Impact of mental disorders on the risk of heart failure among Korean patients with diabetes: a cohort study.

BACKGROUND: Few studies have assessed the correlation between coexisting mental disorders in participants with diabetes mellitus (DM) and the risk of heart failure (HF). Herein, we conducted a cohort study to determine the association between the accumulation of mental disorders in participants with DM and the risk of HF. METHODS: The Korean National Health Insurance Service records were assessed. 2,447,386 adults with DM who underwent health screening between 2009 and 2012 were analyzed. Participants with major depressive disorder, bipolar disorder, schizophrenia, insomnia, or anxiety disorders were included. In addition, participants were categorized based on the number of coexisting mental disorders. Each participant was followed until December 2018 or until the onset of HF. Cox proportional hazard modelling with confounding factors adjustment was conducted. In addition, a competing risk analysis was conducted. Subgroup analysis assessed the impact of clinical variables on the association between the accumulation of mental disorders and the risk of HF. RESULTS: The median follow-up duration was 7.09 years. The accumulation of mental disorders was associated with a risk of HF (zero mental disorder (0), reference; 1 mental disorder, adjusted hazard ratio (aHR): 1.222, 95% confidence intervals (CI): 1.207-1.237; 2 mental disorders, aHR: 1.426, CI: 1.403-1.448; ≥3 mental disorders, aHR: 1.667, CI: 1.632-1.70. In the subgroup analysis, the strength of association was the strongest in the younger age group (< 40 years, 1 mental disorder, aHR 1.301, CI 1.143-1.481; ≥2 mental disorders, aHR 2.683, CI 2.257-3.190; 40-64 years, 1 mental disorder, aHR 1.289, CI 1.265-1.314; ≥2 mental disorders, aHR 1.762, CI 1.724-1.801; ≥65 years, 1 mental disorder, aHR 1.164, CI 1.145-1.183; ≥2 mental disorders, aHR 1.353, CI 1.330-1.377; Pinter<0.001). In addition, income, BMI, hypertension, chronic kidney disease, history of cardiovascular disease, insulin use, and duration of DM showed significant interactions. CONCLUSIONS: Comorbid mental disorders in participants with DM are associated with an increased risk of HF. In addition, the association was stronger in a younger age group. Participants with DM and mental disorders should be monitored with increased frequency for signs of HF; for which they have a higher risk than the general population.

Acromegaly and the long-term fracture risk of the vertebra and hip: a national cohort study.

In this national cohort study, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58-2.78]) and hip (HR 2.52 [1.61-3.95]) fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up. PURPOSE: Acromegaly is characterized by the overproduction of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), both play important roles in regulating bone metabolism. We investigated the risk of vertebral and hip fractures in patients with acromegaly compared to age- and sex-matched controls. METHODS: This nationwide population-based cohort study included 1,777 patients with acromegaly aged 40 years or older in 2006-2016 and 8,885 age- and sex-matched controls. A Cox proportional hazards model was used to estimate the adjusted hazard ratio (HR) [95% confidence interval]. RESULTS: The mean age was 54.3 years and 58.9% were female. For approximately 8.5 years of follow-up, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58-2.78]) and hip (HR 2.52 [1.61-3.95]) fractures than the controls in the multivariate analyses. There were significant differences in the risks of clinical vertebral (P < 0.0001) and hip (P < 0.0001) fractures between the patients with acromegaly and the controls in the Kaplan-Meier survival analysis. The multivariable-adjusted HRs for clinical vertebral fractures comparing the patients with acromegaly with controls during and excluding the first 7 years of observation were 1.69 [1.15-2.49] and 2.70 [1.75-4.17], respectively. The HRs for hip fractures during and excluding the first 7 years of observation were 2.29 [1.25-4.18] and 3.36 [1.63-6.92], respectively. CONCLUSIONS: The patients with acromegaly had a higher risk of hip fractures as well as clinical vertebral fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up.

Metformin, resveratrol, and exendin-4 inhibit high phosphate-induced vascular calcification via AMPK-RANKL signaling.

Vascular calcification increases the risk of developing cardiovascular disease, and it is closely associated with metabolic disorders such as diabetes mellitus and non-alcoholic fatty liver disease. We investigated whether the activators of AMP-activated protein kinase (AMPK), metformin, resveratrol, and exendin-4, improved inorganic phosphate (Pi)-induced vascular calcification in rat vascular smooth muscle cells (VSMCs) and whether these effects were via AMPK. Pi increased calcium deposition in a dose-dependent manner, and metformin, resveratrol, and exendin-4 significantly decreased calcium deposition in the Pi-treated VSMCs. Moreover, metformin and exendin-4 increased the expression of a SMC marker gene, α-smooth muscle actin, and Ampk and reduced the receptor activator of nuclear factor kappa-Β ligand (Rankl)/osteoprotegerin ratio. Metformin, resveratrol, and exendin-4 reduced the expression of osteoblast differentiation-associated factors, such as runt-related transcription factor 2, bone morphogenic protein-2, p-small mothers against decapentaplegic 1/5/8, and Rankl. Inhibition of AMPK by siRNA adversely affected the anti-calcification effects of metformin, resveratrol, and exendin-4 and reversed the reduction of the expression of Rankl by metformin and exendin-4 in the Pi-treated VSMCs. These data suggest that metformin, resveratrol, and exendin-4 ameliorate Pi-induced vascular calcification by inhibiting osteoblast differentiation of VSMCs, which is mediated by AMPK.

Association between thyroid hormone levels, body composition and insulin resistance in euthyroid subjects with normal thyroid ultrasound: The Kangbuk Samsung Health Study.

OBJECTIVE: Thyroid hormones play crucial roles in the control of energy homoeostasis and can influence body composition. In contrast, the changes in body composition might influence thyroid hormone levels. We evaluated associations between thyroid hormone levels, body composition and insulin resistance in euthyroid subjects with normal thyroid ultrasound (US) findings. DESIGN AND PATIENTS: This retrospective cross-sectional study included 36 655 euthyroid subjects who joined the medical health check-up programme at our institution. Serum thyroid hormone levels were analysed in association with body fat percentage (BFP), skeletal muscle mass index (SMI) and homoeostatic model assessment of insulin resistance (HOMA-IR). Linear regression analyses were performed to evaluate relationships between thyroid hormone levels and anthropometric parameters. RESULTS: Mean age was 36.4 years, and 49% of subjects were female. In multiple linear regression analysis, serum-free triiodothyronine (FT3) levels exhibited positive associations with waist circumference (WC) and HOMA-IR and a negative association with body weight, body mass index (BMI) and SMI among both men and women. The association between serum-free thyroxine (FT4) levels and anthropometric markers showed inconsistent results in men and women. Serum thyroid-stimulating hormone (TSH) levels showed a positive association with HOMA-IR in both men and women. CONCLUSIONS: Lower SMI was significantly associated with higher serum FT3 levels, the active form of thyroid hormone, in both men and women. Higher insulin resistance was positively associated with serum FT3 levels and inversely associated with serum TSH levels in euthyroid subjects with normal thyroid US findings.

A 52-week extension study of switching from gemigliptin vs sitagliptin to gemigliptin only as add-on therapy for patients with type 2 diabetes who are inadequately controlled with metformin alone.

We investigated the long-term efficacy and safety of gemigliptin and the efficacy and safety of gemigliptin treatment after once-daily treatment with sitagliptin 100 mg, in patients with type 2 diabetes. This was a 28-week extension of a 24-week, randomized, double-blind, parallel study of gemigliptin or sitagliptin added to ongoing metformin therapy. After randomization to sitagliptin 100 mg qd (S), gemigliptin 25 mg bid (G1) or gemigliptin 50 mg qd (G2) and after completing 24 weeks of treatment, 118 patients switched from gemigliptin 25 mg bid to 50 mg qd (G1/G2), 111 patients continued gemigliptin 50 mg qd (G2/G2) and 106 patients switched from sitagliptin 100 mg qd to gemigliptin 50 mg qd (S/G2). All 3 treatments reduced glycated haemoglobin (HbA1c) (S/G2,-0.99% [95% CI -1.25%, -0.73%]; G1/G2, -1.11% [95% CI -1.33%, -0.89%]; G2/G2, -1.06% [95% CI -1.28%, -0.85%]). The percentage of patients achieving HbA1c < 6.5% was 27.6% in the G1/G2 group at both Week 24 and Week 52, and ranged from 27.3% to 32.7% in the G2/G2 group (difference in proportions, 5% [95% CI -6%, 17%]), while it increased from 6.8% to 27.3% from Week 24 to Week 52 in the S/G2 group (difference in proportions, 20% [95% CI 7%, 34%]). Addition of gemigliptin 50 mg qd to metformin was shown to be efficacious for 52 weeks. Switching from sitagliptin 100 mg to gemigliptin 50 mg showed consistent glyacemic control over the previous treatment.

Probucol in Albuminuric Type 2 Diabetes Mellitus Patients on Renin-Angiotensin System Blockade: A 16-Week, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. APPROACH AND RESULTS: This was a 16-week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of ≥300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 (ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change±SE from baseline in urinary albumin/creatinine ratio at week 16 was -7.2±639.5 mg/g in the probucol 250 mg/d group (n=43; P=0.2077 versus placebo group), 9.3±587.4 mg/g in the probucol 500 mg/d group (n=40; P=0.1975 versus placebo group), and 259.0±969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively. CONCLUSIONS: Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion.

Lobeglitazone, a Novel Thiazolidinedione, Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness.

Despite the rapidly increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D), few treatment modalities are currently available. We investigated the hepatic effects of the novel thiazolidinedione (TZDs), lobeglitazone (Duvie) in T2D patients with NAFLD. We recruited drug-naïve or metformin-treated T2D patients with NAFLD to conduct a multicenter, prospective, open-label, exploratory clinical trial. Transient liver elastography (Fibroscan®; Echosens, Paris, France) with controlled attenuation parameter (CAP) was used to non-invasively quantify hepatic fat contents. Fifty patients with CAP values above 250 dB/m were treated once daily with 0.5 mg lobeglitazone for 24 weeks. The primary endpoint was a decline in CAP values, and secondary endpoints included changes in components of glycemic, lipid, and liver profiles. Lobeglitazone-treated patients showed significantly decreased CAP values (313.4 dB/m at baseline vs. 297.8 dB/m at 24 weeks; P = 0.016), regardless of glycemic control. Lobeglitazone improved HbA(1C) values (7.41% [57.5 mM] vs. 6.56% [48.2 mM]; P < 0.001), as well as the lipid and liver profiles of the treated patients. Moreover, multivariable linear regression analysis showed that hepatic fat reduction by lobeglitazone was independently associated with baseline values of CAP, liver stiffness, and liver enzymes, and metformin use. Lobeglitazone treatment reduced intrahepatic fat content, as assessed by transient liver elastography, and improved glycemic, liver, and lipid profiles in T2D patients with NAFLD. Further randomized controlled trials using liver histology as an end point are necessary to evaluate the efficacy of lobeglitazone for NAFLD treatment.

Association of low baseline free thyroxin levels with progression of coronary artery calcification over 4 years in euthyroid subjects: the Kangbuk Samsung Health Study.

OBJECTIVE: Overt and subclinical hypothyroidism are risk factors for atherosclerosis and cardiovascular diseases. It is unclear whether thyroid hormone levels within the normal range are also associated with atherosclerosis measured by coronary artery calcium (CAC). CONTEXT: This study aimed to examine the relationship between normal variations in thyroid function and changes in CAC. MEASUREMENTS: We conducted a 4-year retrospective study of 2173 apparently healthy men and women with normal thyroid hormone levels. Their free thyroxin (FT4), free triiodothyronin (FT3) and thyroid-stimulating hormone (TSH) levels were measured by electrochemiluminescent immunoassay. The CAC score (CACS) of each subject was measured by multidetector computed tomography in both 2010 and 2014. Progression of CAC was defined as a CACS change over 4 years > 0. RESULTS: The mean CACS changes over 4 years by quartiles of baseline FT4 level (lowest to highest) were 12·9, 8·43, 7·82 and 7·81 (P = 0·028). CAC progression was not significantly associated with either the baseline FT3 or TSH levels. The odds ratios (OR) for CAC progression over 4 years (highest vs lowest quartile for baseline FT4) were 0·647 (95% confidence interval (CI) 0·472-0·886) after adjustment for confounding factor, which were attenuated with further adjustment for lipid profiles, homoeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein and hypertension [0·747 (95% CI 0·537-1·038)]. Quartiles of baseline FT3 or TSH level did not show any increased OR for CAC progression after adjustment for confounding factors. CONCLUSIONS: In this cohort of euthyroid men and women, a low baseline FT4 level was associated with a high risk of CACS progression over 4 years.

Relationship of retinal vascular caliber variation with intracranial arterial stenosis.

BACKGROUND & PURPOSE: To investigate the associations of retinal vessel parameters with intracranial arterial stenosis (ICAS) assessed by Transcranial Doppler ultrasonography. METHOD: Data on transcranial Doppler ultrasonography and quantitative retinal vessel parameters from 627 participants in a health screening program were included in this study. ICAS was defined as >50% intracranial arterial stenosis (ICAS) based on criteria modified from the stroke outcomes and neuroimaging of intracranial atherosclerosis (SONIA) trial assessed by transcranial Doppler (TCD) ultrasonography. A semi-automated computer-assisted program (Singapore I Vessel Assessment) was used to measure the retinal vascular parameters from the photographs. Multivariate analysis was performed to identify which retinal vessel parameters were associated with increased risk of ICAS. RESULTS: Among 627 participants, 24 (3.8%) had ICAS diagnosed by TCD. Subjects with ICAS had eyes with wider mean central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) in comparison to subjects without ICAS. Men (odds ratio [OR]:13.1, 95% confidence interval: 3.13-33.33) and a large standard deviation of mean arterial width (STDWa) were associated with ICAS (first vs. third tertile: OR ratio: 14.04, 95% confidence interval: 1.71-115.32; first vs. third tertile: OR ratio: 22.1, 95% confidence interval: 2.56-190.97) after adjusting for possible confounders. CONCLUSION: A large variation in retinal arteriolar diameter is associated with ICAS. This study suggests the possible relationship between retina vessel and early changes within the cerebrovascular network.

The relationship between serum fatty-acid binding protein 4 level and lung function in Korean subjects with normal ventilatory function.

BACKGROUND: The aim of this study was to assess the association of lung function with serum fatty-acid binding protein 4 (FABP4) in apparently healthy Korean adults. METHODS: In 495 participants in a health screening program, Force Exploratory Volume (FEV) 1 and Forced Vital Capacity (FVC) were assessed with standard spirometry. Subjects with obstructive (n = 19) and restrictive (n = 45) lung function were excluded from the analysis. Serum FABP4 level was measured by enzyme-linked immunosorbent assay and transformed into Ln(FABP4). 431 subjects with normal ventilator function (72.4% men, mean age 41 years) were included in the final analysis. RESULTS: Mean Ln(FABP4) significantly decreased in subjects from 1(st) quartile to 4(th) quartile of FVC (p = 0.008). Ln(FABP4) did not show significant differences across the quartile groups of FEV1. The odds ratio (OR) of being in the lowest quartile of FVC was 2.704 in subject with 3(rd) tertile of Ln(FABP4) after full adjustment for confounding variables {95% confidence interval (CI) 1.397 ~ 5.357}. OR of being in the lowest quartile of FEV1 was 1.822 (95% CI 1.021 ~ 3.298) in subjects with 3(rd) tertile of Ln(FABP4) after adjustment of age and sex, which was attenuated after full adjustment for confounding variables. CONCLUSION: Increased FABP4 level showed increased risk for reduced lung function in subjects with normal ventilatory function.

Blood Pressure Is the Determinant for the Increased Risk for Intracranial Arterial Stenosis in Subjects with Elevated Glycated Hemoglobin Levels: The Kangbuk Samsung Health Study.

BACKGROUND AND PURPOSE: Ischemic stroke is known to be an important vascular complication of diabetes. Intracranial arterial stenosis (ICAS) is considered as an important cause of stroke in Asians. We aimed to analyze the risk for ICAS assessed by transcranial Doppler (TCD) ultrasonography in different groups of young Korean subjects divided by glycated hemoglobin (HbA1c) levels. METHODS: This study included 10,437 participants without history of cardiovascular diseases (81.3% men, mean age 43 years) from a health screening program, in whom TCD ultrasonography was used to detect greater than 50% ICAS based on criteria modified from the SONIA (Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis) trial. The subjects were divided into 3 groups according to HbA1c levels: HbA1c < 5.7%, 5.7 ≤ HbA1c < 6.5%, and HbA1c ≥ 6.5% or under medication for diabetes. RESULTS: Among the participants, 3.0% of the subjects had ICAS. The subjects with ICAS tended to have higher mean HbA1c level compared with those without ICAS (5.8 ± .8 versus 5.7 ± .6, P = .063). The proportion of subjects with ICAS significantly increased as the HbA1c increased from the first to the third group (2.8%, 3.0%, 4.6%, P for linear trend = .022). In logistic regression analysis with ICAS as the dependent variable, the group with HbA1c ≥ 6.5% showed significantly increased odds ratio for ICAS with subjects with HbA1c < 5.7% as the reference after adjustment for confounding variables (1.575, 95% confidence interval 1.056-2.347). However, this significance disappeared with inclusion of presence of hypertension in the model. CONCLUSIONS: The risk for ICAS assessed by TCD was increased in young Korean subjects with HbA1c ≥ 6.5%. However, this significance was attenuated after adjustment for presence of hypertension, suggesting the importance of hypertension in ICAS.

Increased risk for intracranial arterial stenosis in subjects with coronary artery calcification.

BACKGROUND AND PURPOSE: Intracranial arterial stenosis (ICAS) is considered an important cause of stroke in Asians. Coronary artery calcification (CAC) is a surrogate marker for subclinical atherosclerosis. We aimed to analyze the association of ICAS assessed by transcranial Doppler ultrasonography and CAC in middle-aged Korean population. METHODS: This study included 10 550 participants (81.3% men, mean age 43 years) from a health screening program, in whom transcranial Doppler ultrasonography was used to detect >50% intracranial stenosis based on criteria modified from the stroke outcomes and neuroimaging of intracranial atherosclerosis trial. Multidetector computed tomography was used to assess coronary artery calcium score (CACS). CAC grade (0, 1-100, and >100) was defined by CACS. RESULTS: The subjects with CAC showed significantly higher proportion of subjects with ICAS compared with those without CAC (4.4% versus 2.8%; P<0.01). Conversely, the subjects with ICAS showed significantly higher proportion of subjects with CAC (24.8% versus 17.1%; P<0.01). When logistic regression analysis was performed with ICAS as the dependent variable, the presence of CAC showed significantly increased risk for ICAS after adjustment for confounding variables (odds ratio, 1.439; 95% confidence interval, 1.095-1.891). When CACS grade was included in the model, the odds ratio for ICAS was the highest in subjects with CACS >400 compared with those with CACS=0 (odds ratio, 2.754; 95% confidence interval, 1.205-2.936). CONCLUSIONS: The risk for ICAS was significantly increased in middle-aged Korean subjects with CAC compared with that in those without CAC. These findings suggest the possibility of a separate undetected atherosclerotic focus in subjects with 1 atherosclerotic event.

Higher association of coronary artery calcification with non-alcoholic fatty liver disease than with abdominal obesity in middle-aged Korean men: the Kangbuk Samsung Health Study.

BACKGROUND: It is uncertain whether non-alcoholic fatty liver disease (NAFLD) or abdominal obesity is more associated with atherosclerosis. The aim of this study was to determine whether NAFLD or abdominal obesity is more strongly associated with subclinical atherosclerosis represented by coronary artery calcification (CAC). METHODS: A total of 21,335 male participants in a health screening program (mean age 41 years) were enrolled. Ultrasonographic measurements of fatty liver and multi-detector computed tomography were performed to determine the coronary artery calcium score (CACS). The presence of CAC was defined as CACS > 0. Subjects were divided into four groups according to the presence or absence of NAFLD and/or abdominal obesity as assessed by waist-hip ratio (WHR) > 0.9. RESULTS: The presence of CAC was detected in 2,385 subjects (11.2%). The proportion of subjects with CAC was highest in the abdominal obesity only group (23.2%). After adjustment for age, diabetes history, hypertension, cigarette smoking, and physical inactivity, the odds ratio (OR) for CAC was the highest in the group with both abnormalities [1.465 (1.324-1.623)]. The NAFLD only group showed significantly increased OR for CAC compared to that in the abdominal obesity only group [1.286 (1.151-1.436) vs. 1.076 (0.939-1.233)]. CONCLUSION: Non-alcoholic fatty liver disease is more closely associated with CAC than abdominal obesity as assessed by the WHR. NAFLD could be considered an independent determinant of subclinical atherosclerosis as assessed by CAC.

Thyroid hormones and coronary artery calcification in euthyroid men and women.

OBJECTIVE: Overt and subclinical hypothyroidism are risk factors for atherosclerosis. It is unclear whether thyroid hormone levels within the normal range are also associated with atherosclerosis measured by coronary artery calcium (CAC). APPROACH AND RESULTS: We conducted a cross-sectional study of 41 403 apparently healthy young and middle-aged men and women with normal thyroid hormone levels. Free thyroxin, free triiodothyronine, and thyroid-stimulating hormone levels were measured by electrochemiluminescent immunoassay. CAC score was measured by multidetector computed tomography. The multivariable adjusted CAC ratios comparing the highest versus the lowest quartile of thyroid hormones were 0.74 (95% confidence interval, 0.60-0.91; P for trend <0.001) for free thyroxin, 0.81 (0.66-1.00; P for trend=0.05) for free triiodothyronine, and 0.78 (0.64-0.95; P for trend=0.01) for thyroid-stimulating hormone. Similarly, the odds ratios for detectable CAC (CAC >0) comparing the highest versus the lowest quartiles of thyroid hormones were 0.87 (0.79-0.96; P for linear trend <0.001) for free thyroxin, 0.90 (0.82-0.99; P for linear trend=0.02) for free triiodothyronine, and 0.91 (0.83-1.00; P for linear trend=0.03) for thyroid-stimulating hormone. CONCLUSIONS: In a large cohort of apparently healthy young and middle-aged euthyroid men and women, low-normal free thyroxin and thyroid-stimulating hormone were associated with a higher prevalence of subclinical coronary artery disease and with a greater degree of coronary calcification.

Association between underweight and risk of heart failure in diabetes patients.

BACKGROUND: The risk of heart failure (HF) in underweight diabetes mellitus (DM) patients has rarely been studied. We conducted a cohort study to investigate the association between underweight (BMI < 18.5 kg/m2) and BMI change over time and the risk of HF in patients with type 2 DM. METHODS: We utilized the health screening data from the National Health Insurance Service and the Korean National Health Screening database from 2009 to 2012, with follow-up until December 2018. Participants with DM were categorized into four groups based on their BMI at 4 years before study inclusion and BMI at the study entry: (1) Always Normal Weight (BMI at 4 years ago/BMI at study entry ≥18.5/≥18.5 kg/m2, reference group); (2) Transitioned to Underweight (≥18.5/<18.5 kg/m2); (3) Transitioned to Normal Weight (<18.5/≥18.5 kg/m2) and (4) Always Underweight (<18.5/<18.5 kg/m2). Participants were followed until the development of HF or at the end of the follow-up. Initial screening data included participants with DM who had the health screening during the study period (n = 2,746,079). Participants aged <20 years (n = 390), those who did not undergo health examination 4 years prior (n = 1,306,520), and those with missing data (n = 77,410) were excluded. Participants diagnosed with HF before study participation (n = 81,645) and within 1 year of study enrolment (n = 11,731) were excluded. After applying exclusion criteria, 1,268,383 participants were finally included in the analysis. The primary outcome was the development of HF. We employed Cox proportional hazards models, adjusting for various confounding factors, to assess the risk of developing HF. RESULTS: Median follow-up duration was 6.88 years and men were 63.16%. The mean ages of each groups were as follows: Always Normal Weight (57.92 ± 11.64 years), Transitioned to Underweight (62 ± 13.5 years), Transitioned to Normal Weight (56.6 ± 15.29 years) and Always Underweight (57.76 ± 15.35 years). In comparison with the Always Normal Weight group (n = 1,245,381, HF = 76,360), Transitioned to Underweight group (≥18.5/<18.5 kg/m2, n = 9304, HF = 880, adjusted Hazard Ratio (aHR)1.389, 95% confidence interval (CI) 1.3-1.485) or Transitioned to Normal Weight (<18.5/≥18.5 kg/m2, n = 6024, HF = 478, aHR 1.385, 95% CI 1.266-1.515) exhibited an increased risk of HF. The highest risk was observed in the Always Underweight group (<18.5/<18.5 kg/m2, n = 7674, HF = 665, aHR 1.612, 95% CI 1.493-1.740). CONCLUSIONS: Underweight was significantly associated with the risk of HF in the DM population. Active surveillance for HF in an underweight DM population is needed.

Risk of Cardiovascular Disease according to Baseline Low-Density Lipoprotein Cholesterol Level in Different Age Groups in Korean Diabetes Population: A Cohort Study.

BACKGRUOUND: The association between low-density lipoprotein (LDL-C) levels and cardiovascular disease (CVD) risk in different age groups within the diabetes mellitus (DM) population remains unclear. The cohort study was conducted to investigate this relationship. METHODS: We assessed the 2009 to 2012 Korean National Health Screening and National Health Insurance Service records, with follow-up to the primary outcome (myocardial infarction [MI] or stroke) or December 2018. After excluding the participants with a history of MI or stroke, 2,227,394 participants with DM were included and categorized according to baseline LDL-C levels and age. Cox proportional hazards modeling was conducted. The CVD risk of age <40 years and LDL-C <70 mg/dL was set as the reference. In each age group, LDL-C <70 mg/dL was used as a reference for the subgroup analysis. RESULTS: The cut-off LDL-C value for increased MI risk in each age group varied (<40 years old, LDL-C ≥160 mg/dL: hazard ratios [HR], 2.03; 95% confidence interval [CI], 1.644 to 2.506) (40-49-year-old, LDL-C <115 mg/dL: HR, 1.245; 95% CI, 1.04 to 1.489) (50-59-year-old, LDL-C <115 mg/dL: HR, 1.21; 95% CI, 1.014 to 1.445) (60-69-year-old, LDL-C <145 mg/dL: HR, 1.229; 95% CI, 1.022 to 1.479) (≥70 years old group, LDL-C <100 mg/dL: HR, 1.238; 95% CI, 1.018 to 1.504). The cut-off LDL-C values for increased stroke risk varied in each age subgroup (<40 years old, LDL-C ≥160 mg/dL: HR, 1.395; 95% CI, 1.094 to 1.779) (40-49-year-old, LDL-C <145 mg/dL: HR, 1.13; 95% CI, 1.019 to 1.253) (50-59-year-old, LDL-C <160 mg/dL: HR, 1.079; 95% CI, 1.008 to 1.154) (60-69-year-old, LDL-C <130 mg/dL: HR, 1.07; 95% CI, 1.022 to 1.119) (≥70 years old, LDL-C <115 mg/dL: HR, 1.064; 95% CI, 1.019 to 1.112). CONCLUSION: The effect of LDL-C on the risk of CVD differs depending on the age of the population with DM.

Nonalcoholic Fatty Liver Disease and the Risk of Thyroid Cancer Among Young Adults in South Korea.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Obesity and metabolic syndrome are known risk factors for thyroid cancer. OBJECTIVE: We investigated the association between NAFLD and thyroid cancer risk in young adults. METHODS: This nationwide cohort study included 1 135 967 participants aged 20 to 39 years who underwent 4 consecutive health screenings in South Korea. NAFLD was categorized using the fatty liver index (FLI), as follows: ≥60, 30 to 60, and <30. The cumulative FLI points were defined as the number of times participants had a FLI of ≥30 (0-4). RESULTS: During a median follow-up of 5.2 years, 4126 participants (0.36%) were newly diagnosed with thyroid cancer. Compared with the participants with an FLI of <30, those with an FLI of 30 to 60 (men: hazard ratio [HR] 1.36 [95% CI, 1.22-1.51] and women: HR 1.44 [1.21-1.70]) and those with an FLI of ≥60 (men: HR 1.71 [1.53-1.92] and women: HR 1.81 [1.46-2.25]) had a significantly higher risk of thyroid cancer. Participants with higher cumulative FLI points had a higher risk of thyroid cancer compared to those with a cumulative FLI point of 0 (P < .001). During the follow-up period, the participants with an increased FLI exhibited an increased risk of thyroid cancer. CONCLUSION: NAFLD was associated with an increased risk of thyroid cancer in young adults. Repeatedly elevated FLI and progression of NAFLD were associated with an increased risk of thyroid cancer in this study.

Glucagon-Like Peptide Receptor Agonist Inhibits Angiotensin II-Induced Proliferation and Migration in Vascular Smooth Muscle Cells and Ameliorates Phosphate-Induced Vascular Smooth Muscle Cells Calcification.

BACKGRUOUND: Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system. METHODS: To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide. RESULTS: Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors AT1 and AT2, proliferation marker of proliferation Ki-67 (Mki-67), proliferating cell nuclear antigen (Pcna), and cyclin D1 (Ccnd1), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of Pcna, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs. CONCLUSION: These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1Rdependent and independent pathways and inhibit Pi-induced vascular calcification.

Impact of Antidiabetic Drugs on Clinical Outcomes of COVID-19: A Nationwide Population-Based Study.

BACKGRUOUND: Inconsistent results have been reported regarding the association between the use of antidiabetic drugs and the clinical outcomes of coronavirus disease 2019 (COVID-19). This study aimed to investigate the effect of antidiabetic drugs on COVID-19 outcomes in patients with diabetes using data from the National Health Insurance Service (NHIS) in South Korea. METHODS: We analyzed the NHIS data of patients aged ≥20 years who tested positive for COVID-19 and were taking antidiabetic drugs between December 2019 and June 2020. Multiple logistic regression analysis was performed to analyze the clinical outcomes of COVID-19 based on the use of antidiabetic drugs. RESULTS: A total of 556 patients taking antidiabetic drugs tested positive for COVID-19, including 271 male (48.7%), most of whom were in their sixties. Of all patients, 433 (77.9%) were hospitalized, 119 (21.4%) received oxygen treatment, 87 (15.6%) were admitted to the intensive care unit, 31 (5.6%) required mechanical ventilation, and 61 (11.0%) died. Metformin was significantly associated with the lower risks of mechanical ventilation (odds ratio [OR], 0.281; 95% confidence interval [CI], 0.109 to 0.720; P=0.008), and death (OR, 0.395; 95% CI, 0.182 to 0.854; P=0.018). Dipeptidylpeptidase-4 inhibitor (DPP-4i) were significantly associated with the lower risks of oxygen treatment (OR, 0.565; 95% CI, 0.356 to 0.895; P=0.015) and death (OR, 0.454; 95% CI, 0.217 to 0.949; P=0.036). Sulfonylurea was significantly associated with the higher risk of mechanical ventilation (OR, 2.579; 95% CI, 1.004 to 6.626; P=0.049). CONCLUSION: In patients with diabetes and COVID-19, metformin exhibited reduced risks of mechanical ventilation and death, DPP- 4i was linked with lower risks of oxygen treatment and death, while sulfonylurea was related to the increased risk of mechanical ventilation.

Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells.

BACKGRUOUND: Polyunsaturated fatty acids (PUFAs) reportedly have protective effects on pancreatic ß-cells; however, the underlying mechanisms are unknown. METHODS: To investigate the cellular mechanism of PUFA-induced cell protection, mouse insulinoma 6 (MIN6) cells were cultured with palmitic acid (PA) and/or docosahexaenoic acid (DHA), and alterations in cellular signaling and apoptosis were examined. RESULTS: DHA treatment remarkably repressed caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL)-positive red dot signals in PA-treated MIN6 cells, with upregulation of autophagy, an increase in microtubule- associated protein 1-light chain 3 (LC3)-II, autophagy-related 5 (Atg5), and decreased p62. Upstream factors involved in autophagy regulation (Beclin-1, unc51 like autophagy activating kinase 1 [ULK1], phosphorylated mammalian target of rapamycin [mTOR], and protein kinase B) were also altered by DHA treatment. DHA specifically induced phosphorylation on S2448 in mTOR; however, phosphorylation on S2481 decreased. The role of G protein-coupled receptor 120 (GPR120) in the effect of DHA was demonstrated using a GPR120 agonist and antagonist. Additional treatment with AH7614, a GPR120 antagonist, significantly attenuated DHA-induced autophagy and protection. Taken together, DHA-induced autophagy activation with protection against PA-induced apoptosis mediated by the GPR120/mTOR axis. CONCLUSION: These findings indicate that DHA has therapeutic effects on PA-induced pancreatic ß-cells, and that the cellular mechanism of ß-cell protection by DHA may be a new research target with potential pharmacotherapeutic implications in ß-cell protection.