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Protectin DX (PDX), which is a novel regulator of 5' adenosine monophosphate-activated protein kinase (AMPK), has recently gained attention for its ability to improve several metabolic diseases. However, the function of PDX in vascular endothelial cells remains unclear. To confirm the protective effects of PDX on endothelial oxidative stress, human umbilical vein endothelial cells (HUVECs) were treated with hydroperoxide (H2O2) and PDX. PDX treatment significantly increased the level of AMPK phosphorylation, and this elevation was attenuated after treatment with G-protein coupled receptor 120 (GPR120) antagonist or GPR120 knockdown. Expressions and activities of antioxidant proteins, including catalase and superoxide dismutase 2 (SOD2), were elevated by PDX and were inhibited by treatment with AMPK inhibitor or with GPR120 antagonist. Production of H2O2-induced reactive oxygen species (ROS), the Bax/Bcl-2 ratio, and the loss of mitochondrial membrane potential were all reversed by PDX, leading to improved cell viability and reduced release of lactate dehydrogenase (LDH). Using flow cytometry, we also found that PDX significantly reduced the H2O2-induced apoptotic population of cells. These protective effects of PDX were all reversed after treatment with AMPK inhibitor or GRP120 antagonist. These results show that the PDX-AMPK axis has a protective role against H2O2-induced oxidative stress in vascular endothelial cells.

Aims Previous in-vitro and in-vivo experimental studies have shown that Sestrin2 attenuates oxidative stress and the pro-inflammatory pathway, resulting in improving metabolic homeostasis. However, the relationship between circulating Sestrin2 concentration and cardiometabolic risks in humans has not been explored. Methods Sestrin2 concentration was measured in 240 subjects (46 without diabetes and 194 with diabetes), and the associations between Sestrin2 level and various cardiometabolic risk factors including body composition, insulin resistance, and atherosclerosis was assessed. Results Sestrin2 concentration showed a trend of increasing in subjects with metabolic syndrome. After adjustment for age and gender, Sestrin2 level had a positive relationship with serum triglyceride, alanine aminotransferase (ALT), and creatinine levels, but no association with carotid atherosclerosis. Especially, in subjects with type 2 diabetes Sestrin2 concentration exhibited a significant positive correlation with body mass index (P = 0.015), waist circumference (P = 0.020), high-sensitivity C-reactive protein (P = 0.008), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (P = 0.041), percentage body fat (P = 0.001), and truncal fat mass (P = 0.005) after adjusting age and gender. Multiple stepwise regression analysis identified age, serum ALT and creatinine levels, and percentage body fat as independent determining factors for Sestrin2 concentration in patients with type 2 diabetes (R2 = 0.173). Conclusions This study is the first to demonstrate a trend for increased Sestrin2 level in subjects with metabolic syndrome. In particular, in subjects with type 2 diabetes, Sestrin2 was significantly related to insulin resistance and percentage body fat, suggesting its potential as a novel modulatory factor for metabolic disorders in humans.

Background & Objective Sestrin2 (sesn2) has recently gained attention as an important regulator for various metabolic disorders. Sesn2 is involved in AMP-activated protein kinase (AMPK) activation, which leads to anti-inflammatory and anti-oxidative responses. However, the role of sesn2 in the endothelium has not yet been clarified. Methods To evaluate sesn2-mediated anti-atherosclerotic effects, siRNA to silence sesn2 expression was introduced to human umbilical vein endothelial cells (HUVECs), THP-1 cells and C57BL/6 mice. Lipopolysaccharide (LPS) was administrated to sesn2-knockdown cells and mice to induce atherosclerotic signals. Results Knockdown of sesn2 was involved with atherosclerotic reactions caused by LPS treatment through decrease of AMPK phosphorylation. In sesn2-knockdown HUVECs and THP-1 cells, LPS-mediated nuclear factor kappa B (NF-κB) phosphorylation and secretion of pro-inflammatory cytokines were both significantly increased. In HUVECs, expression of adhesion molecules and LPS-stimulated adhesion of THP-1 cells to the endothelium were significantly increased after sesn2-knockdown. Furthermore, LPS-induced reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, and cell toxicity were all significantly elevated after sesn2-knockdown in HUVECs. Interestingly, all these pro-atherosclerotic effects were fully abrogated by treatment with an AMPK activator. In aortic tissue samples from C57BL/6 mice, sesn2-knockdown using siRNA oligomers resulted in reduced AMPK phosphorylation and induction of LPS-mediated NF-κB phosphorylation, leading to up-regulation of adhesion molecules and ER stress-related signaling. Conclusion Knockdown of sesn2 aggravates atherosclerotic processes by increasing pro-inflammatory reactions and ER stress in the endothelium via an AMPK-dependent mechanism, suggesting that sesn2 might be a novel therapeutic target for atherosclerosis.

Background 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. Methods 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. Results 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. Conclusion 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 /)

A new pooled cohort risk equation to estimate atherosclerotic cardiovascular disease (CVD) risk was recently published, but the equation is based primarily on data from Caucasian populations. The relationship of this new risk scoring system with vascular inflammation and calcification has yet to be examined.A total of 74 participants were retrospectively selected based on inclusion and exclusion criteria. All participants underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and multi-detector computed tomography (MDCT) examination in the Korea University Guro Hospital between June 2009 and May 2013. Vascular inflammation of the carotid artery was measured as target-to-background ratio (TBR) using (18)F-FDG-PET/CT and coronary artery calcification was quantified as Agatston score by MDCT.Agatston scores were not significantly associated with any metabolic risk factors, but maximum TBR values exhibited a significant positive correlation with body mass index (r=0.31, P=0.01), waist circumference (r=0.42, P0.01), waist-to-hip ratio (r=0.49, P0.01), and systolic (r=0.35, P0.01) and diastolic blood pressure (r=0.39, P0.01). Furthermore, maximum TBR values were significantly correlated with serum high-sensitivity C-reactive protein (hsCRP) levels (r=0.26, P=0.03), whereas Agatston scores had no correlation. When pooled cohort risk equation scores were divided into incremental tertiles, age, waist circumference, waist-to-hip ratio and systolic blood pressure showed significant incremental trends. In particular, pooled cohort risk scores exhibited a significant positive correlation with maximum TBR values (r=0.35, P0.01), but not with Agatston scores (r=0.11, P=0.34).The pooled cohort risk equation exhibited significant positive correlations with vascular inflammation but not with calcification in Asian subjects without CVD, suggesting that this novel risk equation may detect early inflammatory changes preceding the structural modification of vessel walls.

Ethnopharmacological relevance Ginsenoside, a major pharmacologically active ingredient in ginseng, has been known to exhibit beneficial properties such as antioxidant and anti-inflammatory effects. Ginsenoside compound Mc1 is one of the newly identified de-glycosylated ginsenosides. Endoplasmic reticulum (ER) stress has implicated in the development of non-alcoholic fatty liver disease (NAFLD) through apoptosis and lipid accumulation. Aim of the study We aimed to examine the protective effects of Mc1 treatment on ER stress-induced cell death and impaired insulin signaling in HepG2 human hepatoblastoma cells and ER stress-induced liver steatosis and insulin resistance in a diet-induced obesity (DIO) mouse model. Materials and methods HepG2 cells were treated with palmitate and Mc1 to evaluate the effects of Mc1 on ER stress-induced damage. C57BL/6 mice were fed with a high-fat diet (HFD) for 4 weeks and received an intraperitoneal injection of either vehicle or Mc1 (10 mg/kg/day). The control mice were fed with a chow diet and injected with vehicle for the same period. ER stress, cell death, and degree of steatosis were evaluated in the liver tissues of mice. The effect of Mc1 treatment on glucose metabolism was also determined. Results Mc1 co-treatment reduced the palmitate-induced ER stress and death of HepG2 cells. The palmitate-induced insulin resistance improved after Mc1 co-treatment. Consistent with the in vitro data, chronic Mc1 supplementation reduced ER stress and apoptotic damage in the liver of obese mice. Mc1 treatment ameliorated glucose intolerance and insulin resistance through the suppression of c-Jun N-terminal kinase (JNK) phosphorylation. In addition, Mc1 treatment reduced obesity-induced lipogenesis and prevented fat accumulation in the liver of DIO mice. Conclusions Mc1 exerted protective effects against ER stress-induced apoptotic damage, insulin resistance and lipogenesis in palmitate-treated hepatocytes and in the liver of DIO mice. Therefore, Mc1 supplementation could be a potential therapeutic strategy to prevent NAFLD in patients with obesity and insulin resistance.

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.

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.

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.

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.

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.

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.

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.

In low- and middle-income countries, the high personal and economic burden of type 2 diabetes is further compounded by inadequate resources for diabetes care when compared with high-income countries. Health technology assessments (HTAs) aim to inform policy decision makers in their efforts to achieve more effective allocation of resources by providing evidence-based input on new technologies. Within the hierarchy of evidence, randomized controlled trials (RCTs) remain the 'gold standard' used to inform HTAs, but are limited by poor external validity (ie, generalizability to real-world populations). Unlike RCTs, observational studies are able to enrol broader patient populations, but their design renders such studies vulnerable to confounding factors and selection bias. However, it is increasingly recognized that observational studies can complement RCTs by supporting and extending efficacy findings from RCTs to real-world clinical practice, particularly across geographical populations. They can also provide locally relevant baseline and disease natural history data to populate health economic models. Thus, observational data are likely to be of considerable informative value to policy makers in developing countries reaching decisions on diabetes care within an environment of scarce resources.

Objective The use of a real time continuous glucose monitoring system (RT-CGM) was studied as a behavior modification tool and the effectiveness of a RT-CGM in glucose control for patients with type 2 diabetes was determined. Methods We conducted a prospective, open-label, randomized, controlled clinical trial in 65 patients with poorly controlled type 2 diabetes (8.0 ≤ HbA1c ≤ 10%) over a 3-month period. The intervention group was monitored monthly with a RT-CGM (three days at a time for 3 months) and the control group continued self-monitoring blood glucose (SMBG) at least four times a week for 3 months. Results The HbA1c of the RT-CGM group was significantly reduced after 12 weeks compared with the SMBG group (9.1 ± 1.0% to 8.0 ± 1.2% vs. 8.7 ± 0.7% to 8.3 ± 1.1%, respectively; P = 0.004). In the RT-CGM group, there was a significant reduction in total daily calorie intake, weight, body mass index (BMI), and postprandial glucose level, and a significant increase in total exercise time per week after 3 months. Conclusions We demonstrated that the RT-CGM was useful in modifying a patient's diet and exercise habits and could induce better glycemic control than SMBG for patients with type 2 diabetes.

Even though visfatin has been suggested as a proinflammatory adipokine, there are few studies of the relationship between plasma visfatin concentrations and proinflammatory markers in the nondiabetic population. We showed that plasma visfatin concentrations were positively associated with circulating interleukin-6 levels and diastolic blood pressure independent of obesity in nondiabetic healthy Korean women. These results suggest that circulating visfatin may be related with some proinflammatory condition even in a nondiabetic state.

To compare the prevalence of the metabolic syndrome using the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF) definitions and to contrast the association between the prevalence of cardiovascular disease and the metabolic syndrome using both definitions in the Korean population, we used data from the 2001 Korean Nation Health and Nutrition Survey, which is a nationally representative survey of the noninstitutionalized civilian population. The age-adjusted prevalence of the metabolic syndrome was 18.8%+/-0.5% (men, 17.8%+/-0.8%; women, 20.5%+/-0.7%) using the NCEP definition and 19.5%+/-0.5% (men 15.0%+/-0.8%, women 23.9%+/-0.7%) using the IDF definition among participants 20 years or older. The agreement rate, which is the percentage of participants who were classified as either having or not having the metabolic syndrome by both definitions of the metabolic syndrome, was 84.6%+/-0.5% (kappa=0.54). The prevalence of the metabolic syndrome using the NCEP definition was higher in participants with lower body mass index, whereas the prevalence using the IDF definition was higher in subjects with higher body mass index. The odds ratio (OR) for coronary artery disease was 3.5 (95% confidence interval [CI], 2.0-6.1) for participants with the metabolic syndrome defined by the NCEP definition, whereas it was 2.8 (95% CI, 1.6-5.0) for those with the metabolic syndrome defined by the IDF definition. Similarly, the OR for stroke was higher using the NCEP definition (OR, 3.0; 95% CI, 1.7-5.2) compared with that of the IDF definition (OR, 2.3; 95% CI, 1.3-4.0). However, the CIs by both definitions overlapped considerably. In conclusion, the prevalence of the metabolic syndrome using the IDF definition was higher than that using the NCEP definition, whereas the NCEP definition was more closely associated with cardiovascular disease in the Korean population.

A variety of adipocytokines and peptides secreted from adipocytes have been considered to play a crucial role in obesity, insulin resistance, and type 2 diabetes. Recently, visfatin, a new adipocytokine, known as a pre-B cell colony-enhancing factor, has been isolated from visceral fat deposits. It has been shown to activate insulin receptors in a manner different from insulin. To understand the role of adipocytokines in improving insulin sensitivity via activation of the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and -gamma (PPAR-gamma), we examined the expression of visfatin, adiponectin, and TNF-alpha in visceral fat depots of Otsuka Long-Evans Tokushima fatty (OLETF) rats from early to advanced diabetic stage (from 28 to 40 weeks of age). Serum glucose and insulin concentrations significantly (P

Vascular endothelial growth factor (VEGF) and soluble VEGF receptor FLT-1 in diabetic nephropathy. Background Vascular endothelial growth factor (VEGF) and its receptors have been implicated in the pathogenesis of diabetic nephropathy. The objective of this study was to determine whether alterations of the plasma and urinary VEGF and sFLT-1 levels were related to the stages and risk factors of diabetic nephropathy. In addition, we also examined the regulation of the VEGF/sFLT-1 expression by various stimuli in cultured human proximal tubule cells (HPTC). Methods A total of 107 type 2 diabetic patients and 47 healthy control subjects were studied. The expression and protein levels of VEGF and sFLT-1 were measured by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Results The urinary VEGF and sFLT-1 excretions were significantly increased in the microalbuminuric and proteinuric diabetic patients. The urinary VEGF levels were positively correlated with the urinary albumin to creatinine ratio (ACR), urinary sFLT-1 levels, and negatively correlated with creatinine clearance. The urinary sFLT-1 levels also showed a positive relationship with the urinary ACR. In cultured HPTC, high glucose stimuli rapidly up-regulated VEGF synthesis without having any effect on sFLT-1 synthesis. Interestingly, angiotensin II (Ang II) induced a dose-dependent increase in the synthesis of both VEGF and sFLT-1, which was significantly blocked by losartan. Conclusion The urinary excretion of VEGF and sFLT-1 increased at a relatively early stage in diabetic nephropathy associated with urinary albumin excretion. A marked increase in both VEGF/sFLT-1 synthesis in response to Ang II was observed in HPTC, which was different from the response to glucose stimuli. These findings may imply that VEGF and sFLT-1 can actively take part in the pathogenesis of diabetic nephropathy.

Autoimmune type 1 diabetes mellitus is caused by the immunologic destruction of pancreatic beta-cells; therefore, there have been many attempts at immunologic modulation as a block or prevention of the underlying process. The aim of this study is to investigate the effect of BCG vaccination on low dose streptozotocin-induced diabetic (LDSD) mice. The mice were pretreated with BCG 7 days before starting low dose streptozotocin (STZ), observed body weight and blood glucose for 2 months, then analyzed the severity of the STZ-induced insulitis after the animals were sacrificed. In this experiment, the mean body weights in the BCG-STZ group on days 1, 19, 33, 47, and 61 of the experiment were 37.5 +/- 3.6, 37.3 +/- 3.6, 37.5 +/- 3.5, 39.4 +/- 3.9, and 39.3 +/- 4.5 (g), respectively. Those in the STZ group were 37.7 +/- 3.5, 38.3 +/- 4.5, 38.4 +/- 3.9, 36.2 +/- 4.5, and 36.3 +/- 4.0 (g), respectively (P < 0.05). The mean blood glucose levels in the BCG-STZ group on days 1, 19, 33, 47, and 61 were 106.5 +/- 8, 150 +/- 37, 147 +/- 54, 143 +/- 60, and 142 +/- 66 (mg/dl), respectively. Those in the STZ group were 103 +/- 12, 196 +/- 90, 261 +/- 236, 236 +/- 91, and 224 +/- 89 (mg/dl), respectively (P < 0.05). The numbers developing grade 0, I, II, III, and IV insulitis in the BCG-treated group were 63, 48, 33, 4, and 2, respectively, and in the control group were 16, 23, 31, 45, and 35, respectively. This study indicates that BCG vaccination reduces the development of insulitis and overt diabetes in LDSD mice.