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Background: Dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been shown to reduce body weight and liver fat content in patients with type 2 diabetes. Family with sequence similarity 3 member A (FAM3A) plays a vital role in regulating glucose and lipid metabolism. The aim of this study was to determine the mechanisms by which dulaglutide protects against hepatic steatosis in HepG2 cells treated with palmitic acid (PA).Methods: HepG2 cells were pretreated with 400 μM PA for 24 hours, followed by treatment with or without 100 nM dulaglutide for 24 hours. Hepatic lipid accumulation was determined using Oil red O staining and triglyceride (TG) assay, and the expression of lipid metabolism-associated factor was analyzed using quantitative real time polymerase chain reaction and Western blotting. Results: Dulaglutide significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells. However, exendin-(9-39), a GLP-1R antagonist, reversed the expression of FAM3A, and fatty acid oxidation-associated factors increased due to dulaglutide. In addition, inhibition of FAM3A by siRNA attenuated the reducing effect of dulaglutide on TG content and its increasing effect on regulation of fatty acid oxidation. Conclusion: These results suggest that dulaglutide could be used therapeutically for improving nonalcoholic fatty liver disease, and its effect could be mediated in part via upregulation of FAM3A expression through a GLP-1R-dependent pathway.

Background: Fibrosis is the most important prognostic factor for nonalcoholic fatty liver disease (NAFLD). Insulin resistance plays a key role of fibrosis progression. We evaluated the association between changes in homeostasis model assessment of insulin resistance (HOMA-IR) values and changes in fibrosis status in NAFLD.Methods: We analyzed the data of 15,728 participants with NAFLD (86% men, mean age 40.5 years) who had no diabetes at baseline and visited our centers for health check-ups both in 2012 and 2016. The participants were classified into four groups according to the degree of change in HOMA-IR values from baseline to the end of follow-up: G1 (1.00). NAFLD was assessed by ultrasonography, and fibrosis status was evaluated by the NAFLD fibrosis score (NFS) and the aspartate aminotransferase to platelet ratio index (APRI).Results: After the 4-year follow-up, the multivariable-adjusted odds ratio (OR) for progression of fibrosis probability increased with increasing HOMA-IR values (OR, 2.25; 95% confidence interval [CI], 1.87 to 2.71 for NFS; and OR, 2.55; 95% CI, 2.05 to 3.18 for APRI, G4). This tendency remained consistent throughout the subgroup analyses, except in those for female sex and a body mass index

Background: Patients with diabetes have a higher risk of requiring repeated percutaneous coronary intervention (PCI) than non-diabetic patients. We aimed to evaluate and compare the effects of anti-diabetic drugs on the secondary prevention of myocardial infarction among type 2 diabetes mellitus patients.Methods: We analyzed the general health check-up dataset and claims data of the Korean National Health Insurance Service of 199,714 participants (age ≥30 years) who underwent PCIs between 2010 and 2013. Those who underwent additional PCI within 1 year of their first PCI (n=3,325) and those who died within 1 year (n=1,312) were excluded. Patients were classified according to their prescription records for glucose-lowering agents. The primary endpoint was the incidence rate of coronary revascularization.Results: A total of 35,348 patients were included in the study. Metformin significantly decreased the risk of requiring repeat PCI in all patients (adjusted hazard ratio [aHR], 0.77). In obese patients with body mass index (BMI) ≥25 kg/m2, patients treated with thiazolidinedione (TZD) exhibited a decreased risk of requiring repeat revascularization than those who were not treated with TZD (aHR, 0.77; 95% confidence interval, 0.63 to 0.95). Patients treated with metformin showed a decreased risk of requiring revascularization regardless of their BMI. Insulin, meglitinide, and alpha-glucosidase inhibitor were associated with increased risk of repeated PCI.Conclusion: The risk of requiring repeat revascularization was lower in diabetic patients treated with metformin and in obese patients treated with TZD. These results suggest that physicians should choose appropriate glucose-lowering agents for the secondary prevention of coronary artery disease.

Background: Weight loss through lifestyle modification is recommended for patients with nonalcoholic fatty liver disease (NAFLD). Recent studies have suggested that repeated loss and gain of weight is associated with worse health outcomes. This study aimed to examine the association between weight variability and the risk of NAFLD in patients without diabetes.Methods: We examined the health-checkup data of 30,708 participants who had undergone serial examinations between 2010 and 2014. Weight variability was assessed using coefficient of variation and the average successive variability of weight (ASVW), which was defined as the sum of absolute weight changes between successive years over the 5-year period divided by 4. The participants were classified according to the baseline body mass index and weight difference over 4 years.Results: On dividing the participants into four groups according to ASVW quartile groups, those in the highest quartile showed a significantly increased risk of NAFLD compared to those in the lowest quartile (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.63 to 2.19). Among participants without obesity at baseline, individuals with high ASVW showed increased risk of NAFLD (OR, 1.80; 95% CI, 1.61 to 2.01). Participants with increased weight over 4 years and high ASVW demonstrated higher risk of NAFLD compared to those with stable weight and low ASVW (OR, 4.87; 95% CI, 4.29 to 5.53).Conclusion: Regardless of participant baseline obesity status, high weight variability was associated with an increased risk of developing NAFLD. Our results suggest that further effort is required to minimize weight fluctuations after achieving a desirable body weight.

Over the last two decades, our understanding of diabetes and treatment strategies have evolved tremendously, from scientific, mechanistic, and human perspectives. The categories of anti-diabetic medications expanded from a few to numerous, enabling clinicians to personalize diabetes care and treatment. Thanks to rapid growth in the field of science and medical engineering, newer treatment options are coming to the market with various advantages and disadvantages to be aware of. Therefore, clinicians should rapidly adopt new trends based on guidelines and data from many clinical trials in the field of diabetes. In the treatment of dyslipidemia, trends and guidelines are changing every year, and novel therapies are being developed. In this review, we would like to summarize the major achievements in clinical medicine in 2020 in the field of diabetes mellitus and dyslipidemia.

Background: There is a great need to discover factors that could protect pancreatic β-cells from apoptosis and thus prevent diabetes mellitus. Clusterin (CLU), a chaperone protein, plays an important role in cell protection in numerous cells and is involved in various cellular mechanisms, including autophagy. In the present study, we investigated the protective role of CLU through autophagy regulation in pancreatic β-cells.Methods: To identify the protective role of CLU, mouse insulinoma 6 (MIN6) cells were incubated with CLU and/or free fatty acid (FFA) palmitate, and cellular apoptosis and autophagy were examined.Results: Treatment with CLU remarkably upregulated microtubule-associated protein 1-light chain 3 (LC3)-II conversion in a doseand time-dependent manner with a significant increase in the autophagy-related 3 (Atg3) gene expression level, which is a mediator of LC3-II conversion. Moreover, co-immunoprecipitation and fluorescence microscopy experiments showed that the molecular interaction of LC3 with Atg3 and p62 was markedly increased by CLU. Stimulation of LC3-II conversion by CLU persisted in lipotoxic conditions, and FFA-induced apoptosis and dysfunction were simultaneously improved by CLU treatment. Finally, inhibition of LC3-II conversion by Atg3 gene knockdown markedly attenuated the cytoprotective effect of CLU.Conclusion: Taken together, these findings suggest that CLU protects pancreatic β-cells against lipotoxicity-induced apoptosis via autophagy stimulation mediated by facilitating LC3-II conversion. Thus, CLU has therapeutic effects on FFA-induced pancreatic β-cell dysfunction.

Background It is well known that high serum ferritin, a marker of iron storage, predicts incident type 2 diabetes. Limited information is available on the association between transferrin, another marker of iron metabolism, and type 2 diabetes. Thus, we investigated the association between transferrin and incident type 2 diabetes. Methods Total 31,717 participants (mean age, 40.4±7.2 years) in a health screening program in 2005 were assessed via cross-sectional analysis. We included 30,699 subjects who underwent medical check-up in 2005 and 2009 and did not have type 2 diabetes at baseline in this retrospective longitudinal analysis. Results The serum transferrin level was higher in the type 2 diabetes group than in the non-type 2 diabetes group (58.32±7.74 μmol/L vs. 56.17±7.96 μmol/L, Pl0.001). Transferrin correlated with fasting serum glucose and glycosylated hemoglobin in the correlational analysis (r=0.062, Pl0.001 and r=0.077, Pl0.001, respectively) after full adjustment for covariates. Transferrin was more closely related to homeostasis model assessment of insulin resistance than to homeostasis model assessment of β cell function (r=0.042, Pl0.001 and r=-0.019, P=0.004, respectively) after full adjustment. Transferrin predicted incident type 2 diabetes in non-type 2 diabetic subjects in a multivariate linear regression analysis; the odds ratio (95% confidence interval [CI]) of the 3rd tertile compared to that in the 1st tertile of transferrin for incident diabetes was 1.319 (95% CI, 1.082 to 1.607) after full adjustment (P=0.006). Conclusion Transferrin is positively associated with incident type 2 diabetes in Koreans.

Background People with disabilities are at risk of secondary conditions such as diabetes. The aim of this study was to evaluate the prevalence and risk of type 2 diabetes in South Korea, especially among people with all types of disabilities. Methods We conducted a cross-sectional study using data from the Korean National Health Insurance Service, with two disabilityfree controls matched for each participant with disabilities by age and sex. Information regarding the type, severity and grade of disabilities was obtained based on the National Disability Registry. Diagnosis of type 2 diabetes was defined according to the following criteria: presence of International Classification of Diseases, Tenth Revision, Clinical Modification codes E11, E12, E13, or E14 and claims for at least one oral anti-diabetic agent or insulin at baseline, or fasting glucose level ≥126 mg/dL. Results We included 1,297,806 participants with disabilities and 2,943,719 control. Out of 4,241,525 participants, 841,990 (19.9%) were diagnosed with diabetes. The prevalence of diabetes was higher in the disability group compared with individuals without disabilities (23.1% vs. 18.4%). The odds of having diabetes was higher in the disability group compared with the control group (adjusted odds ratio, 1.34; 95% confidence interval, 1.33 to 1.34). The results showed higher prevalence of diabetes in the mildly disabled group (23.2%) than in the severely disabled group (22.7%). Conclusion The prevalence and risk of diabetes were higher in people with disabilities compared with the general population. Physicians and public health authorities should focus on people with disabilities for proper diabetes management.

The world is entering an era of disaster and chaos due to coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2. Since its first emergence in December 2019 in Wuhan, China, COVID-19 has swept through Asia and propagated throughout the world to Europe and North America. As of April 13, 1,773,084 people were infected and 111,652 people had died from COVID-19 globally, and new record levels of infection are being reported every day. Based on the data that have been amassed so far, the primary risk factors for a severe disease course or even mortality from COVID-19 are underlying diseases such as diabetes and hypertension. As the global prevalence of diabetes continues to increase, patients with endocrine diseases such as diabetes mellitus and those who are on long-term corticosteroid therapy due to adrenal insufficiency or hypopituitarism are at risk for a poor prognosis of COVID-19. As endocrinologists, we would like to briefly review the current knowledge about the relationship between COVID-19 and endocrine diseases and to discuss what we can do for the safety and health of our patients with endocrine diseases in this globally threatening situation.

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.

Background To evaluate the changes in cardiovascular risk markers including pulse wave velocity (PWV), microalbuminuria, inflammatory cytokines, and adhesion molecules after treatment with beraprost sodium (BPS) in patients with diabetic nephropathy. Methods This was a multicenter, prospective, randomized, double-blind, placebo-controlled trial. Type 2 diabetes mellitus patients with microalbuminuria were included. The primary endpoints were changes in microalbuminuria in spot urine and PWV after BPS or placebo (PCB) treatment for 24 weeks. The secondary endpoints were changes in clinical and metabolic parameters. Results A total of 52 patients completed the 24-week trial. Changes in PWV were not different significantly in the BPS and PCB groups (right, P=0.16; left, P=0.11). Changes in microalbuminuria were 14.2±157.0 and 34.5±146.6 (μg/mg Cr) in the BPS and PCB groups, respectively (P=0.63). Subgroup analysis in the high blood pressure (BP) group (baseline systolic BP >120 mm Hg and diastolic BP >80 mm Hg), showed that microalbuminuria decreased by ?47.6 in the BPS group compared with an increase by 116.4 (μg/mg Cr) in the PCB group (P=0.04). Also, in the large waist circumference group (>95 cm), microalbuminuria decreased significantly in the BPS group (P=0.04). Conclusion Short-term treatment of BPS for patients with diabetic nephropathy did not show significant improvement in various cardiovascular risk factors. However, BPS significantly decreased microalbuminuria in study subjects with higher cardiovascular risk such as high BP or large waist circumference.

Purpose Obesity is a well-known risk factor for central precocious puberty (CPP). Recently, elevated thyroid stimulating hormone (TSH) was reported in obese youth. However, few data regarding the relationship between CPP and TSH are available. The aim of this study was to evaluate thyroid function in girls with CPP and the relationship between CPP and serum TSH concentration. Methods This was a retrospective cross-sectional study. A total of 1,247 girls aged between 6.0 and 8.9 years who had undergone a gonadotropin-releasing hormone (GnRH) stimulation test to determine the presence of puberty were studied. Subjects were classified into CPP (n=554) and non-CPP (n=693) groups according to the results of the GnRH stimulation test. Characteristics and laboratory data of the CPP and non-CPP groups were compared and correlations between those characteristics and laboratory data and TSH concentration were evaluated. Serum TSH concentration in the CPP group was higher than that of the non-CPP group (3.19±1.55 mIU/L vs. 2.58±1.34 mIU/L, Pl0.001). Results Serum free thyroxine (fT4) concentration in the CPP group was notably lower than that of the non-CPP group (1.38±0.14 ng/dL vs. 1.44±0.18 ng/dL, Pl0.001). Across all subjects, 149 girls (11.9%) had hyperthyrotropinemia. The prevalence of hyperthyrotropinemia was higher in the CPP group compared to the non-CPP group (15.7% vs. 8.9%, Pl0.001). TSH concentrations were positively correlated with age, height, weight, BMI, bone age, bone age advance, insulin-like growth factor 1 (IGF-1), IGF-1 standard deviation score, basal luteinizing hormone (LH), peak LH and basal follicle-stimulation hormone. TSH concentrations were negatively correlated with fT4. Multiple linear regression analysis showed that age (β=0.548, Pl0.001) and peak LH (β=0.019, P=0.008) were independently associated with serum TSH concentration. Conclusion Hyperthyrotropinemia in girls with CPP tends to be associated with pubertal LH elevation. In conclusion, pubertal onset may be associated with thyroid function.

Purpose Bone plays a role in glucose metabolism through the release of uncarboxylated osteocalcin into the systemic circulation. The identified novel roles for osteocalcin include increasing insulin secretion and sensitivity, energy expenditure, reduction of fat mass, and mitochondrial proliferation and functional enhancement. This study aimed to determine serum osteocalcin levels in overweight children and to investigate the relationships of osteocalcin with glucose metabolism and insulin sensitivity. Methods After overnight fasting, serum osteocalcin levels were measured in overweight (n=50) children between 6.0 and 12.9 years of age and nonoverweight controls (n=60). Height, weight, fasting serum glucose, insulin, alkaline phosphatase, total cholesterol, and 25 hydroxy vitamin D3 (25(OH)VitD3) were also measured in all subjects. Results There were significant differences in serum osteocalcin levels between the overweight and control groups (64.00±20.44 vs. 89.56±28.63, Pl0.001). Serum osteocalcin levels were inversely correlated with body mass index (BMI) (r=-0.283, P=0.003), weight standard deviation score (SDS) (r=-0.222, P=0.020), BMI SDS (r=-0.297, P=0.002), insulin (r=-0.313, P=0.001), and homeostasis model assessment of insulin resistance (HOMA-IR) index (r=-0.268, P=0.005). In the subsequent multiple regression analyses, BMI, HOMA-IR, and age were determined to be independent predicting factors for serum osteocalcin. Conclusion Our findings showed associations of serum osteocalcin with glucose metabolism and insulin sensitivity in overweight children, but we could not establish a causal relationship.

Background and aims Fibrosis progression is the most important prognostic factor, and insulin resistance is one of the main mechanisms associated with fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD). We evaluate the association between baseline insulin resistance and future fibrosis progression in patients with NAFLD without diabetes. Approach and results This retrospective longitudinal study with 8-year follow-up period included 32,606 (men, 83%) participants aged >20 years (average age, 38.0 years) without diabetes at baseline who completed at least two comprehensive health checkups from January 1, 2010 to December 31, 2018. NAFLD was diagnosed based on ultrasonography. The homeostasis model assessment of insulin resistance (HOMA-IR) was used to evaluate baseline insulin resistance. Fibrosis progression was assessed using the aspartate aminotransferase to platelet ratio index (APRI). The advanced liver fibrosis with an APRI value above the intermediate fibrosis probability (≥0.5) developed in a total of 2,897 participants during 136,108 person-years. 114 participants progressed to a high fibrosis probability stage (APRI >1.5) during 141,064 person-years. Using the lowest baseline HOMA-IR quartile group (Q1) as a reference, the multivariate-adjusted hazard ratio (HR) for development of advanced liver fibrosis (APRI ≥0.5) in the highest baseline HOMA-IR quartile group (Q4) was 1.95 (95% confidence interval [CI] 1.74–2.19; Model 4). And the HR for development of advanced liver fibrosis with high fibrosis probability was 1.95 (95% CI 1.10–3.46; Model 4). The positive association was maintained throughout the entire follow-up period. The baseline HOMA-IR model was superior to the baseline body mass index (BMI) model in predicting the progression of fibrosis probability. Conclusions In this longitudinal study, we found that the degree of baseline insulin resistance, assessed by HOMA-IR values, was positively associated with future fibrosis progression in patients with NAFLD without diabetes.

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.

Smoking cessation reduces the cardiovascular risk but increases body weight. We investigated the risk of subsequent myocardial infarction and ischemic stroke according to weight gain after smoking cessation, using a nationwide population based cohort. We enrolled 3,797,572 Korean adults aged over 40 years who participated in national health screenings between 2009 and 2010. Subjects who quit smoking were classified into three subgroups according to the weight change between baseline and 4 years prior. Myocardial infarctions and ischemic strokes were followed until the end of 2015. We compared the hazard ratios among smoking cessation subgroups, non-smokers, and current smokers. The mean changes in weight (1.5 ± 3.9 kg) of the smoking cessation group were higher than those of the other groups (p < 0.0001). A total of 31,277 and 46,811 subjects were newly diagnosed with myocardial infarction and ischemic stroke, respectively. Regardless of weight change, all subgroups of smoking cessation had significantly less risk than current smokers. The subgroup of smoking cessation with weight gain over 4kg showed the lowest risk for myocardial infarctions (hazard ratio 0.646, 95% confidence interval 0.583–0.714, p < 0.0001) and ischemic strokes (hazard ratio 0.648, 95% confidence interval 0.591–0.71, p < 0.0001) after multivariable adjustment. In conclusion, weight gain after smoking cessation did not adversely affect the cardiovascular protective effect.

Background Emerging 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). Methods We 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. Results Lack 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. Conclusion Altogether, 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.

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.

Mammalian testes are maintained at a relatively lesser temperature than the abdominal region so that normal spermatogenesis can occur. Germ cell apoptosis has resulted in heat-damaged testes that occurs as a result of cryptorchidism, but the mechanism is not yet fully understood. To elucidate the cause of germ-cell death by cryptorchidism, cryptorchidism was surgically induced in dog testes and histological and molecular analyses were performed. Histological data indicated that the seminiferous tubules of cryptorchid testes and epididymis contained fewer germ cells. Total RNA sequencing was performed to screen for overexpressed genes in cryptorchid dog testes. Clusterin RNA was in greater abundance (approximately 12.8-fold) in cryptorchid testes than in normal testes. In addition, cleaved caspase-3 and -8 were detected in greater abundance in cryptorchid dog testes. Real time RT-PCR and western blotting analysis indicated there was a greater abundance of clusterin in cryptorchid dog testes. Furthermore, clusterin was detected in extracellular regions of cryptorchid dog testes during the 4 weeks after surgery. Thus, germ-cell specific apoptosis and expression of clusterin genes occur with a resulting presence of this protein in extracellular regions of cryptorchid dog testes. This result will facilitate further study of spermatogenesis and the specific mechanisms by which cryptorchidism results in male infertility.

Insulin resistance and inflammation play an important role in a variety of chronic diseases.We investigated the influence of systemic inflammation on the relationship between insulin resistance and mortality risk in apparently healthy adults.This study examined the mortality outcomes for 165,849 Koreans enrolled in a health-screening program. The subjects were divided into four groups according to their homeostatic model assessment of insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hs-CRP) levels: group 0, HOMA-IR75% and hs-CRP2.0mg/L; group 1, HOMA-IR ≥75% and hs-CRP2.0mg/L; group 2, HOMA-IR75% and hs-CRP ≥2.0mg/L; and group 3, HOMA-IR ≥75% and hs-CRP ≥2.0mg/L. The Cox proportional hazard models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular disease, and cancer-related mortality.During the follow-up period of 1,417,325.6person-years, a total of 1316 deaths (182 from cardiovascular disease) occurred. The multivariate-adjusted HRs for all-cause mortality were significantly higher in groups 2 (HR 1.40; 95% CI: 1.19-1.64) and group 3 (HR 1.68; 95% CI: 1.34-2.10) than that in group 0. For cardiovascular mortality, the sex-adjusted hazards were also significantly higher in groups 2 and 3 than that in group 0; however, this increased risk disappeared during multivariate analysis. Groups 2 and 3 had significantly higher risk for cancer-related mortality than group 0, with multivariate-adjusted hazard ratios of 1.48 (95% CI: 1.18-1.86) and 1.84 (95% CI: 1.35-2.51), respectively.Systemic inflammation can be used to stratify the subjects according to the all-cause and cancer-related mortality risks, irrespective of the insulin-resistance status. And this tendency is most pronounced in cancer-related mortality.

Spermatogenesis begins with spermatogonial stem cells (SSCs), which are located in the basement membrane of the adult testes. Previous studies have described specific biomarkers for undifferentiated porcine spermatogonia or SSCs; however, these markers are not sufficient to understand spermatogenesis at different developmental stages. The objective of this study was characterize the expression of DEAD-Box polypeptide 4 (DDX4, also known as VASA) and tyrosine-protein kinase kit (c-kit), as potential markers of male germ cells in the porcine testis. In porcine testis tissue at prepubertal stages (5, 30, and 60 days), DDX4 and c-kit protein expression was detected in the most undifferentiated spermatogonia, which also express protein gene product 9.5 (PGP9.5). However, in porcine testis tissues from pubertal and postpubertal stages (90, 120, and 150 days), DDX4 and c-kit were not detected in PGP9.5-positive undifferentiated spermatogonia. The DDX4 expression pattern was similar to that of c-kit in the porcine testis. In adult porcine testes, DDX4-expressing cells were located on the lumenal side, compared to synaptonemal complex protein 3-positive primary spermatocytes, but DDX-4 was not co-expressed with acrosin, a known acrosome marker. In addition, DDX4 was detected in PGP9.5-expressing porcine SSCs in culture. Based on our results, we suggest that DDX4 and c-kit are putative markers of undifferentiated spermatogonia in the prepubertal porcine testis. While in the postpubertal porcine testis, they are markers of differentiated spermatocytes. These findings may facilitate future studies of porcine spermatogenesis.

Osteocalcin is the non-collagenous protein produced by osteoblasts in bone. When it is released into systemic circulation in its uncarboxylated form, it regulates fat and glucose metabolism. Recent studies have shown that osteocalcin is also involved in male fertility. Because the onset of puberty is determined by ethnic, genetic, environmental, and metabolic factors, we focused on determining the role of osteocalcin in the onset of puberty. Central precocious puberty (CPP) is defined as the activation of the hypothalamic-pituitary-gonadal axis before the age of 8 in girls and 9 in boys. CPP is diagnosed when peak luteinizing hormone (LH) reaches ≥ 5.0 IU/l after stimulation with gonadotropin-releasing hormone (GnRH). This retrospective study included 206 girls who showed breast budding before the age of 8 and whose bone age was more advanced than their chronological age. The CPP group included 100 girls who were diagnosed with CPP, and 106 girls were the non-CPP group whose peak LH did not reach ≥ 5.0 IU/l after GnRH stimulation test. Serum osteocalcin levels were measured to investigate the relationship between osteocalcin and the onset of puberty. Our data showed that serum osteocalcin levels were significantly higher in the CPP group (87.7 ± 24.4 ng/ml vs. 68.3 ± 19.5 ng/ml, P < 0.001). The multivariate analysis revealed that an increase in bone age and peak LH was significantly associated with the serum osteocalcin level. The results of this study suggest that serum osteocalcin is associated with the onset of puberty in girls.

Background: Age-related decreases in lean mass represent a serious health problem. We aimed to analyze the risks of rapid decreas es in lean mass by age and sex in relatively young Korean adults during a 4-year follow-up study. Methods: A total of 65,856 non-diabetic participants (59.5% men, mean age 39.1 years) in a health screening program were subject ed 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. Results: The 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

Spermatogenesis begins after puberty and continues throughout a male's life, and is regulated by spermatogonial stem cells in the seminiferous tubules. Markers of male germ cells, including undifferentiated spermatogonia to fully developed spermatozoa have been identified in rodents, but not in dogs. In this study, to characterize the markers of undifferentiated spermatogonia, histological and immunohistochemical analyses were performed on pre-pubertal (1-month-old), early pubertal (4-month-old), and post-pubertal (7-month-old) dog testes. Expression of chemokine receptor 4 (CXCR4), insulin-like growth factor binding protein 3 (IGFBP3), LIN28, and Sal-like protein 4 (SALL4) genes was confirmed by immunohistochemical analysis. In pre-pubertal and early pubertal dog testes, CXCR4, IGFBP4, and LIN28 genes were expressed in undifferentiated spermatogonia, whereas the SALL4 gene was not expressed in the pre-pubertal stage. In adult dog testes, CXCR4 and IGFBP3 gene expression was detected in undifferentiated spermatogonia and co-localized with protein gene product 9.5 (PGP9.5) near the basement membrane of the seminiferous tubules. The LIN28 and SALL4 genes were expressed in synaptonemal complex protein 3-positive spermatocytes. The CXCR4 and IGFBP3 gene expression is conserved among other species, while LIN28 and SALL4 gene expression varies. Based on results of the present study, it is suggested that undifferentiated spermatogonia markers detected in other species are conserved in dogs. These results may facilitate further studies of the cellular mechanisms of spermatogenesis in dogs.

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.

No cohort studies have evaluated the effect of obesity on the incidence of thyroid cancer according to metabolic health status. Therefore, this study examined the association of body mass index (BMI) and metabolic health status with thyroid cancer risk.A cohort study was performed involving 255,051 metabolically healthy (MH) and metabolically unhealthy (MUH) adults free of thyroid cancer at baseline who were followed for a median of 5.3 years. A parametric proportional hazard model was used to estimate the adjusted hazard ratio (aHR) and confidence interval (CI).During 1,402,426.3 person-years of follow-up, 2927 incident thyroid cancers were identified. Among men, the multivariable aHR for thyroid cancer comparing obesity, defined as a BMI ≥25 kg/mIn both MH and MUH men, obesity was associated with an increased risk of incident thyroid cancer, indicating excessive adiposity per se as an independent risk factor for thyroid cancer. Conversely, women with MUH obesity but not MH obesity were found to have an increased risk of thyroid cancer, indicating that obesity with accompanying metabolic abnormalities may affect thyroid cancer risk in women.

Background We 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. Methods Thirty-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. Results When 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]). Conclusion Participants 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.

Results from previous studies support the association of lipoprotein(a) [Lp(a)] levels and coronary artery disease risk. In this study, we analyzed the association between baseline Lp(a) levels and future progression of coronary artery calcification (CAC) in apparently healthy Korean adults.A total of 2611 participants (mean age: 41years, 92% mend) who underwent a routine health check-up in 2010 and 2014 were enrolled. Coronary artery calcium score (CACS) were measured by multi-detector computed tomography. Baseline Lp(a) was measured by high-sensitivity immunoturbidimetric assay. Progression of CAC was defined as a change in CACS0 over four years.Bivariate correlation analyses with baseline Lp(a) and other metabolic parameters revealed age, total cholesterol, HDL-C, LDL-C and CACS to have a significant positive correlation, while body weight, fasting glucose level, blood pressure and triglyceride level were negatively correlated with baseline Lp(a) level. After four years of follow-up, 635 subjects (24.3%) had CAC progression. The participants who had CAC progression were older, composed of more men, more obese, and had higher fasting glucose levels and worse baseline lipid profiles compared to those who did not have CAC progression. The mean serum Lp(a) level was significantly higher in subjects who had CAC progression compared to those who did not (32.5 vs. 28.9mg/dL, p0.01). When the risk for CAC progression according to baseline Lp(a) was calculated, those with Lp(a) level≥50mg/dL had an odds ratio of 1.333 (95% CI 1.027-1.730) for CAC progression compared to those with Lp(a)50mg/dL after adjusting for confounding factors.In this study, the subjects who had higher Lp(a) were at significantly higher risk for CAC progression after four years of follow-up, suggesting the role of high Lp(a) in CAC progression.

Background The 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. Methods Renal 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

Background Diabetes 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. Methods This 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. Results Thirty 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). Conclusion C-peptide-based index was more closely related to incident type 2 diabetes in non-diabetic subjects than insulin-based index.

The visceral adiposity index (VAI) is a mathematical tool that reflects a patient's visceral adiposity and insulin resistance. Recent studies have noted an association between VAI and cardiovascular event. We analyzed the association between VAI and coronary artery calcium score (CACS) in Korean adults.For 33,468 participants (mean age 42 yrs) in a health screening program, VAI was calculated using the following formulae: [waist circumference (WC)/{39.68 + (1.88 * body mass index (BMI))}] * (triglyceride/1.03) * {1.31/high-density lipoprotein cholesterol (HDL-C)} for men and [WC/{36.58 + (1.89 * BMI)}] * (triglyceride/0.81) * (1.52/HDL-C) for women. Coronary artery calcium scores were measured with multi-detector computed tomography.CACS was positively correlated with VAI (r = 0.027, p 0.001). Subjects with 0 CACS100 and CACS ≥ 100 had significantly higher VAI compared to those with CACS = 0 (2.04 ± 1.97, 2.08 ± 1.67 vs. 1.68 ± 1.50, p 0.001). In logistic regression analyses with CACS0 as the dependent variable, subjects in the highest tertile of VAI (1.777) had significantly increased odds ratio for CACS0 compared to subjects in the lowest tertile (0.967), even after adjusting for confounding variables, including BMI (OR 1.26, 95% CI 1.147-1.381).Subjects with high VAI had increased risk for subclinical atherosclerosis, as assessed by CACS. Key messages Recent studies have noted an association between visceral adiposity index (VAI) and cardiovascular event. Subjects with coronary artery calcification (CAC) showed significantly higher VAI compared to those without CAC. The subjects with high VAI showed increased odds ratio for CAC as compared to subjects with low VAI, suggesting high VAI reflects increased risk for subclinical atherosclerosis.

Background Waist-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. Methods A 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. Results During 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. Conclusion Increased 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.

Objective Diabetes and prediabetes subjects have increased risk for mortality. We analyzed the mortality risk due to all causes, cardiovascular disease (CVD) and cancer in Korean subjects participating in a health-screening program according to baseline glycemic status and HbA1c levels. Materials/methods Among 241,499 participants of a health-screening program between 2005 and 2012, the risk of death from all causes, CVD, and cancer was calculated based on the baseline glycemic status (normoglycemia, prediabetes, and diabetes) and HbA1c levels. Uncontrolled diabetes was defined as HbA1c ≥ 7.0%. Vital status and confirmation of the cause of death were based on the analysis of death certificate records from the National Death Index. Results During 923,343.1 person-years of follow-up, 877 participants died. The multivariable-adjusted hazard ratios (HR) of subjects with controlled and uncontrolled diabetes to normoglycemic subjects for all-cause mortality were 1.58 (95% CI 1.24–2.03) and 2.26 (95% CI 1.78–2.86), respectively. The HRs of subjects with controlled and uncontrolled diabetes to normoglycemic subjects for mortality due to cancer were 1.75 (95% CI 1.23–2.48) and 1.67 (95% CI 1.13–2.45). However, glycemic status was not significantly associated with the risk of mortality due to CVD. The subjects with HbA1c higher than 6.5% showed more than 2-fold increased risk for all-cause mortality and the subjects with HbA1c lower than 5.2% showed increased HR (1.45, 95% CI 1.06–1.97) compared with those with HbA1c of 5.5% in subjects not taking anti-diabetic medications. Conclusions Mortality risk from all causes and cancer significantly increased in diabetes subjects regardless of the glucose control status. In subjects not taking anti-diabetic medications, both high and low HbA1c resulted in increased risk for all-cause mortality.

Background We evaluated the association of visceral-to-subcutaneous fat ratio (VSR) with nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis degree based on noninvasive serum fibrosis markers in the general population with NAFLD. Methods This is a cross-sectional study, in 7,465 Korean adults who underwent health screening examinations. NAFLD was defined as fatty liver detected on ultrasonography, and visceral and subcutaneous abdominal fat was measured using computed tomography. We predicted fibrosis based on the fibrosis-4 (FIB-4) score and aspartate aminotransferase-to-platelet ratio index (APRI) and categorized the risk for advanced fibrosis as low, indeterminate, or high. Results The multivariable-adjusted prevalence ratios for indeterminate to high risk of advanced fibrosis based on FIB-4, determined by comparing the second, third, and fourth quartiles with the first quartile of VSR, were 3.38 (95% confidence interval [CI], 0.64 to 17.97), 9.41 (95% CI, 1.97 to 45.01), and 19.34 (95% CI, 4.06 to 92.18), respectively. The multivariable-adjusted prevalence ratios for intermediate to high degree of fibrosis according to APRI also increased across VSR quartiles (5.04 [95% CI, 2.65 to 9.59], 7.51 [95% CI, 3.91 to 14.42], and 19.55 [95% CI, 9.97 to 38.34], respectively). High VSR was more strongly associated with the prevalence of NAFLD in nonobese subjects than in obese subjects, and the associations between VSR and intermediate to high probability of advanced fibrosis in NAFLD were stronger in obese subjects than in nonobese subjects. Conclusion High VSR values predicted increased NAFLD risk and advanced fibrosis risk with NAFLD, and the predictive value of VSR for indeterminate to high risk of advanced fibrosis was higher in obese subjects than in nonobese subjects.

Rationale: Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]–related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation. Objective: To investigate the physiological/pathophysiological role of CTRP1 in BP regulation. Methods and Results: CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ΔCAG ). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)–signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice. Conclusions: For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.

Aims Weight cycling is defined as cyclical loss and gain of weight and recent studies suggest deleterious effects of weight cycling on cardiometabolic health. We aimed to analyze the risk for diabetes development in association with weight cycling over 4 years of follow-up. Methods A retrospective study performed in 4,818 non-diabetic participants (mean age 43 years, 78.3% men) in a health screening program in whom serial health examinations were performed in 5 consecutive years from 2010 to 2014. Average successive variability of weight (ASVW) was defined by the amount of body weight change in absolute value between the successive years over 5 years summed and divided by four. The subjects were divided into two groups according to body mass index (BMI), normal weight ( Results Over 4 years, 3.2% developed diabetes. When the subjects were divided into 3 groups according to tertile groups of ASVW, those in the highest tertile showed significantly increased risk for diabetes development compared to those with the lowest tertile {odds ratio (OR) 1.860; 95% CI 1.130–3.063}. When similar analyses were performed according to the 4 groups divided by baseline body weight and ASVW over four years, those who were more than overweight at baseline with high ASVW showed significantly increased risk of diabetes development compared to those had normal weight and low ASVW (OR 2.266; 95% 1.123–4.572). When the subjects were divided into six group according to weight change and ASVW, those with increased weight over 4 years and high ASVW showed the highest risk for diabetes development among the groups compared to those with stable weight and low ASVW over four years (OR 3.660; 95% CI 1.402–9.553). Conclusions Those with high ASVW showed significantly increased risk for diabetes development over four years compared with those who had low ASVW. Weight cycling was significantly associated with increased risk for diabetes.

Background The 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. Methods A 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. Results The 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. Conclusion The risk for NAFLD was lower in MHO subjects than in MUNO subjects.

Aim To determine whether preadipocyte factor 1 could be a predictive marker for the development of diabetes in people without diabetes at baseline. Methods We conducted a population-based, nested case–control study of individuals who progressed to diabetes (n = 43) or prediabetes (n = 345) and control participants matched on age, sex and fasting plasma glucose concentration, who maintained normal glucose tolerance (n = 389) during a 4-year follow-up using data from the Chungju Metabolic disease Cohort Study. Circulating levels of preadipocyte factor 1 were measured using an enzyme-linked immunosorbent assay. Results Baseline serum preadipocyte factor 1 levels showed a stepwise decrease across the glucose tolerance status groups at follow-up (normal glucose tolerance: 10.02 ± 3.02 ng/ml; prediabetes: 9.48 ± 3.35 ng/ml; diabetes: 8.66 ± 3.29 ng/ml; P for trend, 0.0151). Individuals whose fasting plasma glucose level had increased or whose homeostasis model assessment of β-cell function had decreased at follow-up showed significantly lower levels of preadipocyte factor 1 compared with their control group counterparts. After adjusting for age, BMI, fasting plasma glucose, serum insulin levels, systolic blood pressure and triglycerides, the incidence of diabetes was nearly threefold higher in the lowest vs. the upper three quartiles of circulating preadipocyte factor 1 (relative risk 2.794; 95% CI 1.188–6.571; P = 0.0185). Notably, these findings were significant in women but not in men. Conclusions Levels of circulating preadipocyte factor 1 may be a useful biomarker for identifying women at high risk of developing diabetes.

Background: Selenoprotein 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. Methods: The 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. Results: Exendin-4 reduced the expression of SEPP1, fetuin-A, and ER stress markers including PKR-like ER kinase, inositolrequiring 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. Conclusion: These data suggest that exendin-4 can attenuate the expression of hepatic SEPP1 and fetuin-A via improvement of PA-induced ER stress by AMPK.

The present study was investigated the effects of biochanin A (BCA) on arsenic toxicity in rats. For this purpose, rats were orally treated with arsenic in the form of sodium meta-arsenite alone (10mg/kg body weight (bw)/day) and co-administered selenium (10mg/kgbw/day) and BCA at different doses (10, 20 and 40mg/kgbw/day) for 6 weeks. Arsenic altered the oxidative stress indices in both renal and cardiac tissues. There was an increase in plasma renal markers, triglyceride, lipoproteins with no alterations in cholesterol levels were noted in arsenic-intoxicated rats. Non-significant changes of phospholipids and free fatty acids levels in the tissues of arsenic-exposed rats. The biochemical disturbances were well correlated with the histological findings in the kidney, but not in the heart. The administration of BCA and selenium significantly reversed the alterations in the above-mentioned parameters in arsenic-intoxicated rats. Our findings revealed the beneficial effects of BCA against arsenic toxicity.

Objective Ezetimibe is known as a Niemann-Pick C1-Like 1 (NPC1L1) inhibitor and has been used as an agent for hypercholesterolemia. In our previous study, ezetimibe administration improved glycemic control and increased glucagon like peptide-1 (GLP-1), an incretin hormone with anti-diabetic properties. However, the mechanisms by which ezetimibe stimulates GLP-1 secretion are not fully understood. Thus, the specific aim of this study was to investigate the mechanism(s) by which ezetimibe stimulates GLP-1 secretion. Materials/methods Male KK/H1J mice were divided into following groups: AIN-93G (NC), NC with ezetimibe (10mg/kg/day), 45% high fat (HF) diet, and HF diet with ezetimibe. To investigate the role of ezetimibe in glucose homeostasis and GLP-1 secretion, an insulin tolerance test was performed and serum and intestinal GLP-1 levels and intestinal mRNA expression involved in GLP-1 synthesis were measured after 6weeks of ezetimibe treatment. In vivo and in vitro dipeptidyl peptidase-4 (DPP-4) inhibition assays were employed to demonstrate the association between ezetimibe-induced GLP-1 change and DPP-4. The molecular mechanism by which ezetimibe affects GLP-1 secretion was evaluated by using human enteroendocrine NCI-H716 cells. Results Ezetimibe supplementation significantly ameliorated HF-increased glucose and insulin resistance in the type 2 diabetic KK/H1J mouse model. Serum and intestinal active GLP-1 levels were significantly increased by ezetimibe in HF-fed animals. However, mRNA expression of genes involved in intestinal GLP-1 synthesis was not altered. Furthermore, ezetimibe did not inhibit the activity of either in vivo or in vitro dipeptidyl peptidase-4 (DPP-4). The direct effects of ezetimibe on GLP-1 secretion and L cell secretory mechanisms were examined in human NCI-H716 intestinal cells. Ezetimibe significantly stimulated active GLP-1 secretion, which was accompanied by the activation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Ezetimibe-increased GLP-1 secretion was abrogated by inhibiting the MEK/ERK pathway with PD98059. Conclusion These findings suggest a possible novel biological role of ezetimibe in glycemic control to stimulate intestinal GLP-1 secretion via the MEK/ERK signaling pathway.

In 2014, the journal published many excellent articles in the fields of endocrinology and metabolism. I believe that these works increased scientific knowledge and the standards of medical care. Updated information is freely available to readers. I would like to briefly introduce a number of excellent articles published in 2014 in 'Endocrinology and Metabolism' (Endocrinol Metab).

Background and Aims We undertook this study to compare the prevalence of coronary artery calcification (CAC) across glycated hemoglobin A1c (HbA1c) in nondiabetic males and to evaluate the impact of insulin resistance on CAC in relation to HbA1c levels. Methods A cross-sectional study was performed in 18,504 adult males without diabetes mellitus and cardiovascular disease (CVD). CAC scores were measured by multidetector computed tomography; CAC was defined as a CAC score >0. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). Subjects were grouped by HbA1c quartile (≤5.4%, 5.4–5.6%, 5.7%, 5.8–6.4%). Results Thirteen percent of subjects ( n = 2,406) had a CAC score >0. The prevalence of CAC increased with increasing HbA1c quartile (9.4%, 11.1%, 14.1%, 17.3%). Crude odds ratios (ORs) for CAC were 1.2, 1.58 and 2.01 for the HbA1c quartiles 2, 3, and 4 when compared with the first quartile. Mean HOMA-IR levels were different among HbA1C categories and CAC status. HOMA-IR levels were higher in subjects with CAC than in those without, except in the third HbA1c quartile. Stratification by HbA1c showed a significant association between CAC and insulin resistance only in the first (OR 1.67) and fourth (OR 1.33) HbA1c quartile. After adjustment for CV risk factors, insulin resistance remained an independent predictor of CAC only in the first HbA1c quartile. Conclusions Our study demonstrated that not only glucose status represented by HbA1c but also insulin resistance might be associated with CAC in non-diabetic Korean men. The magnitude of association of CAC with insulin resistance was greater in the lowest HbA1c quartile group.

Background The 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. Methods To 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. Results Palmitate-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. Conclusion Altogether, 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.