Search

Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently discovered hepatokine that mediates obesity-related metabolic disturbances. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel therapeutic agents for inflammatory disorders including nonalcoholic fatty liver disease (NAFLD). However, no research has examined the connections or functions of LECT2 and the novel DPP-4 inhibitor, gemigliptin, in NAFLD pathogenesis. High-fat diet (HFD)-fed C57BL/6 mice were used to investigate the effect of gemigliptin on hepatic steatosis and LECT2 expression. In the HepG2 cell line, LECT2 and gemigliptin signaling were analyzed by Western blot. LECT2 increased mammalian target of rapamycin (mTOR) phosphorylation, sterol regulatory element-binding protein (SREBP)-1 cleavage, lipid accumulation, and insulin resistance in HepG2 cells; these events were significantly decreased by treatment with a c-Jun N-terminal kinase (JNK) inhibitor. Gemigliptin increased AMP-activated protein kinase (AMPK) phosphorylation and inhibited tumor necrosis factor (TNF) α-induced mTOR phosphorylation, SREBP-1 cleavage, lipid accumulation, and LECT2 expression in HepG2 cells; these events were attenuated by an AMPK inhibitor. Gemigliptin recovered TNFα-induced inhibition of insulin receptor substrate (IRS)-1 and Akt phosphorylation that was abolished in LECT2 knockdown cells or by AMPK inhibition. In preliminary in vivo experiments, gemigliptin induced AMPK phosphorylation and inhibited LECT2 expression in liver tissues from HFD-fed mice. Mice fed with HFD and gemigliptin showed improved hepatic steatosis and insulin resistance compared to HFD-fed mice. Gemigliptin might alleviate hepatic steatosis and insulin resistance by inhibiting LECT2 expression by AMPK-dependent and JNK-dependent mechanisms, suggesting a direct protective effect against NAFLD progression.

SummaryObjective Nonalcoholic fatty liver disease (NAFLD) is a well-known contributor for the development of cardiovascular disease (CVD). We examined the influence of NAFLD and metabolic syndrome (MetS) on markers of subclinical atherosclerosis, including carotid intima-media thickness (CIMT), brachial–ankle pulse wave velocity (baPWV) and ankle–brachial pressure index (ABI), after adjusting for cardiometabolic risk factors. Design A cross-sectional study. Patients and measurements The association between NAFLD, MetS and markers of subclinical atherosclerosis was assessed in 955 participants without CVD using multiple logistic regression analysis after adjusting for multiple cardiometabolic risk variables. Results After adjusting for age and sex, CIMT and baPWV were found to be significantly correlated with multiple cardiometabolic risk variables, whereas ABI was only associated with obesity parameters. The prevalence of NAFLD differed significantly according to the presence of subclinical atherosclerosis as defined by both CIMT and baPWV (P = 0·004 and P = 0·007, respectively). After adjusting for potential confounding factors, NAFLD or MetS was not associated with subclinical atherosclerosis as defined by CIMT and baPWV. However, individuals with both NAFLD and MetS had a significantly higher risk of subclinical atherosclerosis as defined by CIMT (OR = 2·06, 95% CI = 1·13–3·74) or baPWV (OR = 2·64, 95% CI = 1·46–4·76) compared to normal subjects, even after adjusting for potential confounders. Conclusions The results show that NAFLD and MetS have a synergistic impact on the subclinical atherosclerosis, which suggests that individuals with both NAFLD and MetS should be strongly advised to engage in CVD prevention strategies.

Background/Aims: Obstructive sleep apnea (OSA) is associated with an increased risk of obesity and non-alcoholic fatty liver disease (NAFLD), but it remains unclear whether the risk of NAFLD is independently related to OSA regardless of visceral obesity. Thus, the aim of the present study was to examine whether OSA alone or in combination with excessive daytime sleepiness (EDS) or short sleep duration was associated with NAFLD independent of visceral fat in Korean adults. Methods: A total of 621 participants were selected from the Korean Genome and Epidemiology Study (KoGES). The abdominal visceral fat area (VFA) and hepatic fat components of the participants were assessed using computed tomography scans and they were then categorized into four groups depending on the presence of OSA and EDS. Results: The proportions of NAFLD were 21.1%, 18.5%, 32.4%, and 46.7% in participants without OSA/EDS, with only EDS, with only OSA, and with both OSA and EDS, respectively. A combination of OSA and EDS increased the odds ratio (OR) for developing NAFLD (OR, 2.75; 95% confidence interval [CI], 1.21 to 6.28) compared to those without OSA/EDS, and this association remained significant (OR, 2.38; 95% CI, 1.01 to 5.59) even after adjusting for VFA. In short sleepers (< 5 hours) with OSA, the adjusted OR for NAFLD was 2.50 (95% CI, 1.08 to 5.75) compared to those sleeping longer than 5 hours without OSA. Conclusions: In the present study, OSA was closely associated with NAFLD in Korean adults. This association was particularly strong in those with EDS or short sleep duration regardless of VFA.

Objective Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently discovered novel hepatokine, leading to skeletal muscle insulin resistance by activating c-Jun N-terminal kinase (JNK). However, its role in atherosclerotic inflammatory reactions has not been examined. Therefore, we investigated the function of LECT2 on the expression of vascular adhesion molecules and inflammatory cytokines in human endothelial cells. Methods Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were treated with various doses of LECT2 and the functions and signaling pathways were analyzed through Western blot and quantitative real-time PCR (qPCR). Results The level of phosphorylated c-Jun N-terminal kinases (JNK) was significantly increased by LECT2 treatment in HUVECs and THP-1 cells, an effect that was not seen in cells treated with CD209 siRNA, a known LECT2 receptor. LECT2 treatment efficiently increased the expression of intercellular adhesion molecule-1 (ICAM-1) and pro-inflammatory cytokines tumor necrosis factor α (TNFα), monocyte chemo-attractant protein-1 (MCP-1), and interleukin-1β (IL-1β) in HUVECs and THP-1 cells. However, all these reactions were significantly reduced in response to treatment with JNK inhibitor. Furthermore, LECT2 treatment significantly exacerbated the adhesion of monocytic cells to human endothelial cells, which was also efficiently attenuated by JNK inhibitor. Conclusions LECT2 significantly induced adhesion molecules and pro-inflammatory cytokines in HUVECs via CD209-mediated JNK phosphorylation, suggesting that liver-derived novel hepatokine, LECT2, might directly mediate in the atherosclerotic inflammatory reactions in human endothelial cells.

Recently, dipeptidyl peptidase-IV (DPP-IV) inhibitor, a major anti-hyperglycemic agent, has received substantial attention as a possible therapeutic target for inflammatory diseases such as atherosclerosis. However, the direct molecular mechanisms through which DPP-IV inhibitor mediates anti-inflammatory effects in vascular endothelial cells have not been clarified. The effects of the DPP-IV inhibitor, gemigliptin, were analyzed in human umbilical vein endothelial cells (HUVECs) and THP-1 cells. Using Western blotting, we demonstrated that gemigliptin efficiently increased the level of AMP-activated protein kinase (AMPK) and Akt phosphorylation in a dose-dependent manner. The levels of lipopolysaccharide (LPS)-mediated phosphorylated nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) were significantly decreased after gemigliptin treatment. Furthermore, gemigliptin reduced LPS-induced expression of adhesion molecules and inflammatory cytokines such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-1β (IL-1β), and IL-6 in HUVECs. In macrophage-like THP-1 cells, gemigliptin effectively inhibited LPS- and low-density lipoprotein (LDL)-induced foam cell formation. However, these anti-inflammatory and anti-atherosclerotic effects of gemigliptin in HUVECs and THP-1 cells were significantly reduced after treatment with an AMPK or an Akt inhibitor. Our results suggest that gemigliptin efficiently inhibited LPS-induced pro-inflammatory effects in vascular endothelial cells by attenuating NF-κB and JNK signaling via Akt/AMPK-dependent mechanisms. Therefore, the DPP-IV inhibitor, gemigliptin, may directly protect the vascular endothelium against inflammatory diseases such as atherosclerosis.

Objective Recent studies reported the presence of unique subsets of body size phenotypes that are more susceptible or more resistant to the development of obesity-associated metabolic disorders, although the underlying mechanism is not yet fully elucidated. We investigated the association between body size phenotypes and sleep duration after adjusting potential confounding factors. Materials and methods We analyzed data from the Korean National Health and Nutrition Examination Survey V (KNHANES V), a nation-wide, population-based health survey including 9077 Korean adults. The average amount of sleep per night was categorized as: ≤ 6, 7, 8, and ≥ 9 h. Body size phenotypes were classified based on body mass index (BMI) and presence of metabolic syndrome; metabolically healthy and normal weight (MHNW), metabolically abnormal but normal weight (MANW), metabolically healthy but obese (MHO), and metabolically abnormal obese (MAO). Results According to sleep duration, there were significant differences in age, gender, BMI, waist circumference, and blood pressure (all P

Recent studies have suggested that body size phenotype may contribute to atherosclerosis and cardiovascular disease. 18 F-fluorodeoxyglucose (FDG) positron emission tomography is a useful imaging technique for detecting vascular inflammation that may reflect plaque vulnerability. Therefore, we analyzed which body size phenotypes cause the increased vascular inflammation using FDG positron emission tomography. We compared 18 F-FDG uptake, measured using the blood-normalized standardized uptake value, known as the target-to-background ratio (TBR), along with various cardiometabolic risk parameters in 250 participants without a history of cardiovascular disease. Body size phenotypes were classified according to body mass index and the presence/absence of metabolic syndrome. Cardiometabolic risk factors were significantly different among the body size phenotype groups. In particular, the maximum TBR (maxTBR) values in the metabolically abnormal but normal-weight, metabolically healthy obese (MHO), and metabolically abnormal obese groups were significantly greater than those of the metabolically healthy normal-weight (MHNW) group. Components of metabolic syndrome, insulin resistance, high-sensitivity C-reactive protein, and Framingham Risk Score were associated with maxTBR value. Interestingly, although the Framingham Risk Score of the MHO group was almost similar to that of the MHNW group, maxTBR value of MHO subjects was significantly higher than that of MHNW subjects (1.38 [1.20, 1.50] vs 1.22 [1.12, 1.37], p = 0.006). In conclusion, the present study suggests that unique subsets of body size phenotype, such as MHO or metabolically abnormal but normal weight, may have distinct effects on vascular inflammation.

This trial was conducted to compare the efficacy and safety of combination therapy with basal insulin glargine plus mitiglinide to that of basal insulin glargine plus voglibosein patients with type 2 diabetes. This was a 20-week, randomized, multicenter non-inferiority trial. Patients with HbA1c levels over 7.0% were randomly assigned to receive either mitiglinide (10 mg tid) or voglibose (0.2 mg tid) concurrent with insulin glargine for 16 weeks after a 4-week of basal insulin glargine monotherapy. The intention-to-treat population included 156 patients; 79 were placed in the mitiglinide group, and 77 were placed in the voglibose group. At 20 weeks, there was no significant difference between the mitiglinide group and the voglibose group in terms of the mean HbA1c level or the mean decrease of the HbAlc level from baseline (-0.9% [-7.5 mmol/mol] and -0.7%, [-5.3 mmol/mol] respectively). The mean fasting plasma glucose level and data of self-monitoring blood glucosewere significantly decreased from baseline to week 20 in both groups, but there was no significant difference between the two groups. The changes in the basal insulin requirements of each group were not significant. The prevalence of adverse events and the risk of hypoglycemia were similar for both groups. Combination therapy with mitiglinide plus basal insulin glargine was non-inferior to voglibose plus basal insulin glargine in terms of the effect on overall glycemic control.

Supplemental Digital Content is available in the text, The fat mass and obesity-associated (FTO) rs9939609 polymorphism have been associated with the increased metabolic risk and mortality, irrespective of obesity. The mechanism underlying this association is not known. We aimed to evaluate whether the FTO rs9939609 risk variant is independently associated with metabolic risk factors and/or leukocyte telomere length (LTL). We further aimed to investigate whether this relationship is modified by obesity status. A total of 2133 participants were recruited from the Korean Genome and Epidemiology Study. LTL was measured using the real-time quantitative polymerase chain reaction methodology. The FTO rs9939609 polymorphism was genotyped using DNA samples collected at baseline. The proportions of the TT, TA, and AA genotypes were 76.7%, 21.5%, and 1.8%, respectively, and obese subjects comprised 44.5% of the total subjects. Among the 1184 nonobese subjects, body mass index, waist circumference, and visceral fat area were higher in subjects with the FTO risk allele than in noncarriers. In contrast, only high-sensitive C-reactive protein level was associated with the FTO risk allele in the obese subjects. LTL was significantly shorter in carriers of the FTO risk allele compared with noncarriers after controlling for several confounding factors (P

Meteorin-like (Metrnl) was recently identified as a novel adipomyokine induced by exercise and cold exposure. Metrnl improves glucose tolerance, increases systemic energy expenditure, induces white adipose browning, and promotes anti-inflammatory gene programs in obese/diabetic mice. However, the relationship of Metrnl with diabetes and cardiometabolic risk variables in humans has not been explored.In 800 subjects (400 patients with type 2 diabetes and 400 non-diabetes), Metrnl concentration was measured with an enzyme-linked immunosorbent assay, and the correlations of Metrnl level with anthropometric parameters, lifestyle factors, body composition values, and laboratory measurements were assessed.Metrnl concentration was significantly higher in patients with diabetes than in those without diabetes [median (inter-quartile range); diabetes: 1219.9 (1020.6, 1535.6), non-diabetes: 1131.2 (993.1, 1313.6) pg/ml, P .001]. After adjustment for age and sex, Metrnl level was significantly associated with fasting plasma glucose, blood pressure, lipid profile, and eGFR, but not with BMI or percent body fat. Multiple stepwise regression analysis exhibited that Metrnl level was independently associated with diabetes status (P .001), eGFR (P .001), and total cholesterol (P = .026) (RThis study is the first to demonstrate that Metrnl level is elevated in human subjects with type 2 diabetes and is inversely related to various cardiometabolic risk factors, including renal function.

Objective Previous studies have shown that leukocyte cell-derived chemotaxin 2 (LECT2), a recently discovered hepatokine, is associated with the inflammatory response and insulin resistance. We examined circulating plasma LECT2 levels in the subjects with non-alcoholic fatty liver disease (NAFLD) or metabolic syndrome. Methods We analyzed plasma LECT2 levels from the subjects of age- and sex-matched 320 adults with or without NAFLD who completed a health check-up at the Health Promotion Center of Korea University Guro Hospital. Results Individuals with NAFLD showed significantly higher LECT2 levels (31.2 [20.9, 41.5] vs. 24.5[16.3, 32.7] ng/ml, P

Background Glycemic variability is associated with the development of diabetic complications through the activation of oxidative stress. This study aimed to evaluate the effects of a dipeptidyl peptidase 4 inhibitor, vildagliptin, or a thiazolidinedione, pioglitazone, on glycemic variability and oxidative stress in patients with type 2 diabetes. Methods In this open label, randomised, active-controlled, pilot trial, individuals who were inadequately controlled with metformin monotherapy were assigned to either vildagliptin (50 mg twice daily, n=17) or pioglitazone (15 mg once daily, n=14) treatment groups for 16 weeks. Glycemic variability was assessed by calculating the mean amplitude of glycemic excursions (MAGE), which was obtained from continuous glucose monitoring. Urinary 8-iso prostaglandin F₂α, serum oxidised low density lipoprotein, and high-sensitivity C-reactive protein were used as markers of oxidative stress or inflammation. Results Both vildagliptin and pioglitazone significantly reduced glycated hemoglobin and mean plasma glucose levels during the 16-week treatment. Vildagliptin also significantly reduced the MAGE (from 93.8±38.0 to 70.8±19.2 mg/dL, P=0.046), and mean standard deviation of 24 hours glucose (from 38±17.3 to 27.7±6.9, P=0.026); however, pioglitazone did not, although the magnitude of decline was similar in both groups. Markers of oxidative stress or inflammation including urinary 8-iso prostaglandin F₂α did not change after treatment in both groups. Conclusion In this 16-week treatment trial, vildagliptin, but not pioglitazone, reduced glycemic variability in individuals with type 2 diabetes who was inadequately controlled with metformin monotherapy, although a reduction of oxidative stress markers was not observed.

The direct effects of dipeptidyl peptidase-IV (DPP-IV) inhibitors on endoplasmic reticulum (ER) stress-induced apoptosis and inflammation in cardiomyocytes have not been elucidated. H9c2 cell viability, which was reduced by tunicamycin, was increased after DPP-IV inhibitor gemigliptin treatment. Gemigliptin significantly decreased the tunicamycin-mediated increase in glucose regulated protein 78 (GRP78) expression and ER stress-mediated signaling molecules such as protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C-EBP homologous protein (CHOP) and inositol-requiring enzyme 1α (IRE1α)/c-Jun N-terminal kinase (JNK)-p38. Furthermore, gemigliptin effectively induced Akt phosphorylation in a dose-dependent manner. Using flow cytometry and Hoechst staining, we showed that treatment with Akt inhibitor significantly blocked the anti-apoptotic effects mediated by gemigliptin. The reduction in tunicamycin-induced GRP78 level and PERK/CHOP pathway activity by gemigliptin was reversed after treatment with Akt inhibitor. In conclusion, gemigliptin effectively inhibited ER stress-induced apoptosis and inflammation in cardiomyocytes via Akt/PERK/CHOP and IRE1α/JNK-p38 pathways, suggesting its direct protective role in cardiovascular diseases.

Free fatty acid-induced lipotoxicity via increased endoplasmic reticulum (ER) stress and hepatocyte apoptosis is a key pathological mechanism of non-alcoholic steatohepatitis. A role of hypoxia-inducible factor 1α (HIF-1α) in this process has been suggested, but direct evidence is lacking. Here, we used HepG2 cells as a model to study whether HIF-1α can reduce palmitic acid-induced lipotoxicity and ER stress. In HepG2 cells treated with 500 µM palmitic acid, HIF-1α expression increased transiently, the decline was associated with increased cleaved caspase-3 expression. Overexpression and knockdown of HIF-1α decreased and exacerbated, respectively, palmitic acid-induced lipoapoptosis. The overexpression also blunted upregulation of the ER stress markers, C/EBP homologous protein (CHOP) and chaperone immunoglobulin heavy chain binding protein (Bip), while the knockdown increased the level of CHOP. In line with this, CHOP promoter activity decreased following HIF-1α binding to the CHOP promoter hypoxia response element. These results indicate that hepatocyte lipotoxicity is associated with decreased HIF-1α expression. It also suggests that upregulation of HIF-1α can be a possible strategy to reduce lipotoxicity in non-alcoholic fatty liver disease. J. Cell. Biochem. 115: 1147–1158, 2014. © 2014 Wiley Periodicals, Inc.

The prevalence and social burden of type 2 diabetes mellitus (T2DM) is increasing. Medication adherence is necessary for positive outcomes in patients with T2DM.This study evaluated the association between medication adherence and clinical/economic outcomes in patients with T2DM in the Republic of Korea over a 3-year period.This study used data from the Korean National Diabetes Program at 5 hospitals. Medication possession ratios of ≥90% and90% were used to define adherent and nonadherent groups, respectively. The degree of glycemic control, changes in blood pressure and lipid profiles, and health care costs were compared.Of the 608 patients, 472 were medication adherent and 136 were nonadherent. The adherent patients displayed improved fasting blood glucose and hemoglobin A1c during the study. Diastolic blood pressure and total cholesterol were lower at 36 months, and lower low-density lipoprotein cholesterol was noted at baseline and 24 months. The total health care costs were $1861, $2060, and $1924, respectively, versus $1617, $1751, and $1602 during the 3-year study period for the adherent group versus the nonadherent group, respectively (P = 0.316, 0.627, and 0.172, respectively), whereas the outpatient drug costs were $1143, $1176, and $1162 in the adherent group versus $925, $778, and $914 in the nonadherent group (P = 0.002, P0.001, and P = 0.001).The adherent patients displayed better glycemic control and lipid profiles. Medication-related expenses were higher in the adherent group, but overall health care costs, including hospitalization costs, were similar between the 2 groups.

Background/Aims Primary aldosteronism (PA) is now widely recognized to have a higher prevalence than was once thought. In view of its increasing prevalence, we compared chronological changes in clinical manifestations of PA according to different times of diagnosis. Methods In total, 85 patients diagnosed with PA from January 1986 through March 2012 were reviewed retrospectively, based on their medical records. During two periods-1986 to 2005 and 2006 to 2012-41 and 44 patients, respectively, were diagnosed with PA. We compared the clinical and biological characteristics of PA between these periods. Results The results demonstrate an increasing trend in the prevalence of idiopathic hyperaldosteronism (IHA; p = 0.19). In the 2006 to 2012 period, patients with PA presented with higher serum potassium levels at the time of diagnosis than in the 1986 to 2005 period (p < 0.0002). Adrenal vein sampling (AVS) was performed mostly in the latter period (82.3%) and the diagnostic accuracy of adrenal computed tomography, compared with AVS, was only 56.2%. About 78.0% versus 86.3% of patients had at least one target organ damage (TOD) in the 1986 to 2005 and 2006 to 2012 periods, respectively (p = 0.39). However, patients with TOD were older and had longer durations of hypertension than patients without, in both periods. Conclusions PA is becoming more prevalent. There was an increasing tendency for IHA, and more PA patients presented with normokalemia than in the earlier period. Early and accurate diagnosis of PA with AVS and proper treatment should have substantial prognostic value.

Carrageenan (CGN) has been shown to cause inflammation through toll-like receptor 4, which may play an important role in insulin resistance and type 2 diabetes mellitus. Selenoprotein P (SeP) has recently been identified as a novel hepatokine that causes insulin resistance. Here, we report that treatment of HepG2 cells with CGN increased both CCAAT enhancer binding protein homologous protein (CHOP) and SeP expression. Pretreatment with 4-phenylbutyrate (4-PBA), an endoplasmic reticulum stress inhibitor, and PD98059, a c-Jun N-terminal kinase (JNK) inhibitor, reversed CGN-induced SeP expression. Moreover, both 4-PBA and knock-down of SeP improved CGN-induced insulin resistance. In addition, we found that adenosine monophosphate-activated protein kinase (AMPK) activators ameliorated CGN-induced insulin resistance in addition to suppressing CHOP and SeP expression. In conclusion, CGN-induced ER stress increased the expression of SeP through the JNK pathway, while AMPK activators ameliorated CGN-induced insulin resistance via SeP inhibition through the AMPK-mediated alleviation of ER stress in hepatocytes.

Supplemental Digital Content is available in the text, Increased glycemic variability (GV) is an independent risk factor for cardiovascular complications in patients with diabetes. We evaluated the risk of future development of cardiovascular disease (CVD) and death according to GV in a general population without diabetes. We used the National Health Insurance Service, providing a population-based, nationwide database of Koreans. We included individuals without diabetes who underwent glucose measurement at least 3 times during 2002 to 2006. GV was calculated as standard deviation (SD) of fasting plasma glucose (FPG) levels. We observed development of CVD or all-cause death from 2007 to 2015, and also evaluated the mortality within 1 year after CVD. Among 3,211,319 people, we found 23,374 incident cases of myocardial infarction (MI), 27,705 cases of stroke, and 63,275 deaths during 8.3 years of follow-up. After multivariate adjustment, GV was found to be a significant predictor of MI, stroke and all-cause death for their highest quartile, with corresponding hazard ratios (HR) of 1.08 (95% confidence interval, CI 1.04–1.11), 1.09 (95% CI 1.06–1.13), and 1.12 (95% CI 1.10–1.15), respectively. The risk of death increased more in those who had both impaired fasting glucose and the highest quartile of GV (HR 1.24 [95% CI 1.21–1.28]). Moreover, early death rate after 1 year of CVD was higher in the highest quartile of GV compared to the lowest quartile (HR 1.21 [95% CI 1.03–1.41]). Long-term FPG variation was independently associated with CVD and mortality in a general population without diabetes.

Background Recent evidences indicate that early rapid renal function decline is closely associated with the development and progression of diabetic kidney disease. We have investigated the association between carotid atherosclerosis and rapid renal function decline in patients with type 2 diabetes mellitus and preserved renal function. Methods In a prospective, multicenter cohort, a total of 967 patients with type 2 diabetes mellitus and preserved renal function were followed for 6 years with serial estimated glomerular filtration rate (eGFR) measurements. Common carotid intima-media thickness (CIMT) and presence of carotid plaque were assessed at baseline. Rapid renal function decline was defined as an eGFR decline >3.3% per year. Results Over a median follow-up of 6 years, 158 participants (16.3%) developed rapid renal function decline. While there was no difference in CIMT, the presence of carotid plaque in rapid decliners was significantly higher than in non-decliners (23.2% vs. 12.2%, P

Gestational diabetes mellitus (GDM) is a strong predictor of postpartum prediabetes and transition to overt type 2 diabetes (T2DM). Although many reports indicate that low magnesium is correlated with deteriorated glucose tolerance, the association between postpartum serum magnesium level and the risk for T2DM in women with a history of GDM has not been evaluated. We analyzed postpartum serum magnesium levels and development of prediabetes and T2DM in women with prior GDM according to American Diabetes Association (ADA) criteria using the Korean National Diabetes Program (KNDP) GDM cohort. During a mean follow-up of 15.6 ± 2.0 months after screening, 116 women were divided into three groups according to glucose tolerance status. Ultimately, eight patients (6.9%) were diagnosed with T2DM, 59 patients (50.9%) with prediabetes, and 49 patients (42.2%) with normal glucose tolerance (NGT) after follow-up. The T2DM group had the lowest serum magnesium level (0.65 [0.63-0.68] mM/L) in the postpartum period, but there was no significant difference between the prediabetes group (0.70 [0.65-0.70] mM/L) and the NGT group (0.70 [0.65-0.70] mM/L) (P = 0.073) Multiple logistic regression analysis showed that postpartum HOMA-IR was a significant predictor of both prediabetes and T2DM. Moreover, we found that postpartum serum magnesium level was also a possible predictor for T2DM development. Serum magnesium level in the postpartum period may be a possible predictor for T2DM development in women with a history of GDM.

OBJECTIVE The purpose of this study was to investigate whether the impact of obstructive sleep apnea (OSA) on glucose metabolism was different according to the presence or absence of obesity. RESEARCH DESIGN AND METHODS A total of 1,344 subjects >40 years old from the Korean Genome and Epidemiology Study were included. OSA was detected by home portable sleep monitoring. Plasma glucose, HbA1c, and insulin resistance were compared according to OSA and obesity status. The associations between OSA and impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG + IGT, and diabetes were evaluated in subjects with and without obesity after adjusting for several confounding variables. The effect of visceral obesity on this association was evaluated in 820 subjects who underwent abdominal computed tomography scanning. RESULTS In subjects without obesity, fasting glucose, 2-h glucose after 75-g glucose loading, and HbA1c were higher in those with OSA than in those without after controlling for age, sex, and BMI. In addition, the presence of OSA in nonobese subjects was associated with a higher prevalence of IFG + IGT and diabetes after adjusting for several confounding variables (odds ratio 3.15 [95% CI 1.44–6.90] and 2.24 [1.43–3.50] for IFG + IGT and diabetes, respectively). Further adjustment for visceral fat area did not modify this association. In contrast, in those with obesity, none of the abnormal glucose tolerance categories were associated with OSA. CONCLUSIONS The presence of OSA in nonobese individuals is significantly associated with impaired glucose metabolism, which can be responsible for future risk for diabetes and cardiovascular disease.

OBJECTIVE To examine the effect of a combined exercise program on C1q/tumor necrosis factor-related protein (CTRP) 3 and CTRP-5 levels and novel adiponectin paralogs suggested to be links between metabolism and inflammation and to evaluate sex differences and association with cardiometabolic risk factors in humans with use of a newly developed ELISA. RESEARCH DESIGN AND METHODS This cross-sectional study explored the implications of CTRP-3 and CTRP-5 on cardiometabolic parameters in 453 nondiabetic Korean adults. In addition, we evaluated the impact of a 3-month combined exercise program on CTRP-3 and CTRP-5 levels in 76 obese women. The exercise program consisted of 45 min of aerobic exercise at an intensity of 60–75% of the age-predicted maximum heart rate (300 kcal/session) and 20 min of resistance training (100 kcal/session) five times per week. RESULTS Both CTRP-3 and CTRP-5 concentrations were significantly higher in women (P < 0.001) than in men (P = 0.030). In a multiple stepwise regression analysis, CTRP-3 levels were independently associated with age, sex, and triglyceride, LDL cholesterol, adiponectin, and retinol-binding protein 4 (RBP4) levels (R2 = 0.182). After 3 months of a combined exercise program, cardiometabolic risk factors, including components of metabolic syndrome, insulin resistance, and RBP4 levels, decreased significantly. In particular, CTRP-3 levels decreased significantly (median [interquartile range] 444.3 [373.8–535.0] to 374.4 [297.2–435.9], P < 0.001), whereas CTRP-5 levels were slightly increased (34.1 [28.6–44.3] to 38.4 [29.8–55.1], P = 0.048). CONCLUSIONS A 3-month combined exercise program significantly decreased CTRP-3 levels and modestly increased CTRP-5 levels in obese Korean women.

Objective The purpose of this study was to investigate the impact of body mass index (BMI) and the presence of metabolic syndrome (MetS) on all-cause and cardiovascular mortality in elderly Korean men and women, and especially to compare metabolically obese normal-weight (MONW) and metabolically healthy obese (MHO) subjects. Patients and methods A total of 2317 elderly people (over 60 years of age) were studied using follow-up data from the South-West Seoul (SWS) Study, a prospective cohort study. Mortality from all causes and cardiovascular disease (CVD) were evaluated according to the combination of the presence or absence of MetS and Asian-specific body mass index (BMI) criteria (BMI

SummaryObjective It has been suggested that insulin resistance, low-grade inflammation and vitamin D deficiency are associated with obesity and sarcopenia. However, their relationships with sarcopenic obesity (SO) are unclear. We evaluated the impact of homoeostasis model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein (hsCRP) and 25-hydroxyvitamin D (25[OH]D) levels on SO in Korean adults. Study subject/measurements This study included 493 apparently healthy adults (180 men and 313 women) enrolled in the Korean Sarcopenic Obesity Study. Sarcopenia was defined as a skeletal muscle mass index (SMI) of 1 SD below the sex-specific mean value for a young reference group. Obesity was defined as a visceral fat area (VFA) ≥100 cm2. We classified the participants into four sarcopenia/obesity groups based on both SMI and VFA. Results The prevalence of SO was 17·8% in men and 24·9% in women. In women, the SO group had higher HOMA-IR and hsCRP levels compared with the non-SO group. In men, the 25[OH]D levels were significantly lower in the SO group than the non-SO group. Both hsCRP and HOMA-IR levels were negatively correlated with SMI and positively correlated with VFA in both men and women, whereas 25[OH]D levels were positively correlated with SMI in both men and women. Multiple binary logistic regression analysis showed that HOMA-IR and 25[OH]D levels were independently associated with SO in men, while HOMA-IR and hsCRP were significant factors predicting SO in women. Conclusion Insulin resistance, inflammation and vitamin D deficiency were associated with SO in a Korean adult population.

To evaluate vascular inflammation according to high-sensitivity C-reactive protein (hsCRP) levels in the low- (10%) and intermediate- (10%-20%) Framingham risk score (FRS) groups using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT, which reflects vascular inflammation and vulnerable atherosclerotic plaque.We measured hsCRP levels and traditional cardiovascular risk factors in 142 non-diabetic subjects without history of cardiovascular disease. To assess the vascular influence of hsCRP on each FRS category, we compared carotid intima-media thickness (CIMT), brachial-ankle pulse wave velocity (baPWV), and vascular inflammation, which was represented as the target-to-background ratio (TBR) measured using FDG-PET/CT.In both low- and intermediate-FRS categories, mean TBR values in subjects with higher hsCRP levels (≥2mg/L) were significantly increased compared to those with lower hsCRP levels (2mg/L) (P=0.001, P0.001, respectively). However, baPWV and CIMT values did not significantly differ according to hsCRP levels in the same FRS categories. Mean TBR levels positively correlated with FRS, body mass index (BMI), whereas negatively correlated with HDL-cholesterol. Multiple stepwise regression analyses showed that hsCRP, LDL-cholesterol, BMI, and insulin resistance were independently associated with mean TBR values (R(2)=0.414).In both intermediate and low FRS risk groups, vascular inflammation measured using FDG-PET/CT was increased in individuals with higher hsCRP levels compared to those with lower hsCRP.

Unique subsets of body size phenotypes seem to be more prone or more resistant to the development of obesity-associated metabolic disorders, although the underlying mechanism is not yet clearly understood.We investigated the prevalence and risk of low muscle mass in subjects who are classified as either metabolically healthy normal weight (MHNW), metabolically abnormal but normal weight (MANW), metabolically healthy obese (MHO), or metabolically abnormal obese (MAO). Subjects were classified based on body mass index and presence of metabolic syndrome.Thigh muscle cross-sectional area was evaluated using computed tomography as an index of muscle mass in 492 apparently healthy adults enrolled in the Korean Sarcopenic Obesity Study (KSOS), an ongoing prospective observational cohort study. Low muscle mass was defined as thigh muscle cross-sectional area divided by weight (percent) of1 SD below the mean values of young adults in both sexes.The prevalence rates of low muscle mass in MHNW, MANW, MHO, and MAO subjects were 6.2%, 17.8%, 23.2%, and 33.7%, respectively. In a multiple logistic regression analysis, men with the MANW phenotype showed a remarkably increased risk of low muscle mass (odds ratio = 11.30, 95% confidence interval, 1.73-73.28) compared with those with MHNW. Furthermore, in both men and women, MHO or MAO subjects had higher odds ratios of low muscle mass compared with MHNW subjects.The present study suggests that low muscle mass may be associated with different metabolic consequences according to body size phenotype.

BACKGROUND Selenoprotein P (SeP) has recently been reported as a novel hepatokine that regulates insulin resistance and systemic energy metabolism in rodents and humans. We explored the associations among SeP, visceral obesity, and nonalcoholic fatty liver disease (NAFLD). METHODS We examined serum SeP concentrations in subjects with increased visceral fat area (VFA) or liver fat accumulation measured with computed tomography. Our study subjects included 120 nondiabetic individuals selected from participants of the Korean Sarcopenic Obesity Study. In addition, we evaluated the relationship between SeP and cardiometabolic risk factors, including homeostasis model of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hsCRP), adiponectin values, and brachial-ankle pulse wave velocity (baPWV). RESULTS Subjects with NAFLD showed increased levels of HOMA-IR, hsCRP, VFA, and several components of metabolic syndrome and decreased levels of adiponectin and high density lipoprotein cholesterol than those of controls. Serum SeP levels were positively correlated with VFA, hsCRP, and baPWV and negatively correlated with the liver attenuation index. Not only subjects with visceral obesity but also those with NAFLD exhibited significantly increased SeP levels (P

Background and Purpose— Prediabetes is a known risk factor for vascular diseases; however, its differential contribution to mortality risk from various vascular disease subtypes is not known. Methods— The subjects of the National Health Insurance Service in Korea (2002–2013) nationwide cohort were stratified into normal glucose tolerance (fasting glucose Results— When adjusted for age, sex, and body mass index, IFG stage 2, but not stage 1, was associated with significantly higher all-cause mortality (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.18–1.34) and vascular disease mortality (HR, 1.27; 95% CI, 1.08–1.49) compared with normal glucose tolerance. Among the vascular disease subtypes, mortality from ischemic stroke was significantly higher (HR, 1.60; 95% CI, 1.18–2.18) in subjects with IFG stage 2 but not from ischemic heart disease and hemorrhagic stroke. The ischemic stroke mortality associated with IFG stage 2 remained significantly high when adjusted other modifiable vascular disease risk factors (HR, 1.51; 95% CI: 1.10–2.09) and medical treatments (HR, 1.75; 95% CI, 1.19–2.57). Conclusions— Higher IFG degree (fasting glucose, 110–125 mg/dL) was associated with increased all-cause and vascular disease mortality. The increased vascular disease mortality in IFG stage 2 was attributable to ischemic stroke, but not ischemic heart disease or hemorrhagic stroke in Korean adults.

Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease as well as metabolic syndrome. FDG-PET is a novel imaging technique that detects vascular inflammation, which may reflect rupture-prone vulnerable atherosclerotic plaques.Vascular inflammation was measured as the maximum target-to-background ratio (maxTBR), along with various cardiometabolic risk factors in 51 subjects with NAFLD, and compared with 100 age- and gender-matched subjects without NAFLD. The liver attenuation index (LAI), which was measured using computed tomography, was used as a parameter for the diagnosis of NAFLD.After adjusting for age and sex, both maxTBR and LAI values were associated with several cardiometabolic risk parameters. Furthermore, there was a significant inter-relationship between LAI and maxTBR values (r=-0.227, P=0.005). Individuals with NAFLD had higher maxTBR values than those without NAFLD (P=0.026), although their carotid intima-media thickness (CIMT) values did not differ. The proportion of subjects with NAFLD showed a step-wise increment following the tertiles of maxTBR values (P for trend=0.015). In multiple logistic regression analysis, maxTBR tertiles were independently associated with NAFLD after adjusting for age, gender, systolic blood pressure, triglycerides, HDL-cholesterol, glucose, BUN, creatinine and homeostasis model assessment of insulin resistance (HOMA-IR) (P=0.030). However, their relationship was attenuated after further adjustment for waist circumference or high sensitive C-reactive protein.Patients with NAFLD have an increased risk for vascular inflammation as measured via FDG-PET/CT even without difference in CIMT. (Clinical trials No. NCT01958411, http://www.clinicaltrials.gov/).

We compared heart rate variability (HRV) values according to the following body size phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy but normal weight (MUNW), metabolically healthy but obese (MHO), and metabolically unhealthy obese (MUO). We retrospectively analyzed a dataset from 1200 participants who had visited the Cardiovascular Center at Korea University Guro Hospital between March 2009 and February 2014 and underwent Holter monitoring for 24h. HRV was calculated from standard deviation of normal-to-normal R-R intervals (SDNN), standard deviation of the average normal-to-normal intervals (SDANN), and root mean square of successive differences (rMSSD) measurements, and study subjects were classified according to body mass index (BMI) and presence or absence of metabolic syndrome. Various HRV indices, including SDNN, SDANN, and rMSSD, were significantly lower in MUNW subjects than in MHNW or MHO subjects, while there were no significant differences between MUNW and MUO subjects. Although BMI had no significant correlation with any HRV indices, SDNN, SDANN, and rMSSD values had significant negative correlations with waist circumference and levels of C-reactive proteins, AST, ALT, fasting glucose, and HOMA-IR. A significant positive correlation was observed between HRV index and HDL level. Furthermore, the SDNN value significantly decreased with an increase in the number of metabolic syndrome components after adjusting for other covariates. Compared to MHNW or MHO subjects, Korean men and women with the MUNW phenotype exhibited decreased HRV, suggesting that low HRV is related to adverse cardiovascular outcomes in MUNW individuals.

Age-related declines in skeletal muscle mass may confer significant metabolic consequences for older adults. Associations of low muscle mass and metabolic syndrome (MetS) in Caucasians, and comparisons with associations observed in Asian populations, have not been reported. We examined associations of low muscle mass and metabolic syndrome (MetS) in Asian and Caucasian middle-aged and older men and women using criteria for low muscle mass.Two population-based studies of Australian (Tasmanian Older Adult Cohort Study; TASOAC; N=1005) and Korean (Korean Sarcopenic Obesity Study; KSOS; N=376) community-dwelling adults, mean age 62 and 58 years, respectively.Appendicular lean mass (aLM) determined by dual-energy X-ray absorptiometry and normalised to height squared (aLM/Ht2), weight (aLM/Wt) or body mass index (aLM/BMI). Participants in the lowest sex-specific 20% for aLM measures were defined as having low muscle mass. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria.Although Australians demonstrated generally unfavourable anthropometric and metabolic characteristics compared to Koreans, prevalence of MetS was similar (29.5% in Australians and 31.4% in Koreans, respectively). Low aLM/Ht2 was associated with significantly reduced likelihood of MetS in both Australians (OR: 0.30, 95% CI 0.19 - 0.46) and Koreans (OR: 0.31, 95% CI 0.16 - 0.62). Conversely, low aLM/BMI was associated with increased odds for MetS in Australians (OR: 1.78, 95% CI 1.12 - 2.84), but not Koreans (OR: 1.33, 95% CI = 0.67 - 2.64).Low aLM/BMI is associated with significantly increased likelihood of MetS in Australian adults, but not Koreans, suggesting potential differences in effects of low muscle mass relative to body mass on cardiometabolic health in Caucasian and Asian middle-aged and older adults. Low muscle mass relative to height is associated with reduced likelihood of MetS in both populations.

Supplemental Digital Content is available in the text, There are very few predictive indexes for long-term mortality among community-dwelling elderly Asian individuals, despite its importance, given the rapid and continuous increase in this population. We aimed to develop 10-year predictive mortality indexes for community-dwelling elderly Korean men and women based on routinely collected clinical data. We used data from 2244 elderly individuals (older than 60 years of age) from the southwest Seoul Study, a prospective cohort study, for the development of a prognostic index. An independent longitudinal cohort of 679 elderly participants was selected from the Korean Genome Epidemiology Study in Ansan City for validation. During a 10-year follow-up, 393 participants (17.5%) from the development cohort died. Nine risk factors were identified and weighed in the Cox proportional regression model to create a point scoring system: age, male sex, smoking, diabetes, systolic blood pressure, triglyceride, total cholesterol, white blood cell count, and hemoglobin. In the development cohort, the 10-year mortality risk was 6.6%, 14.8%, 18.2%, and 38.4% among subjects with 1 to 4, 5 to 7, 8 to 9, and ≥10 points, respectively. In the validation cohort, the 10-year mortality risk was 5.2%, 12.0%, 16.0%, and 16.0% according to these categories. The C-statistic for the point system was 0.73 and 0.67 in the development and validation cohorts, respectively. The present study provides valuable information for prognosis among elderly Koreans and may guide individualized approaches for appropriate care in a rapidly aging society.

Background Previous studies have shown that angiopoietin-like protein 8 (ANGPTL8), also called as betatrophin, acts together with ANGPTL3 to regulate lipid metabolism, glucose metabolism, and energy homeostasis. Moreover, ANGPTL8 promotes proliferation of pancreatic β-cells and induces insulin secretion. However, there are no previous longitudinal studies in humans. Methods We analyzed the age- and sex-matched data of 240 normal weight and overweight Korean children from the Korean Metabolic disorders and Obesity Study in Elementary School children (K-MOSES), a prospective observational cohort study. Results At baseline, ANGPTL8 concentrations were positively associated with triglycerides (TG) (r = 0.168, P = 0.010), whereas ANGPTL3 levels were associated with fasting insulin (r = 0.248, P

Recent studies have suggested that a novel adipokine, C1q/tumor necrosis factor-related protein-3 (CTRP-3), a paralog of adiponectin, may play an important role in the regulation of glucose metabolism and innate immunity. Pigment epithelium-derived factor (PEDF), a multifunctional protein with antioxidant and anti-inflammatory properties, is associated with insulin resistance and metabolic syndrome. We examined circulating CTRP-3 and PEDF concentrations in 345 subjects with diverse glucose tolerance statuses. Furthermore, we evaluated the involvement of CTRP-3 and PEDF with cardiometabolic risk factors including insulin resistance, high-sensitivity C-reactive protein (hsCRP), estimated glomerular filtration rate (eGFR), and brachial-ankle pulse wave velocity (baPWV). CTRP-3 concentrations were significantly higher in patients with type 2 diabetes or prediabetes than the normal glucose tolerance group, whereas PEDF levels were not different. Subjects with metabolic syndrome showed significantly higher levels of both CTRP-3 and PEDF compared with subjects without metabolic syndrome. Both CTRP-3 and PEDF were significantly associated with cardiometabolic parameters, including waist-to-hip ratio, triglycerides, HDL-cholesterol, alanine aminotransferase, eGFR, hsCRP, and baPWV. In conclusion, circulating CTRP-3 concentrations were elevated in patients with glucose metabolism dysregulation. Both CTRP-3 and PEDF concentrations were increased in subjects with metabolic syndrome and associated with various cardiometabolic risk factors.

Low levels of soluble receptor for advanced glycation end-products (sRAGE) have been linked to systemic inflammation and vascular complications in patients with type 2 diabetes mellitus (T2DM).We examined the effects of exercise on sRAGE and its association with diverse cardiometabolic risk factors and indicators of atherosclerosis in patients with T2DM.Seventy-five patients with T2DM were randomized into a control group and an aerobic exercise group (60 min at moderate intensity, five times/wk for 12 wk).We evaluated sRAGE, energy expenditure, dietary energy intake, cardiorespiratory fitness, inflammatory markers, visceral fat area, pulse-wave velocity, and flow-mediated dilatation.Baseline sRAGE concentrations were independently associated with age, glycated hemoglobin, glucose, triglyceride, and high-density lipoprotein cholesterol levels (R2=0.244). After 12 wk of exercise training, the exercise group showed significantly decreased body weight, waist circumference, blood pressure, glycated hemoglobin, apolipoprotein B, and free fatty acid levels. Concurrently, cardiorespiratory fitness assessed by oxygen uptake at anaerobic threshold was improved, and body fat percentage and visceral fat area were significantly decreased in the exercise group, although pulse-wave velocity and flow-mediated dilatation were not changed. Furthermore, sRAGE levels were increased and high-sensitivity C-reactive protein levels were decreased in the exercise group but not in the control group. Percent change of sRAGE level was negatively correlated with that of high-sensitivity C-reactive protein during the study period (r=-0.27; P=0.019).Aerobic exercise increases sRAGE levels along with improvement of various cardiometabolic risk factors in patients with T2DM.

The purpose of this study is to examine the association of A1C with beta-cell dysfunction, insulin resistance, and cardiovascular risk factors in Koreans with the relatively high risk for the future development of diabetes. This cross-sectional study recruited subjects from the pre-diabetic cohort of the Korea National Diabetes Program. Among study subjects (n = 616) aged 21-77 years with a history of hyperglycemia (fasting plasma glucose (FPG) ≥ 5.5 mmol/mL), analyses were conducted on 504 participants (296 women, 208 men) except for subjects with FPG ≥ 7.0 mmol/L or 120-min post-challenge plasma glucose ≥ 11.1 mmol/L or A1C ≥ 6.5 %. For insulin sensitivity and β-cell function classified by the categories of A1C levels, ∆Ins(30-0)/∆Glu(30-0) was lower in the highest quartile group than other groups. Although there was no significant difference in HOMA-IR according to the A1C categories, even lowest A1C group (≤ 5.3 %) already included many subjects with abnormal glucose tolerance. A1C showed a significant association with hsCRP, number of metabolic syndrome (MetS) components and ∆Ins(30-0)/∆Glu(30-0) after adjusting for age, gender, BMI, and medications whereas HOMA-IR was insignificantly associated with A1C. Stepwise regression analysis for A1C showed that A1C is independently and negatively associated with ∆Ins(30-0)/∆Glu(30-0), and positively associated with hsCRP. Our study showed that higher A1C was associated with impaired early-phase insulin secretion, MetS, and low grade inflammation in Koreans with the relatively high risk for the future development of diabetes.

Background The receptor for advanced glycation end-products (RAGE) and its diverse ligands play a pivotal role in the development of cardiovascular disease. Soluble forms of RAGE (sRAGE), including the splice variant endogenous secretory RAGE (esRAGE), may neutralize AGE-RAGE mediated vascular damage by acting as a decoy. 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a novel imaging technique for detecting vascular inflammation. Methods We examined vascular inflammation measured using FDG-PET in 41 type 2 diabetes patients and 41 healthy control subjects in the right carotid artery. Vascular 18 F-FDG uptake was measured as the blood-normalized standardized uptake value (SUV), known as the target-to-background ratio (TBR). In addition, their relationship with carotid intima-media thickness (CIMT), estimated GFR (eGFR), and other cardiovascular risk factors was evaluated. Results Both mean and maximum TBR values were significantly higher in patients with type 2 diabetes compared to healthy subjects. After adjusting for age and gender, sRAGE levels were significantly correlated with both mean and maximum TBR values, but not with CIMT values. Multiple linear regression analysis showed that maximum TBR values were independently associated with sRAGE levels in addition to HbA1c and eGFR. Conclusions Circulating sRAGE showed significant association with TBR values measured using FDG-PET, which reflect vascular inflammation.

Aim: Adipokines have been implicated in the pathogenesis of obesity and obesity-related disorders, including atherosclerosis. Chemerin is a recently discovered adipokine which is closely correlated with various metabolic phenotypes in humans. We examined the association between circulating chemerin levels and arterial stiffness, as represented by the brachial ankle pulse wave velocity (baPWV).Methods: Fifty-eight obese and 62 non-obese individuals participated in the study. We measured the serum chemerin and high sensitivity C-reactive protein (hsCRP) levels, and the homeostasis model assessment of insulin resistance (HOMA-IR), as well as other cardiovascular risk factors. Vascular health was assessed by the baPWV and carotid intima-media thickness (IMT).Results: The serum chemerin level was significantly increased in obese individuals compared with lean controls (120.14±19.43 ng/mL vs. 106.81±23.39 ng/mL, p = 0.001). The circulating chemerin level had a significant positive correlation with the body mass index, waist circumference, HOMA-IR, and low-density lipoprotein-cholesterol, triglycerides, and hsCRP levels. The serum chemerin level was significantly associated with the baPWV (r= 0.280, p= 0.002), but not the carotid IMT (r= 0.065, p= 0.504). Multiple stepwise regression analysis showed that age (p < 0.001), waist circumference (p= 0.038), systolic blood pressure (p < 0.001), and serum fasting glucose (p= 0.003) and chemerin levels (p= 0.017) were definitive risk factors for arterial stiffness (r2=0.457).Conclusions: The circulating chemerin level was an independent risk factor for arterial stiffness even after adjusting for other cardiovascular risk factors.

Diabetes mellitus (DM) patients are susceptible to foot injury or foot diseases such as diabetic foot and peripheral arterial disease. Although these conditions are considered important, few studies have investigated them in detail. Therefore, we investigated the epidemiology of diabetic foot complications (DFC) with respect to the effects on the public healthcare system.We evaluated the incidence, clinical characteristics, health service utilization frequency and medical expenses of DFC in type 2 DM patients in the Korea National Diabetes Program (KNDP), the largest multi-center, prospective cohort in Korea (n=4405). To determine precise outcomes, we used national representative databases, including claims data from the Health Insurance ReviewAssessment Service of Korea.During a median follow-up period of 3.30years, 528 patients (12.0%) were newly diagnosed with DFC at an incidence rate of 43.02 cases per 1000 person-years. The patients with DFC were significantly older than patients without DFC, but other clinical characteristics were similar between the two groups. The patients with DFC had more hospital visits (p0.001), longer duration of hospitalization (p0.001), and increased expenses (p0.001) compared to patients without DFC. After multiple adjustments, the differences in number of hospital visits and medical expenses were consistent. In a before and after comparison within the DFC group, all three variables increased significantly after the onset of DFC (p0.001).DFC were significantly associated with poor clinical outcomes and caused a substantial burden to the national healthcare system in Korea. Therefore, intervention to prevent DFC is important.

Objectives Although growing evidence has emphasized the pivotal role of metabolic status irrespective of body mass index (BMI), there has been no study to examine the association of body size phenotype with development of gestational diabetes that requires treatment with oral hypoglycemic agent or insulin (GDM+T) in primiparas. Methods Data from a total of 216,961 women who participated in the National Health Screening Examination (NHSE) between January 2007 and December 2011 and delivered their first babies within two years of the NHSE were analyzed. Body size phenotypes were classified according to body mass index (BMI) and the presence/absence of metabolic syndrome according to the results of the NHSE. GDM+T was identified using the International Classification of Diseases-10th Revision (ICD-10) and prescription codes using Korea National Health Insurance (KNHI) claims. Results Approximately 0.39% of primiparas developed GDM+T. Compared to metabolically healthy normal weight (MHNW) women, both metabolically unhealthy normal weight (MUNW) and metabolically healthy obese (MHO) women had a significantly increased risk for developing GDM+T (odds ratio, OR: 9.53, 95% confidence interval, CI: 5.64–16.09 and OR: 3.30, 95% CI: 2.56–4.25, respectively). Specifically, MUNW individuals had a significantly higher risk of GDM+T when directly compared to MHO women even after adjusting for other GDM risk factors (OR: 2.92, 95% CI: 1.67–5.10). Furthermore, underweight women with metabolic syndrome showed a significantly increased frequency of GDM+T compared to MHNW subjects (OR: 8.87, 95% CI: 1.19–66.32). Conclusions Pre-pregnant metabolic status is critical for development of GDM+T, regardless of their BMI. Therefore, intensive intervention for the components of metabolic syndrome may be helpful for the prevention of GDM+T even in low or normal weight women.

Aim Although hypoglycemia is associated with cognitive dysfunction, including dementia, in patients with type 2 diabetes mellitus (DM), the data are equivocal. The purpose of this study was to investigate the association between hypoglycemia, dementia, and other cognitive dysfunctions. Methods This was a prospective observational study based upon the Korea National Diabetes Program (KNDP). Among the 4540 participants in the KNDP cohort, individuals aged ⩾60years without any history of hypoglycemia or cognitive dysfunction ( n =1957) were included. Nationally representative data from the Health Insurance Review and Assessment Service of Korea claim database were used to obtain a more precise determination of patient outcome. Results During a mean follow-up period of 3.4±0.9years, 118 subjects experienced hypoglycemia-related events. The incidence of dementia and cognitive dysfunction was 7.5 cases per 1000 person-years (PY) and 0.61 cases per 1000 PY, respectively. In the subjects who experienced hypoglycemic events (relative to those who did not), the incidence of dementia was significantly higher ( P =0.0139), but the incidence of cognitive dysfunction was not ( P =0.1106). Hypoglycemic events were associated with dementia (HR, 2.689; 95% CI, 1.080–6.694, P =0.0335) following multiple adjustments. There was also a significant linear trend toward an increased dementia risk commensurate with an increasing number of hypoglycemic events ( P =0.0286). Conclusions Hypoglycemia is significantly associated with the risk of dementia in Korean type 2 DM patients aged ⩾60years.