health and Nutrition Examination Survey. RESULTS: During a median follow-up period of 9.7 years, 22.7% of the participants progressed to diabetes. The Korean Diabetes Risk score included age, living location (urban or rural area), waist circumference, hypertension, family history of diabetes and smoking history. The developed risk score yielded acceptable discrimination for incident diabetes (area under the curve 0.657) and the predictive power was improved when the model included fasting plasma glucose (area under the curve 0.690) or glycated hemoglobin (area under the curve 0.746). In addition, our model predicted incident diabetes more accurately than previous Western or Korean models. CONCLUSIONS: This newly developed self-assessable diabetes risk score is easily applicable to predict the future risk of diabetes even without the necessity for laboratory tests. This score is useful for the Korean diabetes prevention program, because high-risk individuals can be easily screened.

Identification of Novel Genetic Variants Related to Trabecular Bone Score in Community-Dwelling Older Adults.

BACKGROUND: As the genetic variants of trabecular bone microarchitecture are not well-understood, we performed a genome-wide association study to identify genetic determinants of bone microarchitecture analyzed by trabecular bone score (TBS). METHODS: TBS-associated genes were discovered in the Ansung cohort (discovery cohort), a community-based rural cohort in Korea, and then validated in the Gene-Environment Interaction and Phenotype (GENIE) cohort (validation cohort), consisting of subjects who underwent health check-up programs. In the discovery cohort, 2,451 participants were investigated for 1.42 million genotyped and imputed markers. RESULTS: In the validation cohort, identified as significant variants were evaluated in 2,733 participants. An intronic variant in iroquois homeobox 3 (IRX3), rs1815994, was significantly associated with TBS in men (P=3.74E-05 in the discovery cohort, P=0.027 in the validation cohort). Another intronic variant in mitogen-activated protein kinase kinase 5 (MAP2K5), rs11630730, was significantly associated with TBS in women (P=3.05E-09 in the discovery cohort, P=0.041 in the validation cohort). Men with the rs1815994 variant and women with the rs11630730 variant had lower TBS and lumbar spine bone mineral density. The detrimental effects of the rs1815994 variant in men and rs11630730 variant in women were also identified in association analysis (ß=-0.0281, ß=-0.0465, respectively). CONCLUSION: In this study, the rs1815994 near IRX3 in men and rs11630730 near MAP2K5 in women were associated with deterioration of the bone microarchitecture. It is the first study to determine the association of genetic variants with TBS. Further studies are needed to confirm our findings and identify additional variants contributing to the trabecular bone microarchitecture.

Low Predictive Value of FRAX Adjusted by Trabecular Bone Score for Osteoporotic Fractures in Korean Women: A Community-Based Cohort Study.

BACKGROUND: The value of the Fracture Risk Assessment Tool (FRAX) and the trabecular bone score (TBS) for assessing osteoporotic fracture risk has not been fully elucidated in Koreans. We conducted this study to clarify the predictive value of FRAX adjusted by TBS for osteoporotic fractures in Korean women. METHODS: After screening 7,192 eligible subjects from the Ansung cohort, 1,165 women aged 45 to 76 years with available bone mineral density (BMD) and TBS data were enrolled in this study. We assessed their clinical risk factors for osteoporotic fractures and evaluated the predictive value of FRAX with or without BMD and TBS. RESULTS: During the mean follow-up period of 7.5 years, 99 (8.5%) women suffered major osteoporotic fractures (MOFs) and 28 (2.4%) experienced hip fractures. FRAX without BMD, BMD-adjusted FRAX, and TBS-adjusted FRAX were significantly associated with the risk of MOFs (hazard ratio [HR] per percent increase, 1.08; 95% confidence interval [CI], 1.03 to 1.14; HR, 1.09; 95% CI, 1.03 to 1.15; and HR, 1.07; 95% CI, 1.02 to 1.13, respectively). However, BMD-adjusted FRAX and TBS-adjusted FRAX did not predict MOFs better than FRAX without BMD based on the Harrell's C statistic. FRAX probabilities showed limited value for predicting hip fractures. The cut-off values of FRAX without BMD, FRAX with BMD, and FRAX with BMD adjusted by TBS for predicting MOFs were 7.2%, 5.0%, and 6.7%, respectively. CONCLUSION: FRAX with BMD and TBS adjustment did not show better predictive value for osteoporotic fractures in this study than FRAX without adjustment. Moreover, the cut-off values of FRAX probabilities for treatment might be lower in Korean women than in other countries.

Association of Body Mass Index with the Risk of Incident Type 2 Diabetes, Cardiovascular Disease, and All-Cause Mortality: A Community-Based Prospective Study.

BACKGROUND: Type 2 diabetes and cardiovascular disease (CVD) are the most important sequelae of obesity and the leading cause of death. We evaluated the association between body mass index (BMI) and the risk of incident type 2 diabetes, CVD, and all-cause mortality in a prospective study of a Korean population. METHODS: The shapes of the associations were modeled by restricted cubic splines regression analysis. After categorizing all subjects (n=8,900) into octiles based on their BMI levels, we estimated the hazard ratio (HR) for the association of categorized BMI levels with the risk of incident CVD and type 2 diabetes using a Cox's proportional hazard analysis. RESULTS: The mean age of participants was 52 years and 48% were men. Of the subjects at baseline, 39.0% of men and 45.6% of women were classified as obese (BMI ≥25 kg/m2). Over a mean follow-up of 8.1 years, CVD events occurred in 509 participants; 436 died; and 1,258 subjects developed type 2 diabetes. The increased risk of incident diabetes began to be significant at BMI 23 to 24 kg/m2 in both sexes (HR, 1.8). For CVD events, the risk began to increase significantly at BMI 26 to 28 kg/m2 (HR, 1.6). We found a reverse J-shaped relationship between BMI and all-cause mortality, with an increased risk among individuals with BMI values in lower range (BMI <21 kg/m2). CONCLUSION: These results suggest that the BMI cut-off points for observed risk were varied depending on the diseases and that the BMI classification of obesity need to be revised to reflect differential risk of obesity-related diseases.

Longitudinal changes in bone mineral density and trabecular bone score in Korean adults: a community-based prospective study.

The bone mineral densities (BMDs) of the femoral neck and total hip, and the lumbar spine trabecular bone score (TBS), tended to decrease with age in both men and women, whereas the lumbar spine BMD tended to increase. Lumbar spine BMD is thus inappropriate for evaluating longitudinal changes in bone loss; the lumbar spine TBS is an alternative measure. PURPOSE: Aging is associated with a decrease in bone mass and quality. This community-based prospective cohort study investigated longitudinal changes in bone phenotype in Korean adults. METHODS: We analyzed data from a prospective community-based cohort study, the Korean Genome and Epidemiology Study. Postmenopausal women and men who underwent dual-energy X-ray absorptiometry at least twice from 2007 to 2014 were included. Longitudinal changes in bone mineral density (BMD) and trabecular bone score (TBS) over 6 years were analyzed by sex, age, and body mass index. RESULTS: A total of 1895 subjects were enrolled (men 965; postmenopausal women 929). The femoral neck (FN) BMD, total hip (TH) BMD, and lumbar spine (LS) TBS decreased significantly over time, but the LS BMD increased significantly. In men, the average annual changes were 0.3% in LS BMD (p < 0.001), - 0.33% in FN BMD (p < 0.001), - 0.26% in TH BMD (p = 0.001), and - 0.27% in LS TBS (p < 0.001). In women, the average annual changes were 0.27% in LS BMD (p < 0.001), - 0.67% in FN BMD (p < 0.001), - 0.66% in TH BMD (p < 0.001), and - 0.27% in LS TBS (p < 0.001). The longitudinal decrease in TH BMD over time was significantly greater in women (versus men) and those who were older (versus younger). CONCLUSION: The FN and TH BMDs decreased with aging. But, the LS BMD was inappropriate to evaluate longitudinal changes of bone loss. The LS TBS could be alterative.

A Novel Fracture Prediction Model Using Machine Learning in a Community-Based Cohort.

The prediction of fracture risk in osteoporotic patients has been a topic of interest for decades, and models have been developed for the accurate prediction of fracture, including the fracture risk assessment tool (FRAX). As machine-learning methodologies have recently emerged as a potential model for medical prediction tools, we aimed to develop a novel fracture prediction model using machine-learning methods in a prospective community-based cohort. In this study, 2227 participants (1257 females) with a baseline bone mineral density (BMD) and trabecular bone score were enrolled from the Ansung cohort. The primary endpoint was the fragility fractures reported by patients or confirmed by X-rays. We used 3 different models: CatBoost, support vector machine (SVM), and logistic regression. During a mean 7.5-year follow-up (range, 2.5 to 10 years), fragility fractures occurred in 537 (25.6%) of participants. In predicting total fragility fractures, the area under the curve (AUC) values of the CatBoost, SVM, and logistic regression models were 0.688, 0.500, and 0.614, respectively. The AUC value of CatBoost was significantly better than that of FRAX (0.663; p < 0.001), whereas the the SVM and logistic regression models were not. Compared with the conventional models such as SVM and logistic regression, the CatBoost model had the best performance in predicting total fragility fractures (p < 0.001). According to feature importance in the CatBoost model, the top predicting factors (listed in order) were total hip, lumbar spine, and femur neck BMD, subjective arthralgia score, serum creatinine, and homocysteine. The latter three factors were listed higher than conventional predictors such as age or previous fracture history. In summary, we hereby report the development of a prediction model for fragility fractures using a machine-learning method, CatBoost, which outperforms the FRAX model as well as two conventional machine-learning models. The model was also able to propose novel high-ranking predictors. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Author Correction: Sex-based Differences in the Association between Body Composition and Incident Fracture Risk in Koreans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Strengthening the Family - the 'Five-I' Approach.

This article describes the importance of the family in diabetes care. It lists the multiple ways in which the family is related to diabetes: as a cause or culprit of diabetes, as a tool or technique for delivering diabetes care and as a target of diabetes or diabetes-care-related complications. The authors suggest an alliterative 'Five-I' approach to guide diabetes care professionals in addressing needs, and utilising strengths, of the family of a person with diabetes. The five 'I's stand for: involved independence, iterative information, interactive interviews, inspired introspection and integrated incorporation. This strategy, based upon evidence and experience, is supported by pragmatism and practicality.

Dehydroepiandrosterone Sulfate and Free Testosterone but not Estradiol are Related to Muscle Strength and Bone Microarchitecture in Older Adults.

The study aimed to elucidate the relationship between sex steroids and muscle mass, muscle strength, and trabecular bone score (TBS) in a community-dwelling aged population. We analyzed 922 men > 60 years of age and 1244 postmenopausal women. Weak muscle strength was defined as hand grip strength < 26 kg for men and < 18 kg for women, whereas degraded bone microarchitecture was defined as a TBS ≤ 1.2. The mean age was 70.2 ± 6.8 years for men and 71.2 ± 6.7 years for women. Participants within higher dehydroepiandrosterone sulfate (DHEAS) and free testosterone (FT) tertiles were likely to be younger, have greater muscle mass, and have stronger hand grip strength. Based on logistic regression models, men within the lowest FT tertile had weaker muscle strength compared to those in the highest tertile (adjusted odds ratio [OR] 2.28; 95% confidence interval [CI] 1.33-3.91). Women within the lowest DHEAS and FT tertile had weaker muscle strength compared to those in the highest tertile (adjusted OR for DHEAS 1.42; 95% CI 1.02-1.99; adjusted OR for FT 1.77, 95% CI 1.26-2.48). Moreover, men within the lowest FT tertile exhibited degraded bone microarchitecture compared to those in the highest tertile (adjusted OR 2.57, 95% CI 1.46-4.51). However, estradiol was not related to muscle strength or bone microarchitecture in both sexes. In conclusion, in aged men, serum FT was closely associated with muscle strength and bone microarchitecture and in postmenopausal women, serum DHEAS and FT were related to muscle strength.

Disentangling the genetics of lean mass.

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study.

AIMS/HYPOTHESIS: Ketones may be regarded as a thrifty fuel for peripheral tissues, but their clinical prognostic significance remains unclear. We investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic variables in a large population-based observational study. METHODS: We analysed 8703 individuals free of diabetes at baseline enrolled in the Korean Genome and Epidemiology Study, a community-based 12 year prospective study. Individuals with (n = 195) or without fasting ketonuria were matched 1:4 by propensity score. Incident diabetes was defined as fasting plasma glucose ≥7.0 mmol/l, post-load 2 h glucose ≥11.1 mmol/l on biennial OGTTs, or current use of glucose-lowering medication. Using Cox regression models, HRs for developing diabetes associated with the presence of ketonuria at baseline were analysed. RESULTS: Over 12 years, of the 925 participants in the propensity score-matched cohort, 190 (20.5%) developed diabetes. The incidence rate of diabetes was significantly lower in participants with spontaneous ketonuria compared with those without ketonuria (HR 0.63; 95% CI 0.41, 0.97). Results were virtually identical when participants with fasting ketonuria were compared against all participants without ketonuria (after multivariate adjustment, HR 0.66; 95% CI 0.45, 0.96). During follow-up, participants with baseline ketonuria maintained lower post-load 1 h and 2 h glucose levels and a higher insulinogenic index despite comparable baseline values. CONCLUSIONS/INTERPRETATION: The presence of spontaneous fasting ketonuria was significantly associated with a reduced risk of diabetes, independently of metabolic variables. Our findings suggest that spontaneous fasting ketonuria may have a potential preventive role in the development of diabetes.

Oral Glucose Tolerance Testing Allows Better Prediction of Diabetes in Women with a History of Gestational Diabetes Mellitus.

BACKGROUND: We aimed to identify the postpartum metabolic factors that were associated with the development of diabetes in women with a history of gestational diabetes mellitus (GDM). In addition, we examined the role of the oral glucose tolerance test (OGTT) in the prediction of future diabetes. METHODS: We conducted a prospective study of 179 subjects who previously had GDM but did not have diabetes at 2 months postpartum. The initial postpartum examination including a 75-g OGTT and the frequently sampled intravenous glucose tolerance test (FSIVGTT) was performed 12 months after delivery, and annual follow-up visits were made thereafter. RESULTS: The insulinogenic index (IGI30) obtained from the OGTT was significantly correlated with the acute insulin response to glucose (AIRg) obtained from the FSIVGTT. The disposition indices obtained from the OGTT and FSIVGTT were also significantly correlated. Women who progressed to diabetes had a lower insulin secretory capacity including IGI30, AIRg, and disposition indices obtained from the FSIVGTT and OGTT compared with those who did not. However, the insulin sensitivity indices obtained from the OGTT and FSIVGTT did not differ between the two groups. Multivariate logistic regression analysis showed that the 2-hour glucose and disposition index obtained from the FSIVGTT were significant postpartum metabolic risk factors for the development of diabetes. CONCLUSION: We identified a crucial role of ß-cell dysfunction in the development of diabetes in Korean women with previous GDM. The 2-hour glucose result from the OGTT is an independent predictor of future diabetes. Therefore, the OGTT is crucial for better prediction of future diabetes in Korean women with previous GDM.