Association between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction: A 7-year retrospective cohort study of 3,380 adults using serial echocardiography.

AIM: Left ventricular diastolic dysfunction (LVDD) has been observed in people with nonalcoholic fatty liver disease (NAFLD) in cross-sectional studies but the causal relationship is unclear. This study aimed to investigate the impact of NAFLD and the fibrotic progression of the disease on the development of LVDD, assessed by serial echocardiography, in a large population over a 7-year longitudinal setting. METHODS: This retrospective cohort study included the data of 3,380 subjects from a medical health check-up program. We defined subjects having NAFLD by abdominal ultrasonography and assessed significant liver fibrosis by the aspartate transaminase (AST) to platelet ratio index (APRI), the NAFLD fibrosis score (NFS), and the fibrosis-4 (FIB-4) index. LVDD was defined using serial echocardiography. A parametric Cox proportional hazards model was used. RESULTS: During 11,327 person-years of follow-up, there were 560 (16.0 %) incident cases of LVDD. After adjustment for multiple risk factors, subjects with NAFLD showed an increased adjusted hazard ratio (aHR) of 1.21 (95 % confidence interval [CI]=1.02-1.43) for incident LVDD compared to those without. The risk of LV diastolic dysfunction increased progressively with increasing degree of hepatic steatosis (P< 0.001). Compared to subjects without NAFLD, the multivariable-aHR (95 % CI) for LVDD in subjects with APRI < 0.5 and APRI ≥ 0.5 were 1.20 (1.01-1.42) and 1.36 (0.90-2.06), respectively (P= 0.036), while other fibrosis prediction models (NFS and FIB-4 index) showed insignificant results. CONCLUSIONS: This study demonstrated that NAFLD was associated with an increased risk of LVDD in a large cohort. More severe forms of hepatic steatosis and/or significant liver fibrosis may increase the risk of developing LVDD.

Development and validation of multivariable quantitative ultrasound for diagnosing hepatic steatosis.

This study developed and validated multivariable quantitative ultrasound (QUS) model for diagnosing hepatic steatosis. Retrospective secondary analysis of prospectively collected QUS data was performed. Participants underwent QUS examinations and magnetic resonance imaging proton density fat fraction (MRI-PDFF; reference standard). A multivariable regression model for estimating hepatic fat fraction was determined using two QUS parameters from one tertiary hospital (development set). Correlation between QUS-derived estimated fat fraction(USFF) and MRI-PDFF and diagnostic performance of USFF for hepatic steatosis (MRI-PDFF ≥ 5%) were assessed, and validated in an independent data set from the other health screening center(validation set). Development set included 173 participants with suspected NAFLD with 126 (72.8%) having hepatic steatosis; and validation set included 452 health screening participants with 237 (52.4%) having hepatic steatosis. USFF was correlated with MRI-PDFF (Pearson r = 0.799 and 0.824; development and validation set). The model demonstrated high diagnostic performance, with areas under the receiver operating characteristic curves of 0.943 and 0.924 for development and validation set, respectively. Using cutoff of 6.0% from development set, USFF showed sensitivity, specificity, positive predictive value, and negative predictive value of 87.8%, 78.6%, 81.9%, and 85.4% for diagnosing hepatic steatosis in validation set. In conclusion, multivariable QUS parameters-derived estimated fat fraction showed high diagnostic performance for detecting hepatic steatosis.

Increased risk of incident diabetes in patients with MAFLD not meeting the criteria for NAFLD.

We aimed to compare the risk of incident diabetes according to fatty liver disease (FLD) definition, focusing on the comparison between those who met criteria for either metabolic dysfunction-associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD) but not the other. This was a 5.0-year (interquartile range, 2.4-8.2) retrospective longitudinal cohort study of 21,178 adults who underwent at least two serial health checkup examinations. The presence of hepatic steatosis was determined by abdominal ultrasonography at the first health examination. Cox proportional hazard analyses were used to compare the risk of incident diabetes among five groups. Incident diabetes cases occurred in 1296 participants (6.1%). When non-FLD without metabolic dysfunction (MD) group was set as a reference, the risk of incident diabetes increased in the order of NAFLD-only, non-FLD with MD, both FLD, and MAFLD-only groups. The presence of excessive alcohol consumption and/or hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, FLD, and MD synergistically increased the risk of incident diabetes. MAFLD-only group showed a greater increase in incidence of diabetes than non-FLD with MD and NAFLD-only groups. The interaction among excessive alcohol consumption, HBV/HCV infection, MD, and hepatic steatosis on the development of diabetes should not be overlooked.

MAFLD and NAFLD in the prediction of incident chronic kidney disease.

Whether metabolic dysfunction-associated fatty liver disease (MAFLD) can replace nonalcoholic fatty liver disease (NAFLD) is under debate. This study evaluated which definition better predicted incident chronic kidney disease (CKD). This was a 5.3-year (range, 2.8-8.3) retrospective cohort study of 21,713 adults who underwent at least two serial health examinations. Cox analyses were used to compare the risk of incident CKD among non-fatty liver disease (FLD) without metabolic dysregulation (MD; reference), non-FLD with MD, MAFLD-only, NAFLD-only, or both-FLD groups. Non-FLD with MD group (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.00-1.53), both-FLD group (HR 1.50, 95% CI 1.19-1.89), and MAFLD-only group (HR 1.97, 95% CI 1.49-2.60), but not NAFLD-only group (HR 1.06, 95% CI 0.63-1.79) demonstrated an increased risk of CKD. The increased risk of CKD was significant in MAFLD subgroups with overweight/obesity (HR 2.94, 95% CI 1.91-4.55), diabetes (HR 2.20, 95% CI 1.67-2.90), MD only (HR 1.50, 95% CI 1.19-1.89), excessive alcohol consumption (HR 2.71, 95% CI 2.11-3.47), and viral hepatitis (HR 2.38, 95% CI 1.48-3.84). The switch from NAFLD to MAFLD criteria may identify a greater number of individuals at CKD risk. The association was also significant in MAFLD patients with excessive alcohol consumption or viral hepatitis.

Low Skeletal Muscle Mass Accompanied by Abdominal Obesity Additively Increases the Risk of Incident Type 2 Diabetes.

CONTEXT: Low skeletal muscle mass often accompanies abdominal obesity in the aging process. OBJECTIVE: We aimed to investigate the effect of reduced skeletal muscle mass and its interaction with abdominal obesity on incident type 2 diabetes. METHODS: This retrospective longitudinal study included 36 304 diabetes-free Koreans who underwent 2 or more health checkups annually or biannually. Appendicular skeletal muscle mass was measured by bioelectrical impedance analysis and was presented as a skeletal muscle mass index (SMI) adjusted for body weight. Presarcopenia was defined as an SMI less than 1 SD of the sex-specific mean for a healthy young reference group. Abdominal obesity was defined using waist circumference greater than or equal to 90 cm for men and greater than or equal to 85 cm for women. Participants were classified into 4 groups of normal, presarcopenia alone, abdominal obesity alone, and presarcopenic obesity according to initial body composition. RESULTS: The cumulative incidence of diabetes was 9.1% during the 7-year follow-up. Compared with the highest tertile, the lowest sex-specific SMI tertile was significantly associated with a greater risk of incident type 2 diabetes (adjusted hazard ratio [HR] = 1.31; 95% CI, 1.18-1.45) in a fully adjusted model. Presarcopenic obesity significantly increased incident diabetes risk (adjusted HR = 1.57; 95% CI, 1.42-1.73) compared with normal body composition, presarcopenia alone, or abdominal obesity alone. CONCLUSION: Low skeletal muscle mass and its coexistence with abdominal obesity additively increased the risk of incident type 2 diabetes independent of the glycometabolic parameters.

The Prevalence of Thyroid Dysfunction in Korean Women Undergoing Routine Health Screening: A Cross-Sectional Study.

Background: Women are more likely to experience thyroid diseases than men. However, thyroid dysfunction risk in women undergoing the menopausal transition remains largely unknown. We explored the prevalence of thyroid dysfunction across menopausal stages. Methods: We conducted a cross-sectional study of 53,230 women aged 40 years or older who underwent health screening between 2014 and 2018. Menopausal stages were categorized into 4 based on the Stages of Reproductive Aging Workshop +10 criteria. A multinomial logistic regression model was used to estimate the prevalence ratios (PRs) with confidence intervals [CIs] for thyroid dysfunction in menopausal stages compared with that in premenopause. Results: The prevalence of overt hypothyroidism was significantly increased during late transition and postmenopause; it remained significant after further adjustments for potential confounders (age, center, year of examination, age at menarche, parity, education level, smoking status, alcohol consumption, physical activity, and body mass index) with corresponding multivariable-adjusted PRs [CI] of 1.61 [1.12-2.30] and 1.66 [1.16-2.37] in the late transition and postmenopausal stages, respectively. A significant increase in the prevalence of subclinical hypothyroidism was also observed in the late transition and postmenopausal stage with multivariable-adjusted PRs [CI] of 1.22 [1.06-1.40] and 1.24 [1.07-1.44], respectively. In contrast, subclinical and overt hyperthyroidism were not significantly associated with menopausal stages. Conclusions: In this study of pre- and perimenopausal Korean women, the prevalence of overt and subclinical hypothyroidism was significantly elevated in the late menopausal transition. Future prospective studies are warranted to investigate the clinical and prognostic significance of thyroid dysfunction in women during menopausal transition.

Bone-density testing interval and transition to osteoporosis in differentiated thyroid carcinoma patients on TSH suppression therapy.

OBJECTIVE: Thyrotropin (TSH) suppression therapy is a standard treatment after surgery for differentiated thyroid carcinoma (DTC). It may be associated with osteoporosis in postmenopausal women. However, there are no guidelines for bone mineral density (BMD) testing intervals to screen for osteoporosis in these patients. Therefore, we evaluated the timing of repeated BMD testing in DTC patients with TSH suppression according to baseline T-scores. DESIGN, PATIENTS, AND MEASUREMENT: We retrospectively evaluated 658 DTC patients who underwent BMD testing more than twice between January 2007 and January 2020. A 1:3 propensity score matching was conducted to compare the timing of repeated BMD tests between the DTC and non-DTC groups. We stratified the participants into four groups based on their baseline T-scores: normal (-1.00 or higher), mild osteopenia (-1.01 to -1.49), moderate osteopenia (-1.50 to -1.99), and severe osteopenia (-2.00 to -2.49). Additionally, the 10% of patients in each group that transitioned to osteoporosis were analysed. RESULTS: The estimated BMD testing interval for 10% of patients who developed osteoporosis was 85 months for patients with initially mild osteopenia, 65 months for those with moderate osteopenia, and 15 months for those with severe osteopenia in the DTC group. In the non-DTC group, the testing intervals for mild, moderate, and severe osteopenia were 98, 57, and 13 months, respectively. On multivariate analysis, baseline T-score (mild osteopenia: hazard ratio [HR] 5.91, p = .105; moderate osteopenia: HR, 25.27, p = .02; and severe osteopenia: HR, 134.82, p < .001) and duration of TSH suppression (tertile 2: HR, 2.25, p = .005; Tertile 3: 1.78, p = .033) were independent risk factors for osteoporosis in the DTC group. CONCLUSION: This study provides guidance for the timing of repeated BMD tests in women over 50 years of age with TSH suppression. The rescreening interval for BMD testing can be modified based on the baseline T-score. The appropriate BMD testing intervals in female DTC patients were similar to those in non-DTC females.

A Simple and High-Throughput LC-MS-MS Method for Simultaneous Measurement of Nicotine, Cotinine, 3-OH Cotinine, Nornicotine and Anabasine in Urine and Its Application in the General Korean Population.

Measuring nicotine metabolites is the most objective method for identifying smoke exposure. Liquid chromatography--tandem mass spectrometry (LC-MS-MS) can measure multiple metabolites and is sensitive enough to detect low concentrations of metabolites. Therefore, we developed a simple and high-throughput method for measuring nicotine, cotinine, trans-3'-hydroxycotinine (3-OH cotinine), nornicotine and anabasine for population-based studies using LC-MS-MS. Each 30 µL of urine sample was diluted with 90 µL of acetonitrile containing five deuterated internal standards. Chromatographic separation used a C18 column, and LC-MS-MS analysis was performed with a multiple reaction monitoring mode. The chromatographic run time for each sample was 6.5 min. The method was validated by evaluating selectivity, interference, limit of detection, lower limit of quantification, precision, accuracy, linearity, extraction recovery, matrix effect and carryover according to guidelines. Our methods required a short preparation time (∼20 min) while simultaneously measuring five markers for smoking status. No endogenous or exogenous interference was found. Our method showed excellent precision and accuracy: within-run coefficient of variation (CV) 2.9-9.4%, between-run CV 4.8-8.7% and bias -10.1 to 5.3%. Linear dynamic ranges were 1-10,000 ng/mL for nicotine, nornicotine and anabasine; 2-5,000 ng/mL for cotinine and 5-15,000 ng/mL for 3-OH cotinine. Extraction recovery was consistent (87-109%) across concentrations. No significant matrix effect or carryover was observed. The validated method was applied to 849 urine samples. In samples from the 125 current smokers, nicotine, cotinine, 3-OH cotinine, nornicotine and anabasine were detected in 97.6, 99.2, 98.4, 96.8 and 87.2%, respectively. No markers were detected in 93.9% of 609 nonsmokers. The overlapping detection of multiple markers made it possible to identify the smoking status even in current smokers with a low concentration of cotinine. Our LC-MS-MS method using a simple sample preparation technique is sensitive and effective for screening of smoking status in the general population.

Delayed heart rate recovery after exercise predicts development of metabolic syndrome: A retrospective cohort study.

AIMS/INTRODUCTION: Several cross-sectional studies have shown that delayed heart rate recovery (HRR) after exercise is associated with the development of metabolic syndrome (MetS). However, there has been a lack of comprehensively designed longitudinal studies. Therefore, our aim was to evaluate the longitudinal association of delayed HRR following a graded exercise treadmill test (GTX) with incident MetS. MATERIALS AND METHODS: This was a retrospective longitudinal cohort study of participants without MetS, diabetes, or cardiovascular diseases. The HRR was calculated as the peak heart rate minus the resting heart rate after a 1 min rest (HRR1), a 2 min rest (HRR2), and a 3 min rest (HRR3). Multivariate Cox proportional hazards analysis was performed to investigate the association between HRR and development of MetS. RESULTS: There were 676 (31.2%) incident cases of MetS identified during the follow-up period (9,683 person-years). The only statistically significant relationship was between HRR3 and the development of MetS. The hazard ratios (HRs) (95% confidence interval [CI]) of incident MetS comparing the first and second tertiles to the third tertile of HRR3 were 1.492 (1.146-1.943) and 1.277 (1.004-1.624) with P = 0.003 after adjustment for multiple risk factors. As a continuous variable, the HR (95% CI) of incident MetS associated with each one-beat decrease in HRR3 was 1.015 (1.005-1.026) with P = 0.004 after full adjustments. An HRR3 value ≤45 beats per minute (bpm) was associated with a higher risk of incident MetS compared with values >45 bpm, with an HR (95% CI) of 1.304 (1.061-1.602) and P = 0.001. CONCLUSIONS: The slow phase of HRR, particularly HRR3, might be more sensitive at predicting the risk of MetS.

Effects of Aerobic and Resistance Exercise Training on Carotid Intima-Media Thickness in Abdominal Obese Women.

Aims: The purpose of this study was to investigate the effects of a 12-week aerobic and resistance training program on waist circumference (WC) and carotid intima-media thickness (CIMT) in abdominal obese middle-aged women. Methods: Subjects were 40 middle-aged women with abdominal obesity (WC >85 cm) but no specific diseases. Subjects were divided into a combined exercise group (aerobic and resistance exercise) and a control group that did not participate in any lifestyle modification. Carotid variables were measured using B-mode ultrasound. A treadmill exercise test was conducted to directly assess the peak oxygen uptake (VO2peak). Differences in the carotid variables and relative changes between baseline and after 12 weeks were evaluated. Results: After 12 weeks, body weight (70.6 ± 7.8 to 65.6 ± 6.3 kg, P < 0.05), WC (88.8 ± 3.6 to 85.6 ± 3.1 cm, P < 0.01), total cholesterol (215.5 ± 38.4 to 188.2 ± 25.8 mmHg, P < 0.05), low-density lipoprotein cholesterol (150.5 ± 30.6 to 131.6 ± 22.3 mmHg, P < 0.05), triglycerides (164.5 ± 82.3 to 119.9 ± 60.6 mmHg, P < 0.01), VO2peak (24.2 ± 6.2 to 28.7 ± 4.4 mL/kg/min, P < 0.01), and CIMT (0.61 ± 0.13 to 0.58 ± 0.12 mm, P < 0.05) were significantly improved in the combined exercise group but not in the control group; changes in CIMT were associated with changes in WC decrease (r = 0.41, P < 0.01) and VO2peak (r = -0.53, P < 0.01). Conclusions: Combined exercise training in abdominal obese women decreased CIMT; these changes were also associated with reduced WC and improved VO2peak.

The Protective Effects of Increasing Serum Uric Acid Level on Development of Metabolic Syndrome.

BACKGROUND: It has not been determined whether changes in serum uric acid (SUA) level are associated with incident metabolic syndrome (MetS). The aim of the current study was to investigate the relationship between changes in SUA level and development of MetS in a large number of subjects. METHODS: In total, 13,057 subjects participating in a medical health check-up program without a diagnosis of MetS at baseline were enrolled. Cox proportional hazards models were used to test the independent association of percent changes in SUA level with development of MetS. RESULTS: After adjustment for age, systolic blood pressure, body mass index, fat-free mass (%), estimated glomerular filtration rate, smoking status, fasting glucose, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and baseline SUA levels, the hazard ratios (HRs) (95% confidence intervals [CIs]) for incident MetS in the second, third, and fourth quartiles compared to the first quartile of percent change in SUA level were 1.055 (0.936 to 1.190), 0.927 (0.818 to 1.050), and 0.807 (0.707 to 0.922) in male (P for trend <0.001) and 1.000 (0.843 to 1.186), 0.744 (0.615 to 0.900), and 0.684 (0.557 to 0.840) in female (P for trend <0.001), respectively. As a continuous variable in the fully-adjusted model, each one-standard deviation increase in percent change in SUA level was associated with an HR (95% CI) for incident MetS of 0.944 (0.906 to 0.982) in male (P=0.005) and 0.851 (0.801 to 0.905) in female (P<0.001). CONCLUSION: The current study demonstrated that increasing SUA level independently protected against the development of MetS, suggesting a possible role of SUA as an antioxidant in the pathogenesis of incident MetS.

Utility of Serum Albumin for Predicting Incident Metabolic Syndrome according to Hyperuricemia.

BACKGROUND: Serum albumin and uric acid have been positively linked to metabolic syndrome (MetS). However, the association of MetS incidence with the combination of uric acid and albumin levels has not been investigated. We explored the association of albumin and uric acid with the risk of incident MetS in populations divided according to the levels of these two parameters. METHODS: In this retrospective longitudinal study, 11,613 non-MetS participants were enrolled among 24,185 individuals who had undergone at least four annual check-ups between 2006 and 2012. The risk of incident MetS was analyzed according to four groups categorized by the sex-specific medians of serum albumin and uric acid. RESULTS: During 55,407 person-years of follow-up, 2,439 cases of MetS developed. The risk of incident MetS increased as the uric acid category advanced in individuals with lower or higher serum albumin categories with hazard ratios (HRs) of 1.386 (95% confidence interval [CI], 1.236 to 1.554) or 1.314 (95% CI, 1.167 to 1.480). However, the incidence of MetS increased with higher albumin levels only in participants in the lower uric acid category with a HR of 1.143 (95% CI, 1.010 to 1.294). CONCLUSION: Higher levels of albumin were associated with an increased risk of incident MetS only in individuals with lower uric acid whereas higher levels of uric acid were positively linked to risk of incident MetS regardless of albumin level.

Relationship Between Relative Skeletal Muscle Mass and Nonalcoholic Fatty Liver Disease: A 7-Year Longitudinal Study.

Nonalcoholic fatty liver disease (NAFLD) has been associated with relative skeletal muscle mass in several cross-sectional studies. We explored the effects of relative skeletal muscle mass and changes in relative muscle mass over time on the development of incident NAFLD or the resolution of baseline NAFLD in a large, longitudinal, population-based 7-year cohort study. We included 12,624 subjects without baseline NAFLD and 2943 subjects with baseline NAFLD who underwent health check-up examinations. A total of 10,534 subjects without baseline NAFLD and 2631 subjects with baseline NAFLD were included in analysis of changes in relative skeletal muscle mass over a year. Subjects were defined as having NAFLD by the hepatic steatosis index, a previously validated NAFLD prediction model. Relative skeletal muscle mass was presented using the skeletal muscle mass index (SMI), a measure of body weight-adjusted appendicular skeletal muscle mass, which was estimated by bioelectrical impedance analysis. Of the 12,624 subjects without baseline NAFLD, 1864 (14.8%) developed NAFLD during the 7-year follow-up period. Using Cox proportional hazard analysis, compared with the lowest sex-specific SMI tertile at baseline, the highest tertile was inversely associated with incident NAFLD (adjusted hazard ratio [AHR] = 0.44, 95% confidence interval [CI] = 0.38-0.51) and positively associated with the resolution of baseline NAFLD (AHR = 2.09, 95% CI = 1.02-4.28). Furthermore, compared with the lowest tertile of change in SMI over a year, the highest tertile exhibited a significant beneficial association with incident NAFLD (AHR = 0.69, 95% CI = 0.59-0.82) and resolution of baseline NAFLD (AHR = 4.17, 95% CI = 1.90-6.17) even after adjustment for baseline SMI. Conclusion: Increases in relative skeletal muscle mass over time may lead to benefits either in the development of NAFLD or the resolution of existing NAFLD.

Increase in relative skeletal muscle mass over time and its inverse association with metabolic syndrome development: a 7-year retrospective cohort study.

BACKGROUND: Skeletal muscle mass was negatively associated with metabolic syndrome prevalence in previous cross-sectional studies. The aim of this study was to investigate the impact of baseline skeletal muscle mass and changes in skeletal muscle mass over time on the development of metabolic syndrome in a large population-based 7-year cohort study. METHODS: A total of 14,830 and 11,639 individuals who underwent health examinations at the Health Promotion Center at Samsung Medical Center, Seoul, Korea were included in the analyses of baseline skeletal muscle mass and those changes from baseline over 1 year, respectively. Skeletal muscle mass was estimated by bioelectrical impedance analysis and was presented as a skeletal muscle mass index (SMI), a body weight-adjusted appendicular skeletal muscle mass value. Using Cox regression models, hazard ratio for developing metabolic syndrome associated with SMI values at baseline or changes of SMI over a year was analyzed. RESULTS: During 7 years of follow-up, 20.1% of subjects developed metabolic syndrome. Compared to the lowest sex-specific SMI tertile at baseline, the highest sex-specific SMI tertile showed a significant inverse association with metabolic syndrome risk (adjusted hazard ratio [AHR] = 0.61, 95% confidence interval [CI] 0.54-0.68). Furthermore, compared with SMI changes < 0% over a year, multivariate-AHRs for metabolic syndrome development were 0.87 (95% CI 0.78-0.97) for 0-1% changes and 0.67 (0.56-0.79) for > 1% changes in SMI over 1 year after additionally adjusting for baseline SMI and glycometabolic parameters. CONCLUSIONS: An increase in relative skeletal muscle mass over time has a potential preventive effect on developing metabolic syndrome, independently of baseline skeletal muscle mass and glycometabolic parameters.

Serum calcium changes and risk of type 2 diabetes mellitus in Asian population.

AIMS: We examined the association between changes in serum calcium levels with the incidence of type 2 diabetes mellitus (T2DM) in apparently healthy South Korean subjects. METHODS: A retrospective longitudinal analysis was conducted with subjects who had participated in comprehensive health check-ups at least four times over a 7-year period (between 2006 and 2012). In total, 23,121 subjects were categorized into tertiles based on changes in their albumin-adjusted serum calcium levels. Multivariate Cox regression models were fitted to assess the association between changes in serum calcium levels during follow-up and the relative risk of diabetes incidence. RESULTS: After a median follow-up of 57.4months, 1,929 (8.3%) new cases of T2DM occurred. Simple linear regression analysis showed serum calcium level changes correlated positively with changes in HbA1c and fasting plasma glucose (FPG) levels (B=5.72, p<0.001 for FPG; B=0.13, p<0.001 for HbA1c). An increase in albumin-adjusted serum calcium levels during follow-up was related to an increased risk of T2DM. After adjustment for potential confounders, the risk of T2DM was 1.6 times greater for subjects whose albumin-adjusted serum calcium levels were in the highest change tertile during follow-up than for subjects whose levels were in the lowest tertile (HR 1.65, 95% CI 1.44-1.88, P<0.001). CONCLUSIONS: The elevation of albumin-adjusted serum calcium levels was associated with an increased risk of T2DM, independent of baseline glycemic status.

Hormetic effect of triiodothyronine in metabolically healthy obese persons.

PURPOSE: Metabolically healthy obese is the designation for a subgroup of obese individuals with normal metabolic features. However, metabolically healthy obese individuals are prone to developing metabolic syndrome. Serum triiodothyronine (T3) levels are associated with various metabolic risk factors including obesity. Therefore, this longitudinal study aimed to explore the possible correlation between serum T3 concentration and the onset of MetS in metabolically healthy obese persons. METHODS: A retrospective analysis of 992 euthyroid metabolically healthy obese subjects who underwent yearly health checkups over 6 years was performed. The risk of developing MetS was analyzed according to baseline T3 concentration, as both tertiles and continuous values, using Cox regression analysis. Serum T3 concentration at the end of the study was further analyzed according to the final metabolic phenotype. RESULTS: The incidence of MetS was 464 cases (46.8%) during a median 3.3 years of follow-up (3168.2 person-years). The hazard ratio for incident MetS enhanced with increasing T3 concentration in both the crude and adjusted models. Higher baseline serum T3 levels were associated with unfavorable metabolic parameters. However, over the course of the study, serum T3 concentration significantly increased in subjects who sustained metabolically healthy phenotypes compared to baseline value, while it significantly decreased in the subjects who developed MetS. CONCLUSIONS: Serum T3 concentrations exhibit distinct associations with development of metabolic syndrome in euthyroid metabolically healthy obese persons, but its increment during follow-up maintained metabolically healthy state. These findings suggest that serum T3 modulation might be an adaptive process to protect against metabolic deterioration.

Increase in serum albumin concentration is associated with prediabetes development and progression to overt diabetes independently of metabolic syndrome.

AIM: Serum albumin concentration is associated with both type 2 diabetes and metabolic syndrome (MetS). We sought to investigate whether baseline serum albumin and change in serum albumin could be independent risk factors for prediabetes in subjects without MetS. We further examined the effect of serum albumin on progression to overt diabetes in subjects who developed prediabetes. METHODS: Among 10,792 participants without diabetes and MetS who consecutively underwent yearly health check-ups over six years, 9,807 subjects without incident MetS were enrolled in this longitudinal retrospective study. The risk of developing prediabetes (impared fasting glucose or hemoglobin A1c) was analyzed according to baseline and percent change in serum albumin concentration using Cox regression analysis. Serial changes in serum albumin concentration were measured from baseline to one year before prediabetes diagnosis, and then from the time of prediabetes diagnosis to progression to overt diabetes or final follow-up. RESULTS: A total of 4,398 incident cases of prediabetes developed during 35,807 person-years (median 3.8 years). The hazard ratio for incident prediabetes decreased as percent change in serum albumin concentration (quartiles and per 1%) increased in a crude and fully adjusted model. However, baseline serum albumin concentration itself was not associated with prediabetic risk. Serum albumin levels kept increasing until the end of follow-up in prediabetic subjects who returned to normal glycemic status, whereas these measures did not change in prediabetic subjects who developed type 2 diabetes. Serum albumin concentration measured at the end of follow-up was the highest in the regression group, compared to the stationary (p = 0.014) or progression groups (p = 0.009). CONCLUSIONS: Increase in serum albumin concentration might protect against early glycemic deterioration and progression to type 2 diabetes even in subjects without MetS.

Decline in lung function rather than baseline lung function is associated with the development of metabolic syndrome: A six-year longitudinal study.

This study was conducted to investigate whether baseline lung function or change in lung function is associated with the development of metabolic syndrome (MS) in Koreans. We analyzed clinical and laboratory data from 3,768 Koreans aged 40-60 years who underwent medical check-ups over a six-year period between 2006 and 2012. We calculated the percent change in forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) over the study period. We tested for an association between baseline lung function or lung function change during the follow-up period and the development of MS. The 533 subjects (14.1%) developed MS after the six-year follow-up. The baseline FVC and FEV1 were not different between the subjects who developed MS after six years and the subject without MS after six years. The percent change in FVC over six years in subjects who developed MS after six years was higher than that in subjects who did not develop MS (-5.75 [-10.19 --1.17], -3.29 [-7.69-1.09], respectively, P = 0.001). The percent change in FVC over six years was associated with MS development after adjusting for age, sex, body mass index (BMI), glucose, HDL, triglyceride, waist circumferences (WC), and systolic blood pressure. However, these association was not significant after adjusting for change of BMI and change of WC over six years (P = 0.306). The greater change in vital capacity over six years of follow-up was associated with MS development, predominantly due to obesity and abdominal obesity. The prospective study is needed to determine the relationship between lung function decline and MS.

TSH increment and the risk of incident type 2 diabetes mellitus in euthyroid subjects.

PURPOSE: Thyroid function is known to influence glucose metabolism, and thyroid-stimulating hormone is the most useful parameter in screening for thyroid dysfunction. Therefore, the aim of this study was to investigate the incidence of type 2 diabetes according to baseline thyroid-stimulating hormone level and thyroid-stimulating hormone change in euthyroid subjects. METHODS: We identified and enrolled 17,061 euthyroid subjects without diabetes among participants who had undergone consecutive thyroid function tests between 2006 and 2012 as a part of yearly health check-up program. Thyroid-stimulating hormone changes were determined by subtracting baseline thyroid-stimulating hormone level from thyroid-stimulating hormone level at 1 year before diagnosis of diabetes or at the end of follow-up in subjects who did not develope diabetes. RESULTS: During 84,595 person-years of follow-up, there were 956 new cases of type 2 diabetes. Cox proportional hazards models showed the risk of incident type 2 diabetes was significantly increased with each 1 µIU/mL increment in TSH after adjustment for multiple confounding factors (hazard ratio = 1.13, 95% confidence interval: 1.07-1.20, P < 0.001). Compared with individuals in the lowest tertile (-4.08 to 0.34 µIU/mL), those in the highest thyroid-stimulating hormone change tertile (0.41-10.84 µIU/mL) were at greater risk for incident type 2 diabetes (hazard ratio = 1.25, 95% confidence interval: 1.05-1.48, P for trend = 0.011). However, baseline thyroid-stimulating hormone level and tertile were not associated with the risk for diabetes. CONCLUSIONS: Prominent increase in thyroid-stimulating hormone concentration can be an additional risk factor for the development of type 2 diabetes in euthyroid subjects.

Association Between Changes in Thyroid Hormones and Incident Type 2 Diabetes: A Seven-Year Longitudinal Study.

BACKGROUND: Thyroid hormones are important regulators of glucose homeostasis. However, the association between thyroid hormones within the reference range and type 2 diabetes mellitus (T2DM) remains unclear. The aim of this study was to clarify the incidence of T2DM according to the baseline levels and changes of thyrotropin (TSH) and thyroid hormones (free thyroxine and triiodothyronine) in euthyroid subjects. METHODS: Among the participants who consecutively underwent thyroid function tests between 2006 and 2012 through a yearly health checkup program, 6235 euthyroid subjects (3619 men and 2616 women) without T2DM were enrolled in the study. The change in each hormone was calculated by subtracting the baseline value from the level at the end of follow-up or one year before the diagnosis of diabetes. RESULTS: During 25,692 person-years of follow-up, there were 229 new cases of T2DM. After full adjustment for potential confounders including HbA1c and fasting glucose in Cox proportional hazards models, the individuals in the highest tertile of TSH change (2.5-4.2 µIU/mL) had a greater risk of incident T2DM (hazard ratio [HR] = 1.44 [confidence interval (CI) 1.04-1.98], p = 0.027) in comparison with individuals in the lowest tertile (-4.1 to -0.5 µIU/mL). Simultaneously, the highest tertile of triiodothyronine change (16.3-104.7 ng/dL) and free thyroxine change (0.2-1.6 ng/dL) conferred protective effects against diabetes (HR = 0.60 [CI 0.43-0.85], p = 0.002, and HR = 0.34 [CI 0.24-0.48], p < 0.001, respectively) compared with those in the lowest tertile (-76.5 to -1.8 ng/dL and -0.6 to 0.0 ng/dL, respectively). These associations remained significant when each of the hormones was analyzed as a continuous variable. However, baseline levels or tertiles of TSH and thyroid hormones were not associated with the risk of diabetes. CONCLUSIONS: Individual changes in TSH and thyroid hormones, even within the normal reference range, were an additional risk factor of incident T2DM.