A Multicentre, Multinational, Open-Label, 52-Week Extension Study of Gemigliptin (LC15-0444) Monotherapy in Patients with Type 2 Diabetes Mellitus.

The purpose of this extension study was to assess the long-term efficacy and safety of gemigliptin 50 mg in patients with type 2 diabetes mellitus (T2DM). Patients with T2DM who had completed the initial 24-week study comparing gemigliptin monotherapy with placebo were eligible to enrol. In the open-label, 28-week extension study, all enrolled patients received gemigliptin, regardless of the treatment received during the initial 24-week study period. The mean reduction±standard deviation (SD) in glycosylated hemoglobin (HbA1c) observed after 24 weeks of treatment (-0.6%±1.1%) was further decreased for the gemi-gemi group and the mean change in HbA1c at week 52 from baseline was -0.9%±1.2% (P<0.0001). For the pbo-gemi group, HbA1c decreased after they were switched to gemigliptin, and the mean change in HbA1c at week 52 from baseline was -0.7%±1.2% (P<0.0001). Furthermore, the overall incidence of adverse events demonstrated that gemigliptin was safe and well tolerated up to 52 weeks.

Safety and Efficacy of Radiofrequency Ablation for Nonfunctioning Benign Thyroid Nodules in Children and Adolescents in 14 Patients over a 10-Year Period.

PURPOSE: To evaluate the efficacy and safety of radiofrequency (RF) ablation for nonfunctioning benign thyroid nodules in children and adolescents. MATERIALS AND METHODS: Fourteen pediatric patients (10 female, 4 male; mean age 15.7 ± 2.3 years, range 12-19 years) with nonfunctioning benign thyroid nodules (mean longest diameter 3.7 ± 1.1 cm, range 2.0-5.6 cm) treated with the use of RF ablation from 2005 to 2015 were evaluated. The inclusion criteria for RF ablation therapy were (i) age <20 years, (ii) benign cytological confirmation by ≥2 separate fine-needle aspiration or core needle biopsies, (iii) pressure symptoms or cosmetic problems caused by thyroid nodules, (iv) absence of any suspicious feature as determined with the use of ultrasound (US), (v) normal serum levels of thyroid hormone and thyrotropin, and (vi) follow-up of >6 months. RF ablation was performed with the use of an RF generator and an 18-gauge internally cooled electrode. RF ablation was performed under local anesthesia without conscious sedation or general anesthesia. Changes in nodules on follow-up US, changes in symptomatic and cosmetic scores, and complications arising during or after RF ablation were evaluated. RESULTS: Mean follow-up period was 36.9 ± 21.7 months (range 6-69 months). At last follow-up visits, mean longest nodule diameter and volume had decreased significantly (3.7 ± 1.1 cm vs 1.4 ± 0.9 cm and 14.6 ± 13.3 mL vs 1.7 ± 4.4 mL; P < 0.001). Both cosmetic and compressive symptoms significantly improved (3.8 ± 0.6 vs 1.4 ± 0.6 and 3.4 ± 1.0 vs 0.1 ± 0.4; P < 0.001). The mean number of ablation sessions was 2.1 ± 1.2 (range 1-5 sessions) and no major complication was encountered during or after RF ablation. CONCLUSIONS: RF ablation might be a safe and effective treatment modality for nonfunctioning benign thyroid nodules in children and adolescents.

Serum magnesium level is associated with type 2 diabetes in women with a history of gestational diabetes mellitus: the Korea National Diabetes Program study.

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.

Salsalate and adiponectin ameliorate hepatic steatosis by inhibition of the hepatokine fetuin-A.

Fetuin-A was recently identified as a novel hepatokine which is associated with obesity, insulin resistance and non-alcoholic fatty liver disease. Salsalate, a prodrug of salicylate with an anti-inflammatory effect and lower side effect profile, significantly lowers glucose and triglyceride levels, and increased adiponectin concentrations in randomized clinical trials. In this study, we examined the effects and regulatory mechanisms of salsalate and full length-adiponectin (fAd) on fetuin-A expression, steatosis and lipid metabolism in palmitate-treated HepG2 cells. Incubation of hepatocytes with palmitate significantly increased fetuin-A and SREBP-1c expression which lead to steatosis and knock-down of fetuin-A by siRNA restored these changes. Salsalate significantly down-regulated palmitate-induced fetuin-A mRNA expression and secretion in a dose- and time-dependent manner. Inhibition of palmitate-induced fetuin-A by salsalate was mediated by AMPK-mediated reduction of NFκB activity, which was blocked by AMPK siRNA or an inhibitor of AMPK. Salsalate attenuated the excessive steatosis by palmitate through SREBP-1c regulation in hepatocytes. Furthermore, fAd also showed suppression of palmitate-induced fetuin-A through the AMPK pathway and improvement of steatosis accompanied by restoration of SREBP-1c, PAPR-α and CD36. In preliminary in vivo experiments, salsalate treatment inhibited high fat diet (HFD)-induced steatosis as well as fetuin-A mRNA and protein expression in SD rats. In conclusion, salsalate and fAd improved palmitate-induced steatosis and impairment of lipid metabolism in hepatocytes via fetuin-A inhibition through the AMPK-NFκB pathway.

Salsalate and Adiponectin Improve Palmitate-Induced Insulin Resistance via Inhibition of Selenoprotein P through the AMPK-FOXO1α Pathway.

Selenoprotein P (SeP) was recently identified as a hepatokine that induces insulin resistance (IR) in rodents and humans. Recent clinical trials have shown that salsalate, a prodrug of salicylate, significantly lowers blood glucose levels and increases adiponectin concentrations. We examined the effects of salsalate and full length-adiponectin (fAd) on the expression of SeP under hyperlipidemic conditions and explored their regulatory mechanism on SeP. In palmitate-treated HepG2 cells as well as high fat diet (HFD)-fed male Spraque Dawley (SD) rats and male db/db mice, SeP expression and its regulatory pathway, including AMPK-FOXO1α, were evaluated after administration of salsalate and salicylate. Palmitate treatment significantly increased SeP expression and aggravated IR, while knock-down of SeP by siRNA restored these changes in HepG2 cells. Palmitate-induced SeP expression was inhibited by both salsalate and salicylate, which was mediated by AMPK activation, and was blocked by AMPK siRNA or an inhibitor of AMPK. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift (EMSA) assay showed that salsalate suppressed SeP expression by AMPK-mediated phosphorylation of FOXO1α. Moreover, fAd also reduced palmitate-induced SeP expression through the activation of AMPK, which results in improved IR. Both salsalate and salicylate treatment significantly improved glucose intolerance and insulin sensitivity, accompanied by reduced SeP mRNA and protein expression in HFD-fed rats and db/db mice, respectively. Taken together, we found that salsalate and adiponectin ameliorated palmitate-induced IR in hepatocytes via SeP inhibition through the AMPK-FOXO1α pathway. The regulation of SeP might be a novel mechanism mediating the anti-diabetic effects of salsalate and adiponectin.

Liver enzymes and vitamin D levels in metabolically healthy but obese individuals: Korean National Health and Nutrition Examination Survey.

OBJECTIVE: Increased liver enzymes and decreased vitamin D levels are associated with insulin resistance and type 2 diabetes. We examined liver enzymes and vitamin D levels in metabolically healthy but obese (MHO) individuals and compared the values with those of other body size phenotypes in the Korean population. MATERIALS/METHODS: A total of 16,190 people over the age of 18years were analyzed using data from the Fourth Korean National Health and Nutrition Examination Survey, which is a nationally representative survey. Body size phenotypes were classified into four groups by body mass index (BMI) and number of metabolic syndrome components. RESULTS: The prevalence of MHO was 14.9% in the entire population and 47.7% in the obese population. In a correlation analysis adjusted for age, sex, and BMI, AST and ALT levels were positively correlated with insulin resistance and cardiometabolic risk factors of the metabolic syndrome, whereas vitamin D level was negatively correlated with these variables. MHO individuals had significantly lower concentrations of AST and ALT compared to metabolically abnormal obese (MAO) subjects, although vitamin D levels were not significantly different. Furthermore, a multiple logistic regression analysis revealed that MHO individuals had lower risk of liver enzyme abnormality compared to MAO after adjusting for potential confounding factors. However, the risk of vitamin D deficiency was not significantly different among groups with different body size phenotypes. CONCLUSIONS: Although both liver enzymes and vitamin D levels are related to insulin resistance and metabolic syndrome, only liver enzymes were independently associated with MHO phenotype.

Insulin secretion and insulin resistance in Korean women with gestational diabetes mellitus and impaired glucose tolerance.

BACKGROUND/AIMS: The aim was to compare the insulin sensitivity and secretion index of pregnant Korean women with normal glucose tolerance (NGT), gestational impaired glucose tolerance (GIGT; only one abnormal value according to the Carpenter and Coustan criteria), and gestational diabetes mellitus (GDM). METHODS: A cross-sectional study was performed with 1,163 pregnant women with positive (1-hour plasma glucose ≥ 7.2 mmol/L) in a 50-g oral glucose challenge test (OGCT). The 100-g oral glucose tolerance test (OGTT) was used to stratify the participants into three groups: NGT (n = 588), GIGT (n = 294), and GDM (n = 281). RESULTS: The GDM group had higher homeostasis model assessment of insulin resistance and lower insulin sensitivity index (ISOGTT), quantitative insulin sensitivity check index, homeostasis model assessment for estimation of index ß-cell secretion (HOMA-B), first and second phase insulin secretion, and insulin secretion-sensitivity index (ISSI) than the NGT group (p ≤ 0.001 for all). Moreover, the GIGT group had lower ISOGTT, HOMA-B, first and second phase insulin secretion, and ISSI than the NGT group (p < 0.001 for all). Among the GIGT subjects, the 1-hour plasma glucose abnormal levels group showed significantly greater weight gain during pregnancy and higher values in the 50-g OGCT than the other two groups. Moreover, the 1-hour and 2-hour abnormal levels groups had poorer insulin secretion status than the 3-hour abnormal levels group. CONCLUSIONS: Korean women with GDM show impairments of both insulin secretion and insulin sensitivity. In addition, GIGT is associated with both ß-cell dysfunction and insulin resistance.

Implication of circulating omentin-1 level on the arterial stiffening in type 2 diabetes mellitus.

Omentin-1 is an adipokine implicated in diabetes, inflammation, and cardiovascular disease. However, no prospective studies have examined the impact of circulating omentin-1 levels on arterial stiffening in patients with type 2 diabetes mellitus. For the purpose of this study, we recruited 120 patients with type 2 diabetes mellitus and measured serum omentin-1, adiponectin, and high-sensitivity C-reactive protein levels as well as other cardiovascular risk factors. Arterial stiffness was assessed by brachial ankle pulse wave velocity (baPWV). An increase in the level of circulating omentin-1 over a period of 1 year was positively correlated with changes in levels of HbA1c and serum adiponectin as well as baPWV. Subjects with higher baseline serum omentin-1 levels tended to have a reduced arterial stiffness after 1 year (P for linear trend = 0.03). In the group with increased baPWV after 1 year, the magnitude of increase of circulating omentin-1 levels was significantly higher than in the group with a lower baPWV after 1 year (134.3 [16.6, 277.1] ng/mL vs. 15.9 [-67.6, 145.7] ng/mL, P < 0.01). Multiple stepwise logistic regression analysis revealed that an increase in systolic blood pressure and an increase in serum omentin-1 level were independently correlated with arterial stiffening, even after adjusting for other cardiovascular risk factors and medication history. Baseline serum omentin-1 levels can predict arterial stiffness changes occurring within a year. Furthermore, changes in serum omentin-1 levels after a year can function as independent markers of arterial stiffening in patients with type 2 diabetes mellitus.

Increased selenoprotein p levels in subjects with visceral obesity and nonalcoholic Fatty liver disease.

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<0.001). In multiple logistic regression analysis, the subjects in the highest SeP tertile showed a higher risk for NAFLD than those in the lowest SeP tertile, even after adjusting for potential confounding factors (odds ratio, 7.48; 95% confidence interval, 1.72 to 32.60; P=0.007). CONCLUSION: Circulating SeP levels were increased in subjects with NAFLD as well as in those with visceral obesity and may be a novel biomarker for NAFLD.

Implication of progranulin and C1q/TNF-related protein-3 (CTRP3) on inflammation and atherosclerosis in subjects with or without metabolic syndrome.

OBJECTIVE: Progranulin and C1q/TNF-related protein-3 (CTRP3) were recently discovered as novel adipokines which may link obesity with altered regulation of glucose metabolism, chronic inflammation and insulin resistance. RESEARCH DESIGN AND METHODS: We examined circulating progranulin and CTRP3 concentrations in 127 subjects with (n = 44) or without metabolic syndrome (n = 83). Furthermore, we evaluated the relationship of progranulin and CTRP3 levels with inflammatory markers and cardiometabolic risk factors, including high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), estimated glomerular filtration rate (eGFR), and adiponectin serum concentrations, as well as carotid intima-media thickness (CIMT). RESULTS: Circulating progranulin levels are significantly related with inflammatory markers, hsCRP (r = 0.30, P = 0.001) and IL-6 (r = 0.30, P = 0.001), whereas CTRP3 concentrations exhibit a significant association with cardiometabolic risk factors, including waist circumference (r = -0.21), diastolic blood pressure (r = -0.21), fasting glucose (r = -0.20), triglyceride (r = -0.34), total cholesterol (r = -0.25), eGFR (r = 0.39) and adiponectin (r = 0.26) levels. Serum progranulin concentrations were higher in patients with metabolic syndrome than those of the control group (199.55 [179.33, 215.53] vs. 185.10 [160.30, 204.90], P = 0.051) and the number of metabolic syndrome components had a significant positive correlation with progranulin levels (r = 0.227, P = 0.010). In multiple regression analysis, IL-6 and triglyceride levels were significant predictors of serum progranulin levels (R(2) = 0.251). Furthermore, serum progranulin level was an independent predictor for increased CIMT in subjects without metabolic syndrome after adjusting for other cardiovascular risk factors (R(2) = 0.365). CONCLUSIONS: Serum progranulin levels are significantly associated with systemic inflammatory markers and were an independent predictor for atherosclerosis in subjects without metabolic syndrome. TRIAL REGISTRATION: ClinicalTrials.gov NCT01668888.

Higher mortality in metabolically obese normal-weight people than in metabolically healthy obese subjects in elderly Koreans.

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 <23 kg/m²; normal weight, BMI 23-24·9 kg/m²; overweight, BMI ≥25 kg/m²; obesity). RESULTS: During a median follow-up of 10·3 years, 393 subjects died, including 126 from CVD. Among subjects with MetS, all-cause and CVD mortality were significantly higher in normal-weight subjects than overweight or obese individuals in Cox proportional-hazard models adjusted for confounding factors. Furthermore, among six groups with various MetS/BMI combinations, MONW individuals had the highest risk, whereas overweight subjects without MetS had the lowest risk of death from all causes and CVD [HR = 2·2 (95% CI = 1·4-3·4), HR = 3·0 (95% CI = 1·4-6·6) respectively]. Interestingly, all-cause mortality was significantly higher in MONW than MHO individuals. CONCLUSIONS: In contrast to MHO subjects, elderly individuals with the MONW phenotype exhibited greater all-cause mortality during 10 years of follow-up.

Body size phenotypes and low muscle mass: the Korean sarcopenic obesity study (KSOS).

CONTEXT: 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. OBJECTIVES: 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. METHODS: 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) of <1 SD below the mean values of young adults in both sexes. RESULTS: 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. CONCLUSIONS: The present study suggests that low muscle mass may be associated with different metabolic consequences according to body size phenotype.

Relationships between sarcopenic obesity and insulin resistance, inflammation, and vitamin D status: the Korean Sarcopenic Obesity Study.

OBJECTIVE: 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 cm(2) . 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.

The effects of caloric restriction on fetuin-A and cardiovascular risk factors in rats and humans: a randomized controlled trial.

OBJECTIVES: The liver-secreted protein fetuin-A is associated with insulin resistance, metabolic syndrome, type 2 diabetes and atherosclerosis. We examined the effect of caloric restriction (CR) on fetuin-A levels and concomitant changes in hepatic steatosis and cardiovascular risk factors in rats and humans. DESIGN AND SUBJECTS: We performed a randomized, controlled clinical trial to examine circulating fetuin-A levels and cardiovascular risk parameters including visceral fat area (VFA), atherogenic lipid profile, inflammatory markers, adipokines levels and brachial artery endothelial function in 76 overweight women with type 2 diabetes before and after 12 weeks of CR. In addition, the effects of CR on hepatic steatosis and fetuin-A mRNA expression were evaluated in Otuska Long Evans Tokushima Fatty (OLETF) rats, an animal model of obesity and type 2 diabetes. RESULTS: Circulating fetuin-A levels were significantly decreased after 12 weeks of CR and were accompanied by improvements in VFA, blood pressure, glucose, lipid profiles and liver function. The CR group also showed a significant decrease in apolipoprotein B, leptin and insulin resistance compared to those in the control group, although endothelial function was not different. Multiple regression analysis showed that the changes in fetuin-A levels were independently associated with CR and changes in hsCRP and adiponectin (R² = 0·156). Moreover, CR significantly reduced hepatic steatosis and fetuin-A expression, as well as weight, glucose, total cholesterol and triglyceride levels, in OLETF rats. CONCLUSION: Caloric restriction significantly reduced the hepatic expression of fetuin-A and its circulating levels and improved several cardiovascular risk factors in obese rats and humans with type 2 diabetes.

High-sensitivity C-reactive protein in the low- and intermediate-Framingham risk score groups: analysis with 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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, P<0.001, 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). CONCLUSIONS: 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.

Effects of exercise on sRAGE levels and cardiometabolic risk factors in patients with type 2 diabetes: a randomized controlled trial.

CONTEXT: 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). OBJECTIVE: We examined the effects of exercise on sRAGE and its association with diverse cardiometabolic risk factors and indicators of atherosclerosis in patients with T2DM. DESIGN, SETTING, AND PARTICIPANTS: 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). MAIN OUTCOME MEASURES: We evaluated sRAGE, energy expenditure, dietary energy intake, cardiorespiratory fitness, inflammatory markers, visceral fat area, pulse-wave velocity, and flow-mediated dilatation. RESULTS: 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). CONCLUSIONS: Aerobic exercise increases sRAGE levels along with improvement of various cardiometabolic risk factors in patients with T2DM.

C1q/TNF-related protein-3 (CTRP-3) and pigment epithelium-derived factor (PEDF) concentrations in patients with type 2 diabetes and metabolic syndrome.

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.

Elevated A1C is associated with impaired early-phase insulin secretion rather than insulin resistance in Koreans at high risk for developing diabetes.

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 ß-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.

Effect of eplerenone, a selective aldosterone blocker, on the development of diabetic nephropathy in type 2 diabetic rats.

BACKGROUND: Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats. METHODS: ANIMALS WERE DIVIDED INTO SIX GROUPS AS FOLLOWS: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks. RESULTS: Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor-1, transforming growth factor-ß1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups. CONCLUSION: Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug.

The differential relationship between fat mass and bone mineral density by gender and menopausal status.

Osteoporosis and obesity are important public health problems in an aging society. We investigated the differential impacts of fat on bone mineral density (BMD) according to gender and menopausal status. We analyzed the baseline data of an ongoing observational cohort study, including a total of 502 healthy subjects 20-88 years of age (144 men, 159 premenopausal women, 199 postmenopausal women). Body composition and fat mass were measured using computed tomography and dual energy X-ray absorptiometry (DXA). BMD was measured at lumbar spines using DXA. In men and postmenopausal women, there was no significant correlation between fat and bone parameters after adjusting for age and body weight. However, in premenopausal women, BMD had significant negative correlations with waist circumference, total fat area, subcutaneous fat area, appendicular fat mass and percentage fat mass after adjusting for age and body weight. Furthermore, only in premenopausal women, the subjects with the highest quartile of percentage fat mass had the lowest BMD even after adjusting for confounding factors including age, body weight, physical activity, alcohol use and smoking history. Multiple linear regression analysis showed that percentage fat mass was a significant negative decisive factor for BMD in premenopausal women. Our study showed the differential relationship between fat mass and BMD according to gender and menopausal status. Only in premenopausal women did fat mass have a significant negative effect on bone mass. This result suggests the importance of reducing fat mass in order to achieve peak bone mass in young adult women.