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Abstract Background Crop breeding should be accelerated to address global warming and climate change. Wheat (Triticum aestivum L.) is a major food crop. Speed breeding (SB) and speed vernalization (SV) techniques for spring and winter wheat have recently been established. However, there are few practical examples of these strategies being used economically and efficiently in breeding programs. We aimed to establish and evaluate the performance of a breeder-friendly and energy-saving generation acceleration system by modifying the SV + SB system. Results In this study, a four-generation advancement system for wheat (regardless of its growth habits) was established and evaluated using an energy-efficient extended photoperiod treatment. A glasshouse with a 22-hour photoperiod that used 10 h of natural sunlight and 12 h of LED lights, and minimized temperature control during the winter season, was successful in accelerating generation. Even with one or two field tests, modified speed breeding (mSB) combined with a speed vernalization system (SV + mSB) reduced breeding time by more than half compared to traditional field-based methods. When compared to the existing SV + SB system, the SV + mSB system reduced energy use by 80% to maintain a 22-hour photoperiod. Significant correlations were found between the SV + mSB and field conditions in the number of days to heading (DTH) and culm length (CL). Genetic resources, recombinant inbred lines, and breeding materials that exhibited shorter DTH and CL values under SV + mSB conditions showed the same pattern in the field. Conclusions The results of our SV + mSB model, as well as its practical application in wheat breeding programs, are expected to help breeders worldwide incorporate generation acceleration systems into their conventional breeding programs.

This study employed a joint strategy high-density SNP Chip DNA markers and multiple Genome Association and Prediction Integrated Tool (GAPIT) models [(Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK), Fixed and random model Circulating Probability Uniform (FarmCPU), General Linear Model (GLM), and Settlement of Mixed Linear Model (MLM) Under Progressively Exclusive Relationship (SUPER)], to investigate novel genetic factors controlling mesocotyl elongation and seedling emergence for direct-seeded rice. Genotype data (230,526 SNP Chip DNA makers) of 117 doubled haploid lines (derived from a cross between 93–11 (Oryza sativa L. ssp. indica) and Milyang352 (O. sativa L. ssp. japonica) were used to perform a Genome-Wide Association Study (GWAS). Results revealed the association between five (5) topmost significant SNP markers, of which number two [AX-155741269, Chr2: 15422406 bp, and AX-155200917, Chr7: 23814085 bp, explaining 37.5% and 13.8% of the phenotypic variance explained (PVE)] are linked to the mesocotyl elongation loci, while three (AX-282097034 and AX-283652873, Chr9: 9882817 bp and 1023383 bp, PVE 64.5%, and 20.2%, respectively, and AX-154356231, Chr1: 17413989 bp, PVE 21.1%) are tightly linked to the loci controlling seedling emergence. The qMEL2-1 and qSEM9-1 are identified as major QTLs explaining 37.5% and 64.5% of the PVE for mesocotyl elongation and seedling emergence, respectively. The AX-282097034 (Chr9: 9882817 bp) was co-detected by four GAPIT models (BLINK, FarmCPU, SUPER, and GLM), while AX-155741269 was co-detected by BLINK and SUPER. Furthermore, a high estimated heritability (Mesocotyl elongation: h2 = 0.955; seedling emergence: h2 = 0.863; shoot length: h2 = 0.707) was observed. Genes harbored by qMEL2-1 and qSEM9-1 have interesting annotated molecular functions that could be investigated through functional studies to uncover their roles during mesocotyl elongation and seedling emergence events in rice. Furthermore, the presence of genes encoding transcription factors, growth- and stress response, or signaling-related genes would suggest that mesocotyl elongation and seedling emergence from deep direct-seeded rice might involve an active signaling cascade and transport of molecules, which could be elucidated through functional analysis. Likewise, genomic selection analysis suggested markers useful for downstream marker-assisted selection (MAS).

This study investigated novel quantitative traits loci (QTLs) associated with the control of grain shape and size as well as grain weight in rice. We employed a joint-strategy multiple GAPIT (Genome Association and Prediction Integrated Tool) models [(Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK)), Fixed and random model Circulating Probability Uniform (FarmCPU), Settlement of MLM Under Progressive Exclusive Relationship (SUPER), and General Linear Model (GLM)]–High-Density SNP Chip DNA Markers (60,461) to conduct a Genome-Wide Association Study (GWAS). GWAS was performed using genotype and grain-related phenotypes of 143 recombinant inbred lines (RILs). Data show that parental lines (Ilpum and Tung Tin Wan Hein 1, TTWH1, Oryza sativa L., ssp. japonica and indica, respectively) exhibited divergent phenotypes for all analyzed grain traits), which was reflected in their derived population. GWAS results revealed the association between seven SNP Chip makers and QTLs for grain length, co-detected by all GAPIT models on chromosomes (Chr) 1–3, 5, 7, and 11, were qGL1-1BFSG (AX-95918134, Chr1: 3,820,526 bp) explains 65.2–72.5% of the phenotypic variance explained (PVE). In addition, qGW1-1BFSG (AX-273945773, Chr1: 5,623,288 bp) for grain width explains 15.5–18.9% of PVE. Furthermore, BLINK or FarmCPU identified three QTLs for grain thickness independently, and explain 74.9% (qGT1Blink, AX-279261704, Chr1: 18,023,142 bp) and 54.9% (qGT2-1Farm, AX-154787777, Chr2: 2,118,477 bp) of the observed PVE. For the grain length-to-width ratio (LWR), the qLWR2BFSG (AX-274833045, Chr2: 10,000,097 bp) explains nearly 15.2–32% of the observed PVE. Likewise, the major QTL for thousand-grain weight (TGW) was detected on Chr6 (qTGW6BFSG, AX-115737727, 28,484,619 bp) and explains 32.8–54% of PVE. The qTGW6BFSG QTL coincides with qGW6-1Blink for grain width and explained 32.8–54% of PVE. Putative candidate genes pooled from major QTLs for each grain trait have interesting annotated functions that require functional studies to elucidate their function in the control of grain size, shape, or weight in rice. Genome selection analysis proposed makers useful for downstream marker-assisted selection based on genetic merit of RILs.

Protein content is one of the main factors determining the end-use quality of wheat. NO APICAL MERISTEM-B1 (NAM-B1) is a major gene regulating wheat grain protein content. The present study aimed to identify new genetic resources using the wild-type NAM-B1 allele to breed high-protein-content wheat cultivars. We genotyped the HIGH GRAIN PROTEIN CONTENT-B1 (GPC-B1) locus and NAM-B1 allele in 165 wheat cultivars. A kompetitive allele-specific polymerase chain reaction (KASP) marker was designed for functional NAM-B1 allele screening. The results revealed that 41 out of 165 cultivars carried the GPC-B1 locus. Among the 41 GPC-B1-carrying cultivars, the wild-type NAM-B1 allele was identified in only 3 cultivars, none of which were Korean. The remaining 38 cultivars showed a 1-bp insertion in NAM-B1, resulting in a stop codon in the middle of the gene, rendering it nonfunctional. Overall, this study reveals that the utilization of the three selected cultivars possessing the wild-type NAM-B1 gene, in conjunction with the developed KASP assay, could increase the protein content in Korean wheat cultivars.

Grain filling is an important trait of rice that affects the yield of grain-oriented crop species with sink capacity-related traits. Here, we used a doubled haploid (DH) population derived from a cross between 93-11 (P1, indica) and Milyang352 (P2, japonica) to investigate quantitative traits loci (QTLs) controlling grain filling in rice employing the Kompetitive allele-specific PCR (KASP) markers. The mapping population was grown under early-, normal-, and late-cultivation periods. The phenotypic evaluation revealed that spikelet number per panicle positively correlated with the grain-filling ratio under early cultivation conditions. Notably, three significant QTLs associated with the control of grain filling, qFG3, qFG5-1, and qFG5-2, were identified. Genes harbored by these QTLs are linked with diverse biological processes and molecular functions. Likewise, genes associated with abiotic stress response and transcription factor activity and redox homeostasis were detected. Genes such as MYB, WRKY60, and OsSh1 encoding transcription factor, β-catenin, and the tubulin FtsZ, as well as those encoding cytochrome P450, would play a forefront role in controlling grain filling under early cultivation conditions. Our results suggest that qFG3-related genes could mediate the transition between grain filling and abiotic stress response mechanisms. Fine-mapping these QTLs would help identify putative candidate genes for downstream functional characterization.

BackgroundAlthough autonomic imbalance is associated with an increased risk for metabolic disease, its effects on nonalcoholic fatty liver disease (NAFLD) remains unclear. We aimed to evaluate whether autonomic dysfunction predicts the risk for nonalcoholic fatty liver disease (NAFLD).MethodsA total of 33,899 participants without NAFLD who underwent health screening programs between 2011 and 2018 were enrolled. NAFLD was identified by ultrasonography. Autonomic activity was estimated using heart rate variability (HRV). Time domain [standard deviation of the normal-to-normal interval (SDNN) and root mean square difference (RMSSD)]; frequency domain [total power (TP), low frequency (LF), and high frequency (HF), and LF/HF ratio were analyzed.FindingsA total 6,466 participants developed NAFLD within a median of 5.7 years. Subjects with incident NAFLD showed decreased overall autonomic modulation and vagal activity with lowered SDNN, RMSSD, HF, normalized HF, compared to those without NAFLD. As the SDNN, RMSSD, TP, LF, and HF tertiles increased, the risk of NAFLD decreased with tertile 1 being the reference group [the hazard ratios (95% confidence intervals) of tertile 3 were 0.90 (0.85–0.96), 0.83 (0.78–0.88), 0.91 (0.86-0.97), 0.93 (0.87-0.99) and 0.89 (0.83-0.94), respectively] after adjusting for potential confounders. The risk for NAFLD was significantly higher in subjects in whom sustained elevated heart rate, normalized LF, and LF/HF ratio values than in those with sustained decrease in these parameters during follow-up.ConclusionsOverall autonomic imbalance, decreased parasympathetic activity, and recently increased sympathetic activity might increase the risk of NAFLD.

Bakanae disease caused by Fusarium fujikuroi causes crop failure and yield losses in the majority of rice-growing countries. In this study, we employed a joint strategy quantitative trait locus (QTL) mapping–Genome-Wide Association Study (GWAS) to investigate novel genetic loci associated with Bakanae disease resistance using a population of 143 BC1F8 RILs derived from a cross between Ilpum × Tung Tin Wan Hien1. The phenotypic data from the bioassay and the genotypic data generated using a DNA chip were utilized to perform QTL mapping and GWAS study. Our results identified a novel genetic locus qBK4T associated with Bakanae disease resistance, which was mapped on chromosome 4 and flanked by AX-116847364 (33.12 Mbp) and AX-115752415 (33.44 Mbp) markers covering a region of 324kbp. There were 34 genes in this region including Os04g55920 (encoding a zinc-finger protein, OsJAZ1), Os04g55970 (encoding AP2-like ethylene-responsive transcription factor), etc. This study proposes qBK4T as a novel locus for Bakanae disease resistance. The identification of qBK4T and its flanking marker information could be useful for marker-assisted breeding and functional characterization of resistance genes against bakanae disease.

Phytophthora blight (PB) caused by Phytophthora nicotianae is a highly destructive disease in sesame (Sesamum indicum L.). In this study, we used linkage mapping and genome-wide association study (GWAS) to identify quantitative trait loci (QTL) and candidate genes associated with PB resistance. The QTL mapping in 90 RILs of the Goenbaek × Osan cross using genotyping-by-sequencing detected significant QTLs for PB resistance on chromosome 10, explaining 12.79%–13.34% of phenotypic variation. Association of this locus to PB resistance was also revealed through bulked segregant analysis in second RIL population (Goenbaek × Milsung cross) comprising 188 RILs. The GWAS of 87 sesame accessions evaluated against three P. nicotianae isolates identified 29 SNPs on chromosome 10 significantly associated with PB resistance. These SNPs were located within a 0.79 Mb region, which co-located with the QTL intervals identified in RIL populations, and hence scanned for identifying candidate genes. This region contained several defense-related candidate R genes, five of which were selected for quantitative expression analysis. One of these genes, SIN_1019016 was found to show significantly higher expression in the resistant parent compared to that in the susceptible parents and selected RILs. Paired-end sequencing of the gene SIN_1019016 in parental cultivars revealed two synonymous SNPs between Goenbaek and Osan in exon 2 of coding DNA sequence. These results suggested SIN_1019016 as one of the candidate gene conferring PB resistance in sesame. The findings from this study will be useful in the marker-assisted selection as well as the functional analysis of PB resistance candidate gene(s) in sesame.

BackgroundEmerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB).MethodsWe examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels.ResultsLack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends.ConclusionAltogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.

BackgroundThe nuclear receptor peroxisome proliferator-activator gamma (PPARγ) is a useful therapeutic target for obesity and diabetes, but its role in protecting β-cell function and viability is unclear.MethodsTo identify the potential functions of PPARγ in β-cells, we treated mouse insulinoma 6 (MIN6) cells with the PPARγ agonist pioglitazone in conditions of lipotoxicity, endoplasmic reticulum (ER) stress, and inflammation.ResultsPalmitate-treated cells incubated with pioglitazone exhibited significant improvements in glucose-stimulated insulin secretion and the repression of apoptosis, as shown by decreased caspase-3 cleavage and poly (adenosine diphosphate [ADP]-ribose) polymerase activity. Pioglitazone also reversed the palmitate-induced expression of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], and IL-1β) and ER stress markers (phosphor-eukaryotic translation initiation factor 2α, glucose-regulated protein 78 [GRP78], cleaved-activating transcription factor 6 [ATF6], and C/EBP homologous protein [CHOP]), and pioglitazone significantly attenuated inflammation and ER stress in lipopolysaccharide- or tunicamycin-treated MIN6 cells. The protective effect of pioglitazone was also tested in pancreatic islets from high-fat-fed KK-Ay mice administered 0.02% (wt/wt) pioglitazone or vehicle for 6 weeks. Pioglitazone remarkably reduced the expression of ATF6α, GRP78, and monocyte chemoattractant protein-1, prevented α-cell infiltration into the pancreatic islets, and upregulated glucose transporter 2 (Glut2) expression in β-cells. Moreover, the preservation of β-cells by pioglitazone was accompanied by a significant reduction of blood glucose levels.ConclusionAltogether, these results support the proposal that PPARγ agonists not only suppress insulin resistance, but also prevent β-cell impairment via protection against ER stress and inflammation. The activation of PPARγ might be a new therapeutic approach for improving β-cell survival and insulin secretion in patients with diabetes mellitus

BackgroundHypertriglyceridemia is known to have an association with increased risks of insulin resistance and diabetes. The aim of this study was to investigate the risk of diabetes mellitus, according to changes in the concentrations of triglycerides, over time.MethodsA total of 15,932 non-diabetic participants (mean age 43.2 years, 68% men) who attended five consecutive annual health check-ups at Kangbuk Samsung Hospital, between January 2010 and December 2014, were recruited. Participants were classified according to their triglyceride concentrations; normal (

BackgroundAge-related decreases in lean mass represent a serious health problem. We aimed to analyze the risks of rapid decreases in lean mass by age and sex in relatively young Korean adults during a 4-year follow-up study.MethodsA total of 65,856 non-diabetic participants (59.5% men, mean age 39.1 years) in a health screening program were subjected to bioimpedance body composition analyses and metabolic parameter analyses at baseline and after 4 years. The participants were sub-divided according to age, and additionally to six groups by age and the degree of body weight change over the 4-year period. The actual changes in body weight, lean mass, and fat mass and the percent changes over the 4-year period were assessed.ResultsThe percent change in lean mass decreased and the percent change of fat mass increased with increasing age in every age and sex group. However, the annual percent decrease in lean mass and percent increase in fat mass were significantly higher among women than among men (−0.26% vs. −0.15% and 0.34% vs. 0.42%, respectively; P

Purpose Insulin resistance is one of the most important mechanisms in the development of diabetes, and it is closely related to the presence and severity of coronary heart disease. Triglyceride glucose (TyG) index is a useful marker of insulin resistance; however, few studies have investigated the relationship between TyG and subclinical atherosclerosis. Therefore, we evaluated the association of TyG and subclinical coronary atherosclerosis as measured by coronary artery calcium score (CACS). Methods Our study included 30,776 participants (mean age of 41 years, 80.4% male) enrolled in a health screening program, in whom CACS were measured. Homeostasis model assessment of insulin resistance (HOMA-IR), TyG index, TyG-body mass index (BMI), and TyG-waist circumference (WC) were subsequently analyzed. Indices were calculated using the following formulae: HOMA-IR=fasting insulin (μU/mL)×fasting plasma glucose (FPG; mmol/L)/22.5; TyG index=Ln [TG (mg/dL)×FPG (mg/dL)/2]; TyG-BMI=TyG index×BMI; and TyG-WC=TyG index×WC. CACS was measured using multidetector computed tomography, and the presence of coronary artery calcification (CAC) was defined by CACS>0. Results The prevalence of CAC was 14.4% in the study population. Multivariate logistic regression analysis showed that participants with TyG-BMI in the highest tertile were 1.638 times more likely to have CAC after adjustment for other metabolic parameters compared with participants with TyG-BMI in the lowest tertile (odds ratio, 1.612; 95% confidence interval, 1.465 to 1.774). The receiver operating characteristics curve for prediction of CAC showed that TyG-WC index had a higher area under the curve (AUC=0.626) than other indices (AUCTyG=0.617, AUCTyG-BMI=0.616, AUCHOMA-IR=0.562). Conclusion TyG index predicted CAC better than other markers of insulin resistance, and could be a useful marker for predicting subclinical atherosclerosis.

BackgroundWe aimed to assess the risk for coronary artery calcification (CAC) according to groups subdivided by body mass index (BMI) and waist circumference (WC) in apparently healthy Korean adults.MethodsThirty-three thousand four hundred and thirty-two participants (mean age, 42 years) in a health screening program were divided into three groups according to BMI: 25 kg/m2 (obese). In addition, the participants were divided into two groups according to WC. Coronary artery calcium score (CACS) was measured with multi-detector computed tomography in all participants. Presence of CAC was defined as CACS >0.ResultsWhen logistic regression analysis was performed with the presence of CAC as the dependent variable, the risk for CAC increased as BMI increased after adjusting for confounding variables (1.102 [95% confidence interval (CI), 1.000 to 1.216]; 1.284 [95% CI, 1.169 to 1.410]; in the overweight and obese groups vs. the normal weight group). When the participants were divided into six groups according to BMI and WC, the subjects with BMI and WC in the obese range showed the highest risk for CAC (1.321 [95% CI, 1.194 to 1.461]) and those with BMI in the overweight range and WC in the obese range showed the second highest risk for CAC (1.235 [95% CI, 1.194 to 1.461]).ConclusionParticipants with obesity defined by both BMI and WC showed the highest risk for CAC. Those with BMIs in the overweight range but with WC in the obese range showed the second highest risk for CAC, suggesting that WC as a marker of obesity is more predictive of CAC than BMI.

BackgroundThe purpose of this study was to investigate the relationship between statin eligibility and the degree of renal dysfunction using the Adult Treatment Panel (ATP) III and the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines in Korean adults.MethodsRenal function was assessed in 18,746 participants of the Kangbuk Samsung Health Study from January 2011 to December 2012. Subjects were divided into three groups according to estimated glomerular filtration rate (eGFR): stage 1, eGFR ≥90 mL/min/1.73 m2; stage 2, eGFR 60 to 89 mL/min/1.73 m2; and stages 3 to 5, eGFR

BackgroundDiabetes can be efficiently prevented by life style modification and medical therapy. So, identification for high risk subjects for incident type 2 diabetes is important. The aim of this study is to identify the best β-cell function index to identify high risk subjects in non-diabetic Koreans.MethodsThis is a retrospective longitudinal study. Total 140 non-diabetic subjects who underwent standard 2-hour 75 g oral glucose tolerance test from January 2007 to February 2007 at Kangbuk Samsung Hospital and followed up for more than 1 year were analyzed (mean follow-up, 54.9±16.4 months). The subjects were consist of subjects with normal glucose tolerance (n=44) and subjects with prediabetes (n=97) who were 20 years of age or older. Samples for insulin and C-peptide levels were obtained at 0 and 30 minutes at baseline.ResultsThirty subjects out of 140 subjects (21.4%) developed type 2 diabetes. When insulin-based index and C-peptide-based index are compared between progressor and non-progressor to diabetes, all C-peptide-based indices were statistically different between two groups, but only insulinogenic index and disposition index among insulin-based index were statistically different. C-peptide-based index had higher value of area under receiver operating characteristic curve (AROC) value than that of insulin-based index. "C-peptidogenic" index had highest AROC value among indices (AROC, 0.850; 95% confidence interval, 0.761 to 0.915). C-peptidogenic index had significantly higher AROC than insulinogenic index (0.850 vs. 0.731 respectively; P=0.014).ConclusionC-peptide-based index was more closely related to incident type 2 diabetes in non-diabetic subjects than insulin-based index.

BackgroundWe investigated the association between the severity of non-alcoholic fatty liver disease (NAFLD) and the estimated 10-year risk of cardiovascular disease (CVD) calculated by Pooled Cohort Equation (PCE) and Framingham risk score (FRS).MethodsA total of 15,913 participants (mean age, 46.3 years) in a health screening program were selected for analysis. The presence and severity of fatty liver was assessed by abdominal ultrasonogram. Subjects who drank alcohol more than three times a week were excluded from the study.ResultsAmong the participants, 57.6% had no NAFLD, 35.4% had grade I, 6.5% had grade II, and 0.5% had grade III NAFLD. Mean estimated 10-year CVD risk was 2.59%, 3.93%, 4.68%, and 5.23% calculated using the PCE (P for trend

BackgroundWaist-to-height ratio (WHtR) is an easy and inexpensive adiposity index that reflects central obesity. In this study, we examined the association of various baseline adiposity indices, including WHtR, with the development of diabetes over 4 years of follow-up in apparently healthy Korean individuals.MethodsA total of 2,900 nondiabetic participants (mean age, 44.3 years; 2,078 men) in a health screening program, who repeated the medical check-up in 2005 and 2009, were recruited. Subjects were divided into two groups according to development of diabetes after 4 years. The cut-off values of baseline body mass index (BMI), waist circumference (WC), and WHtR for the development of diabetes over 4 years were calculated. The sensitivity, specificity, and mean area under the receiver operator characteristic curve (AUROC) of each index were assessed. The odds ratio (OR) for diabetes development was analyzed for each of the three baseline adiposity indices.ResultsDuring the follow-up period, 101 new cases (3.5%) of diabetes were diagnosed. The cut-off WHtR value for diabetes development was 0.51. Moreover, WHtR had the highest AUROC value for diabetes development among the three adiposity indices (0.716, 95% confidence interval [CI], 0.669 to 0.763; 0.702, 95% CI, 0.655 to 0.750 for WC; 0.700, 95% CI, 0.651 to 0.750 for BMI). After adjusting for confounding variables, the ORs of WHtR and WC for diabetes development were 1.95 (95% CI, 1.14 to 3.34) and 1.96 (95% CI, 1.10 to 3.49), respectively. No significant differences were observed between the two groups regarding BMI.ConclusionIncreased baseline WHtR and WC correlated with the development of diabetes after 4 years. WHtR might be a useful screening measurement to identify individuals at high risk for diabetes.

BackgroundThe aim of this study is to compare the risk for future development of nonalcoholic fatty liver disease (NAFLD) according to different status of metabolic health and obesity.MethodsA total of 3,045 subjects without NAFLD and diabetes at baseline were followed for 4 years. Subjects were categorized into four groups according to the following baseline metabolic health and obesity statuses: metabolically healthy, non-obese (MHNO); metabolically healthy, obese (MHO); metabolically unhealthy, non-obese (MUHNO); and metabolically unhealthy, obese (MUHO). Being metabolically healthy was defined as having fewer than two of the following five components: high blood pressure, high fasting blood glucose, high triglyceride, low high density lipoprotein cholesterol, and being in the highest decile of the homeostasis model assessment-insulin resistance index. Obesity was defined as a body mass index >25 kg/m2. The presence of NAFLD was assessed by ultrasonography.ResultsThe proportions of subjects included in the MHNO, MHO, MUHNO, and MUHO groups were 71.4%, 9.8%, 13.0%, and 5.8%, respectively. The proportions of subjects who developed NAFLD were 10.5%, 31.4%, 23.2%, and 42% in the MHNO, MHO, MUHNO, and MUHO groups, respectively. The risk for developing NAFLD was highest in subjects who were metabolically unhealthy both at baseline and after 4 years compared with subjects who were consistently metabolically healthy during the follow-up period (odds ratio, 2.862). Using the MHNO group as reference, the odds ratios for the MHO, MUHNO, and MUHO groups were 1.731, 1.877, and 2.501, respectively.ConclusionThe risk for NAFLD was lower in MHO subjects than in MUNO subjects.

BackgroundThe present study evaluated the efficacy of a combination of ibandronate and cholecalciferol on the restoration of the levels of 25-hydroxyvitamin D (25[OH]D) and various bone markers in postmenopausal women with osteoporosis.MethodsThis was a randomized, double-blind, active-controlled, prospective 16-week clinical trial conducted in 20 different hospitals. A total of 201 postmenopausal women with osteoporosis were assigned randomly to one of two groups: the IBN group, which received a once-monthly pill containing 150 mg ibandronate (n=99), or the IBN+ group, which received a once-monthly pill containing 150 mg ibandronate and 24,000 IU cholecalciferol (n=102). Serum levels of 25(OH)D, parathyroid hormone (PTH), and various bone markers were assessed at baseline and at the end of a 16-week treatment period.ResultsAfter 16 weeks of treatment, the mean serum levels of 25(OH)D significantly increased from 21.0 to 25.3 ng/mL in the IBN+ group but significantly decreased from 20.6 to 17.4 ng/mL in the IBN group. Additionally, both groups exhibited significant increases in mean serum levels of PTH but significant decreases in serum levels of bone-specific alkaline phosphatase and C-telopeptide of type 1 collagen (CTX) at 16 weeks; no significant differences were observed between the groups. However, in subjects with a vitamin D deficiency, IBN+ treatment resulted in a significant decrease in serum CTX levels compared with IBN treatment.ConclusionThe present findings demonstrate that a once-monthly pill containing ibandronate and cholecalciferol may be useful for the amelioration of vitamin D deficiency in patients with postmenopausal osteoporosis. Moreover, this treatment combination effectively decreased serum levels of resorption markers, especially in subjects with a vitamin D deficiency, over the 16-week treatment period.

BackgroundMetabolic health is an emerging concept that is highly correlated with various metabolic complications, and adipocytokines have been causally linked to a wide range of metabolic diseases. Thus, this study compared serum adipocytokine levels according to metabolic health and obesity status.MethodsFour hundred and fifty-six nondiabetic subjects (mean age, 40.5 years) were categorized into four groups according to metabolic health and obesity status: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUHNO), and metabolically unhealthy obese (MUHO). Being metabolically healthy was defined as the presence of fewer than two of the following five metabolic abnormalities: high blood pressure, high fasting blood glucose, high triglyceride, low high density lipoprotein cholesterol, and being in the highest decile of the homeostatic model assessment of insulin resistance index. Obesity status was assessed using body mass index (BMI), with obesity defined as a BMI higher than 25 kg/m2. Levels of serum interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α (TNF-α), and adipocyte fatty acid binding protein (A-FABP) were also evaluated.ResultsOf the 456 subjects, 247 (54.2%) were in the MHNO group, 66 (14.5%) were in the MHO group, 66 (14.5%) were in the MUHNO group, and 77 (16.9%) were in the MUHO group. There were no significant differences in IL-6 or MCP-1 levels among the groups, but levels of TNF-α and A-FABP were significantly higher in the MUHNO group compared to the MHNO group.ConclusionHigh TNF-α and A-FABP levels are significantly associated with metabolically unhealthiness in nonobese Korean individuals.

BackgroundSelenoprotein P (SEPP1) and fetuin-A, both circulating liver-derived glycoproteins, are novel biomarkers for insulin resistance and nonalcoholic fatty liver disease. However, the effect of exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, on the expression of hepatokines, SEPP1, and fetuin-A, is unknown.MethodsThe human hepatoma cell line HepG2 was treated with palmitic acid (PA; 0.4 mM) and tunicamycin (tuni; 2ug/ml) with or without exendin-4 (100 nM) for 24 hours. The change in expression of PA-induced SEPP1, fetuin-A, and endoplasmic reticulum (ER) stress markers by exendin-4 treatment were evaluated using quantitative real-time reverse transcription polymerase chain reaction and Western blotting. Transfection of cells with AMP-activated protein kinase (AMPK) small interfering RNA (siRNA) was performed to establish the effect of exendin-4-mediated AMPK in the regulation of SEPP1 and fetuin-A expression.ResultsExendin-4 reduced the expression of SEPP1, fetuin-A, and ER stress markers including PKR-like ER kinase, inositol-requiring kinase 1α, activating transcription factor 6, and C/EBP homologous protein in HepG2 cells. Exendin-4 also reduced the expression of SEPP1 and fetuin-A in cells treated with tunicamycin, an ER stress inducer. In cells treated with the AMPK activator 5-aminoidazole-4-carboxamide ribonucleotide (AICAR), the expression of hepatic SEPP1 and fetuin-A were negatively related by AMPK, which is the target of exendin-4. In addition, exendin-4 treatment did not decrease SEPP1 and fetuin-A expression in cells transfected with AMPK siRNA.ConclusionThese data suggest that exendin-4 can attenuate the expression of hepatic SEPP1 and fetuin-A via improvement of PA-induced ER stress by AMPK.

BackgroundThe hypertriglyceridemic waist (HTGW) phenotype is a simple and inexpensive screening parameter to identify people at increased risk of cardiovascular disease. We evaluated whether the HTGW phenotype predicts diabetes in urban Korean adults.MethodsA total of 2,900 nondiabetic subjects (mean age 44.3 years), comprising 2,078 males (71.7%) and 822 females (28.3%) who underwent annual medical check-ups at our center between January 2005 and December 2009, were recruited. The subjects were divided into four groups according to baseline serum triglyceride (TG) level and waist circumference (WC): normal WC-normal TG (NWNT) level, normal WC-high TG level, enlarged WC-normal TG level, and enlarged WC-high TG (EWHT) level. High serum TG level was defined as ≥150 mg/dL and enlarged WC was defined as ≥90 cm for men and ≥85 cm for women. New cases of diabetes were determined according to questionnaires filled in by participants and the diagnostic criteria of the American Diabetes Association. Cox proportional hazards model analysis was used to assess the association of HTGW phenotype with the incidence of diabetes.ResultsA total of 101 (3.5%) new diabetes cases were diagnosed during the study period. The EWHT group had a higher incidence of diabetes (8.3%) compared with the NWNT group (2.2%). The adjusted hazard ratio for diabetes for subjects with the EWHT phenotype at baseline was 4.113 (95% confidence interval [CI], 2.397 to 7.059) after adjustment for age, and 2.429 (95% CI, 1.370 to 4.307) after adjustment for age, sex, total cholesterol, systolic blood pressure, and alcohol drinking history. It was attenuated by inclusion of baseline fasting glucose level in the model.ConclusionSubjects with the HTGW phenotype showed the highest risk of incident diabetes. This tool could be useful for identifying individuals at high risk of diabetes.

BackgroundTumor necrosis factor (TNF)-α and AMP-activated protein kinase (AMPK) are known to stimulate and repress lipolysis in adipocytes, respectively; however, the mechanisms regulating these processes have not been completely elucidated.MethodsThe key factors and mechanism of action of TNF-α and AMPK in lipolysis were investigated by evaluating perilipin expression and activity of protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 α (eIF2α) by Western blot and an immunofluorescence assay in 24-hour TNF-α-treated 3T3-L1 adipocytes with artificial manipulation of AMPK activation.ResultsEnhancement of AMPK activity by the addition of activator minoimidazole carboxamide ribonucleotide (AICAR) suppressed TNF-α-induced lipolysis, whereas the addition of compound C, an inhibitor of AMPK phosphorylation, enhanced lipolysis. Perilipin, a lipid droplet-associated protein, was decreased by TNF-α and recovered following treatment with AICAR, showing a correlation with the antilipolytic effect of AICAR. Significant activation of PERK/eIF2α, a component of the unfolded protein response signaling pathway, was observed in TNF-α or vesicle-treated 3T3-L1 adipocytes. The antilipolytic effect and recovery of perilipin expression by AICAR in TNF-α-treated 3T3-L1 adipocytes were significantly diminished by treatment with 2-aminopurine, a specific inhibitor of eIF2α.ConclusionThese data indicated that AICAR-induced AMPK activation attenuates TNF-α-induced lipolysis via preservation of perilipin in 3T3-L1 adipocytes. In addition, PERK/eIF2α activity is a novel mechanism of the anti-lipolytic effect of AICAR.

BackgroundChronic kidney disease (CKD) is considered one of the most common risk factors for cardiovascular disease. Coronary artery calcification (CAC) is a potential mechanism that explains the association between renal function and cardiovascular mortality. We aimed to evaluate the association between renal function and CAC in apparently healthy Korean subjects.MethodsA total of 23,617 participants in a health-screening program at Kangbuk Samsung Hospital were included in the study. Estimated glomerular filtration rate (eGFR) was assessed using the Cockcroft-Gault equation. Coronary artery calcium score (CACS) was measured via multidetector computed tomography. Subjects were divided into three groups according to the CKD Staging system with eGFR grade: stage 1, eGFR ≥90 mL/min/1.73 m2; stage 2, eGFR 60 to 89 mL/min/1.73 m2; and stage 3, eGFR 30 to 59 mL/min/1.73 m2.ResultsThe mean age of the participants was 41.4 years and the mean eGFR was 103.6±21.7 mL/min/1.73 m2. Hypertension and diabetes were noted in 43.7% and 5.5% of the participants, respectively. eGFR showed a weakly negative but significant association with CACS in bivariate correlation analysis (r=-0.076, P

BackgroundAdipocyte-specific fatty acid-binding protein (A-FABP) is a cytoplasmic protein expressed in macrophages and adipocytes and it plays a role in insulin resistance and metabolic syndrome. Recently, the fatty liver index (FLI) was introduced as an indicator of nonalcoholic fatty liver disease (NAFLD). In this study, we aimed to investigate the relationship between baseline serum A-FABP levels and FLI after 4 years in apparently healthy subjects.MethodsA total of 238 subjects without a past history of alcoholism or hepatitis were recruited from a medical check-up program. The NAFLD state was evaluated 4 years later in the same subjects using FLI. Fatty liver disease was diagnosed as diffusely increased echogenicity of the hepatic parenchyma compared to the kidneys, vascular blurring, and deep-echo attenuation. NAFLD was defined as subjects with fatty liver and no history of alcohol consumption (>20 g/day).ResultsBaseline serum A-FABP levels were significantly associated with FLI after adjustment for age and sex (P

BackgroundTumor necrosis factor (TNF)-α is associated with insulin resistance and systemic inflammatory responses. The aim of this study was to investigate the relationship between TNF-α and the development of nonalcoholic fatty liver disease (NAFLD) in a longitudinal study.MethodsThree hundred and sixty-three apparently healthy subjects (mean age, 40.5±6.1 years; male, 57.6%) without NAFLD were enrolled in 2003. Anthropometric and laboratory measurements were performed. The participants were grouped into tertiles according to their serum TNF-α levels from samples taken in 2003. At a 4-year follow-up, we compared the odds ratios (ORs) of the development of NAFLD according to the tertiles of TNF-α levels measured in 2003.ResultsAt the 4-year follow-up, the cumulative incidence of NAFLD was 29.2% (106/363). The group that developed NAFLD had higher levels of TNF-α than those in the group without NAFLD (3.65±1.79 pg/mL vs. 3.15±1.78 pg/mL; P=0.016). When the 2003 serum TNF-α levels were categorized into tertiles: incidence of NAFLD observed in 2007 was significantly higher with increasing tertiles (22.6%, 35.8%, and 41.5%, respectively; P

BackgroundWe investigated the association of coronary artery calcium score (CACS) with body composition and insulin resistance in apparently healthy Korean adults.MethodsNine hundred forty-five participants (mean age, 48.9 years; 628 men) in a medical check-up program were selected for analysis. Body composition was assessed by bioelectrical impedance analysis (BIA). Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). The CACS was assessed by multidetector computed tomography.ResultsOne hundred forty-six subjects (15.4%) showed coronary artery calcification and 148 subjects (15.7%) had metabolic syndrome. CACS showed a significant positive correlation with age, fasting glucose level, waist circumference (WC), blood pressure, hemoglobin A1c, HOMA-IR, and waist-hip ratio (WHR) assessed by BIA. CACS had a negative correlation with high density lipoprotein cholesterol (HDL-C). Subjects with high CACS showed significantly higher mean WHRs and lower mean values for lean body mass compared with subjects without coronary artery calcification. In logistic regression analyses with coronary artery calcification as the dependent variable, the highest quartile of WHR showed a 3.125-fold increased odds ratio for coronary artery calcification compared with the lowest quartile after adjustment for confounding variables. When receiver operating characteristics analyses were performed with coronary artery calcification as the result variable, WHR showed the largest area under the curve (AUC) value among other variables except for age and WC in women (AUC=0.696 for WHR, 0.790 for age, and 0.719 for WC in women).ConclusionIn our study population of apparently healthy Korean adults, WHR was the most significant predictor for coronary artery calcification among other confounding factors, suggesting that it may have implication as a marker for early atherosclerosis.

Recent studies suggest an association between Lipoprotein(a) [Lp(a)] and the development of diabetes mellitus. We analyzed the association between baseline Lp(a) levels and diabetes development after 4 years of follow-up, in a population of apparently healthy Korean subjects.A total of 2,536 non-diabetic participants (mean age: 41 years, men: 92%) of a health checkup program were included in the study. Diabetes development was defined by fasting blood glucose ≥126 mg/dL, HbA1c ≥6.5%, and self-reported treatment of diabetes. Homeostasis model assessment (HOMA) indices were used to assess insulin resistance (IR) and insulin secretion (IS). Presence of IR and impaired IS was defined by being in the highest quartile of HOMA-IR and in the lowest quartile HOMA-IS.After four years, 3.4% of the participants developed diabetes. The odds ratio (OR) of developing diabetes was lowest in the 4th quartile group of baseline Lp(a) (0.323 [95% CI 0.153-0.685])with the 1st quartile group as the reference. The subjects with both IR & impaired IS plus baseline Lp(a)

Recent studies have suggested the importance of non-alcoholic fatty liver disease (NAFLD) and systemic inflammation in the development of atherosclerosis. The aim of this study was to compare the risk for coronary artery calcification (CAC) development according to the status of NAFLD and inflammation over four years of follow-up in subjects without baseline CAC.A total of 1,575 participants in a health screening program were divided into four groups according to baseline NAFLD state and high-sensitivity C-reactive protein (hs-CRP) (median 0.06 mg/L) levels as follows: no NAFLD and hs-CRP

BackgroundWe performed a retrospective longitudinal study on the effects of changes in weight, body composition, and homeostasis model assessment (HOMA) indices on glycemic progression in subjects without diabetes during a four-year follow-up period in a community cohort without intentional intervention.MethodsFrom 28,440 non-diabetic subjects who participated in a medical check-up program in 2004, data on anthropometric and metabolic parameters were obtained after four years in 2008. Body composition analyses were performed with a bioelectrical impedance analyzer. Skeletal muscle index (SMI, %) was calculated with lean mass/weight×100. Subjects were divided into three groups according to weight change status in four years: weight loss (≤-5.0%), stable weight (-5.0 to 5.0%), weight gain (≥5.0%). Progressors were defined as the subjects who progressed to impaired fasting glucose or diabetes.ResultsProgressors showed worse baseline metabolic profiles compared with non-progressors. In logistic regression analyses, the increase in changes of HOMA-insulin resistance (HOMA-IR) in four years presented higher odds ratios for glycemic progression compared with other changes during that period. Among the components of body composition, a change in waist-hip ratio was the strongest predictor, and SMI change in four years was a significant negative predictor for glycemic progression. Changes in HOMA β-cell function in four years was a negative predictor for glycemic progression.ConclusionIncreased interval changes in HOMA-IR, weight gain and waist-hip ratio was associated with glycemic progression during a four-year period without intentional intervention in non-diabetic Korean subjects.

The Triglyceride Glucose Index (TyG index) is considered a surrogate marker of insulin resistance. The aim of this study is to investigate whether the TyG index has a predictive role in identifying individuals with a high risk of incident diabetes and to compare it with other indicators of metabolic health. A total 2900 non-diabetic adults who attended five consecutive annual health check-ups at Kangbuk Samsung Hospital was divided into four subgroups using three methods: (1) baseline TyG index; (2) obesity status (body mass index ≥25 kg/m2) and cutoff value of TyG index; (3) obesity status and metabolic health, defined as having fewer than two of the five components of high blood pressure, fasting blood glucose, triglyceride, low high-density lipoprotein cholesterol, and highest decile of homeostasis model assessment-insulin resistance. The development of diabetes was assessed annually using self-questionnaire, fasting glucose, and glycated hemoglobin. We compared the risk of incident diabetes using multivariate Cox analysis. During 11623 person-years there were 101 case of incident diabetes. Subjects with high TyG index had a high risk of diabetes. For TyG index quartiles, hazard ratios (HRs) of quartiles 3 and 4 were 4.06 (p = 0.033) and 5.65 (p = 0.006) respectively. When the subjects were divided by obesity status and cutoff value of TyG index of 8.8, the subgroups with TyG index ≥ 8.8 regardless of obesity had a significantly high risk for diabetes (HR 2.40 [p = 0.024] and 2.25 [p = 0.048]). For obesity status and metabolic health, the two metabolically unhealthy subgroups regardless of obesity had a significantly high risk for diabetes (HRs 2.54 [p = 0.024] and 2.73 [p = 0.021]). In conclusion, the TyG index measured at a single time point may be an indicator of the risk for incident diabetes. The predictive value of the TyG index was comparable to that of metabolic health.

BACKGROUND: Recent studies report the importance of metabolic health beyond obesity. The aim of this study is to compare the risk for diabetes development according to different status of metabolic health and obesity over a median follow-up of 48.7 months. METHODS: 6,748 non-diabetic subjects (mean age 43 years) were divided into four groups according to the baseline metabolic health and obesity status: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUHNO) and metabolically unhealthy obese (MUHO). Being metabolically healthy was defined by having less than 2 components among the 5 components, that is, high blood pressure, high fasting blood glucose, high triglyceride, low high-density lipoprotein cholesterol and being in the highest decile of homeostasis model assessment-insulin resistance (HOMA-IR) index. Obesity status was assessed by body mass index (BMI) higher than 25 kg/m2. The development of diabetes was assessed annually from self-questionnaire, fasting glucose and HbA1c. RESULTS: At baseline, 45.3% of the subjects were MHNO, 11.3% were MHO, 21.7% were MUHNO, and 21.7% were MUHO. During a median follow-up of 48.7 months, 277 subject (4.1%) developed diabetes. The hazard ratio for diabetes development was 1.338 in MHO group (95% CI 0.67-2.672), 4.321 in MUHNO group (95% CI 2.702-6.910) and 5.994 in MUHO group (95% CI 3.561-10.085) when MHNO group was considered as the reference group. These results were similar after adjustment for the changes of the risk factors during the follow-up period. CONCLUSION: The risk for future diabetes development was higher in metabolically unhealthy subgroups compared with those of metabolically healthy subjects regardless of obesity status.

An analysis of the yield of eleutherosides B and E in Acanthopanax divaricatus and A. koreanum was performed using high performance liquid chromatography to evaluate production by different cultivation methods. In A. divaricatus and A. koreanum, the total content of eleutherosides B and E was 2.466–7.360 mg/g varying by plant section, 3.886–11.506 mg/g by pinching site, 3.655–10.083 mg/g by planting time, and 3.652–10.108 mg/g by fertilizer ratio. Thus the total content of eleutherosides B and E in A. divaricatus and A. koreanum differed depending on cultivation methods. These results present useful information for high eleutheroside content applications in A. divaricatus and A. koreanum. This information can affect selection of plant section and cultivation methods for nutraceutical, pharmaceutical, and cosmeceutical material development.

BackgroundRecent studies have suggested that metabolic health may contribute more to the atherosclerosis than obesity. The aim of this study is to compare coronary artery calcium scores (CACS) among patients with different metabolic health and obesity status.MethodsA health-screening program of 24,063 participants (mean age 41 years) was conducted, and CACS was assessed by multi-detector computerized tomography (MDCT). Being metabolically healthy was defined as having fewer than two of the following risk factors: high blood pressure, high fasting blood glucose, high triglyceride, low high-density lipoprotein cholesterol, highest decile of homeostasis model assessment-insulin resistance (HOMA-IR) index, and highest decile of high-sensitivity C-reactive protein (hs-CRP). Obesity status was defined as body mass index (BMI) higher than 25 kg/m(2). Analyses were performed in four groups divided according to metabolic health and obesity: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUHNO), and metabolically unhealthy obese (MUHO).ResultsMean values of CACS in the four groups were significantly different, except those between MHNO and MHO and between MUHNO and MUHO. When multinomial logistic regression analysis was performed with five CACS categories as the dependent variables and after adjusting for age, sex, and smoking status, the MHO, MUHNO, and MUHO groups showed significantly increased odds ratio for increasing CACS categories compared with no calcification status (5.221 for CACS >400 in MUHO group with 95% CI 2.856∼5.032 with MHNO group as the reference). When other variables including the metabolic parameters were included in the same model, the risks were attenuated.ConclusionMetabolic health is more closely associated with subclinical atherosclerosis than obesity as assessed by CACS.

The effects of exendin-4 on Sirt1 expression as a mechanism of reducing fatty liver have not been previously reported. Therefore, we investigated whether the beneficial effects of exendin-4 treatment on fatty liver are mediated via Sirt1 in high-fat (HF) diet-induced obese C57BL/6J mice and related cell culture models. Exendin-4 treatment decreased body weight, serum free fatty acid (FA), and triglyceride levels in HF-induced obese C57BL/6J mice. Histological analysis showed that exendin-4 reversed HF-induced hepatic accumulation of lipids and inflammation. Exendin-4 treatment increased mRNA and protein expression of Sirt1 and its downstream factor, AMPK, in vivo and also induced genes associated with FA oxidation and glucose metabolism. In addition, a significant increase in the hepatic expression of Lkb1 and Nampt mRNA was observed in exendin-4-treated groups. We also observed increased expression of phospho-Foxo1 and GLUT2, which are involved in hepatic glucose metabolism. In HepG2 and Huh7 cells, mRNA and protein expressions of GLP-1R were increased by exendin-4 treatment in a dose-dependent manner. Exendin-4 enhanced protein expression of Sirt1 and phospho-AMPKα in HepG2 cells treated with 0.4 mM palmitic acid. We also found that Sirt1 was an upstream regulator of AMPK in hepatocytes. A novel finding of this study was the observation that expression of GLP-1R is proportional to exendin-4 concentration and exendin-4 could attenuate fatty liver through activation of Sirt1.

Background: Coronary artery calcium score (CACS) has become an important tool for evaluating cardiovascular disease (CVD). This study evaluated the significance of CACS for future CVD through more than 10 years of follow-up in asymptomatic Korean populations with type 2 diabetes mellitus (T2DM) known to have a relatively low CACS burden. Methods: We enrolled 981 asymptomatic T2DM patients without CVD at baseline who underwent CACS evaluation using multidetector computed tomography between January 2008 and December 2014. They were grouped into five predefined CACS categories based on Agatston scores and followed up by August 2020. The primary endpoint was incident CVD events, including coronary, cerebrovascular, and peripheral arterial disease. Results: The relative risk of CVD was significantly higher in patients with CACS =10, and the significance persisted after adjustment for known confounders. A higher CACS category indicated a higher incidence of future CVD: hazard ratio (95% confidence interval) 4.09 (1.79 to 9.36), 12.00 (5.61 to 25.69), and 38.79 (16.43 to 91.59) for 10= CACS <100, 100= CACS <400, and CACS =400, respectively. During the 12-year follow-up period, the difference in event-free survival more than doubled as the category increased. Patients with CACS below 10 had very low CVD incidence throughout the follow-up. The receiver operating characteristic analysis showed better area under curve when the CACS cutoff was 10 than 100. Conclusion: CACS can be a sensitive marker of CVD risk. Specifically, CACS above 10 is an indicator of CVD high-risk requiring more intensive medical treatment in Koreans with T2DM. [ABSTRACT FROM AUTHOR]