Endothelin-1-mediated miR-let-7g-5p triggers interlukin-6 and TNF-α to cause myopathy and chronic adipose inflammation in elderly patients with diabetes mellitus.

BACKGROUND: Diabetes and sarcopenia are verified as mutual relationships, which seriously affect the quality of life of the elderly. Endothelin-1 is well investigated, is elevated in patients with diabetes, and is related to muscle cellular senescence and fibrosis. However, the mechanism of ET-1 between diabetes and myopathy is still unclear. The aim of this study was to evaluate the prevalence of sarcopenia in the elderly with diabetes and to clarify its relationship with ET-1 molecular biological mechanism, progress as well as changes in muscle and fat. METHODS: We recruited 157 type 2 diabetes patients over 55 years old and investigated the prevalence of sarcopenia in diabetes patients and examined the association of ET-1 alterations with HbA1c, creatinine, or AMS/ht2. Next, sought to determine how ET-1 regulates inflammation in muscle cells by western blot and qPCR assay. Using XF Seahorse Technology, we directly quantified mitochondrial bioenergetics in 3T3-L1 cells. RESULTS: ET-1 was positively correlated with HbA1c, creatinine levels, and duration of disease, and negatively correlated with AMS/ht2. We found that ET-1 dose-dependently induces tumor necrosis factor-α (TNF-α) and interleukin (IL)-6ß expression through the PI3K/AKT, and NF-κB signaling pathways in C2C12 cells. Also identified that TNF-α, IL-6ß, and visfatin releases were found in co-cultured with conditioned medium of ET-1/C2C12 in 3T3-L1 cells. ET-1 also reduces the energy metabolism of fat and induces micro-environment inflammation which causes myopathy. ET-1 also suppresses miR-let-7g-5p expression in myocytes and adipocytes. CONCLUSION: We describe a new mechanism of ET-1 triggering chronic inflammation in patients with hyperglycemia.

Glycaemic control for painful diabetic peripheral neuropathy is more than fasting plasma glucose and glycated haemoglobin.

BACKGROUND: The relationship between postprandial hyperglycaemia and diabetic peripheral neuropathy (DPN), whether painful or painless, has yet to be determined. Thus, the aim of this study was to investigate the relationship in patients with type 2 diabetes (T2D). METHODS: This cross-sectional study was conducted in adults with T2D between January and October 2013. Blood samples were collected after overnight fasting every 3 months prior to enrolment. For this study, increased postprandial glycaemic exposure was defined as high glycated haemoglobin (HbA1c) and near-normal mean fasting plasma glucose (FPG) levels. Both painless and painful DPN were evaluated using two validated tools, the Michigan Neuropathy Screening Instrument (MNSI) and Douleur Neuropathique 4 (DN4) questionnaire. RESULTS: This study included 1040 participants with mean FPG levels<140mg/dL, 535 of which were<126mg/dL. Of these patients, 200/1040 (19.2%) and 105/535 (19.6%) had DPN. Multivariate analysis demonstrated that higher HbA1c levels (≥7%) did not increase risk of painless DPN, but did significantly increase risk of painful DPN in T2D patients with FPG<140mg/dL and<126mg/dL, with corresponding odds ratios of 2.49 and 3.77 (95% confidence intervals: 1.09-5.71 and 1.20-11.79), respectively, after adjusting for demographic factors, diabetes-related variables and comorbidities. CONCLUSION: This study is the first to reveal that increased postprandial glycaemic exposure, as assessed by high HbA1c and near-normal FPG levels, is associated with an increased risk of painful DPN in adults with T2D.

Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium.

By means of a combination of genome-wide and follow-up studies, recent large-scale association studies of populations of European descent have now identified over 46 loci associated with coronary artery disease (CAD). As part of the TAICHI Consortium, we have collected and genotyped 8556 subjects from Taiwan, comprising 5423 controls and 3133 cases with coronary artery disease, for 9087 CAD SNPs using the CardioMetaboChip. We applied penalized logistic regression to ascertain the top SNPs that contribute together to CAD susceptibility in Taiwan. We observed that the 9p21 locus contributes to CAD at the level of genome-wide significance (rs1537372, with the presence of C, the major allele, the effect estimate is -0.216, standard error 0.033, p value 5.8x10-10). In contrast to a previous report, we propose that the 9p21 locus is a single genetic contribution to CAD in Taiwan because: 1) the penalized logistic regression and the follow-up conditional analysis suggested that rs1537372 accounts for all of the CAD association in 9p21, and 2) the high linkage disequilibrium observed for all associated SNPs in 9p21. We also observed evidence for the following loci at a false discovery rate >5%: SH2B3, ADAMTS7, PHACTR1, GGCX, HTRA1, COL4A1, and LARP6-LRRC49. We also took advantage of the fact that penalized methods are an efficient approach to search for gene-by-gene interactions, and observed that two-way interactions between the PHACTR1 and ADAMTS7 loci and between the SH2B3 and COL4A1 loci contribute to CAD risk. Both the similarities and differences between the significance of these loci when compared with significance of loci in studies of populations of European descent underscore the fact that further genetic association of studies in additional populations will provide clues to identify the genetic architecture of CAD across all populations worldwide.

Contribution of postprandial glucose to excess hyperglycaemia in Asian type 2 diabetic patients using continuous glucose monitoring.

BACKGROUND: previous studies examining the contributions of fasting glucose (FG) and postprandial glucose (PPG) to glycated haemoglobin (HbA(1c)) have yielded conflicting results. We aimed to clarify the contributions of PPG to hyperglycaemia in Asian type 2 diabetic patients using continuous glucose monitoring. METHODS: continuous glucose monitoring was conducted in 121 non-insulin-using type 2 diabetic outpatients, who were divided into five groups according to quintiles of HbA(1c) (ranging from 5.7 to 12.7%). Glucose area under the curve (AUC) above a glucose value of 5.5 mmol/L 24 or 4 h after meals was defined as AUC(total). Glucose AUC above FG or preprandial glucose levels was defined as AUC(PPG). The contribution of PPG to hyperglycaemia was calculated as (AUC(PPG)/AUC(total) × 100%. The contribution of FG or preprandial glucose was calculated as [(AUC(total) - AUC(PPG))/AUC(total)] × 100%. RESULTS: the contribution of PPG to either 24-h hyperglycaemia or 4-h hyperglycaemia after meals was significantly higher than FG and preprandial glucose in the lowest quintile of HbA(1c) (both p < 0.001). However, no difference was observed in the other four quintiles. Peak PPG and glucose excursions were higher after breakfast than those after lunch and dinner (p < 0.01 for all comparisons). CONCLUSIONS: in Asian patients with type 2 diabetes, PPG 24 and 4 h after meals was a predominant contributor to excess hyperglycaemia in well-controlled patients and was equally important as FG or preprandial glucose in moderately to poorly controlled patients with mean HbA(1c) up to 10%.

Visfatin-induced expression of inflammatory mediators in human endothelial cells through the NF-kappaB pathway.

BACKGROUND: Visfatin is an adipokine that is highly expressed in visceral fat. Plasma levels of visfatin have been reported to be higher in subjects with obesity and/or type 2 diabetes mellitus. However, the role of visfatin in endothelial dysfunction has been largely unexplored. OBJECTIVES: We investigated the possible pathogenic role of visfatin in endothelial dysfunction, particularly focusing on its effect on inflammatory mediators. DESIGN: Primary human umbilical vein endothelial cells (HUVECs) pretreated with visfatin (1, 10 and 50 ng ml(-1)) were used to study the relationship between visfatin and endothelium dysfunction. Expressions of adhesion molecules (ICAM-1, VCAM-1 and E-selectin) and cytokines (interleukin (IL)-6 and IL-8) affected by visfatin were investigated by enzyme-linked immunosorbent assay, flow cytometry and real-time PCR. Activity of nuclear factor (NF)-kappaB was examined by electrophoretic mobility shift assay. RESULTS: At a visfatin concentration of 50 ng ml(-1), significant increases in IL-6, IL-8, ICAM-1, VCAM-1 and E-selectin gene expression along with increased IL-6, IL-8 and sE-selectin protein levels in the conditioned medium were detected. Flow cytometry showed that the addition of visfatin significantly increased ICAM-1 expression and VCAM-1 expression (10 and 50 ng ml(-1), respectively). Electrophoretic mobility shift assay confirmed that visfatin increased the DNA-binding activity of NF-kappaB. In addition, pretreatment with visfatin (10 and 50 ng ml(-1)) increased human monocyte cell line THP-1 adhesion to HUVECs. CONCLUSIONS: Our findings suggest that visfatin causes endothelial dysfunction by increasing inflammatory and adhesion molecule expression at least partly through the upregulation of NF-kappaB activity.

Effect of cranberry extracts on lipid profiles in subjects with Type 2 diabetes.

AIM: To examine the effect of cranberry ingestion on lipid profiles in Type 2 diabetic patients taking oral glucose-lowering drugs. METHODS: Thirty Type 2 diabetic subjects (16 males and 14 females; mean age 65 +/- 1 years) who were taking oral glucose-lowering medication regularly were enrolled in this randomized, placebo-controlled, double-blind study. Changes in lipid profiles, oxidized low-density lipoprotein (ox-LDL), glycaemic control, components of the metabolic syndrome, C-reactive protein (CRP) and urinary albumin excretion (UAE) were assessed after cranberry or placebo treatment for 12 weeks. RESULTS: Low-density lipoprotein (LDL) cholesterol decreased significantly in the cranberry group (from 3.3 +/- 0.2 to 2.9 +/- 0.2 mmol/l, P = 0.005) and the decrease was significantly greater than that in the placebo group (-0.4 +/- 0.1 vs. 0.2 +/- 0.1 mmol/l, P < 0.001). Total cholesterol and total : high-density lipoprotein (HDL) cholesterol ratio also decreased significantly (P = 0.020 and 0.044, respectively) in the cranberry group and the reductions were significantly different from those in the placebo group (P < 0.001 and P = 0.032, respectively). However, ox-LDL levels did not change significantly in response to cranberry consumption. Neither fasting glucose nor glycated haemoglobin improved in either group. Changes in components of the metabolic syndrome, UAE and CRP were not significantly different between groups. CONCLUSIONS: Cranberry supplements are effective in reducing atherosclerotic cholesterol profiles, including LDL cholesterol and total cholesterol levels, as well as total : HDL cholesterol ratio, and have a neutral effect on glycaemic control in Type 2 diabetic subjects taking oral glucose-lowering agents.

Dose reconstruction for residents living in 60Co-contaminated rebar buildings.

The first 60Co-contaminated rebar building was discovered in Taipei city in 1992. As of 18 July 1997, 144 buildings with 1,327 housing units were confirmed to contain 60Co-contaminated rebars. All these reinforced concrete buildings were constructed between 1982 and 1984. Thousands of residents have been exposed to ionizing radiation of various degrees. Preliminary assessments by the Atomic Energy Council showed that the accumulated maximal doses ranged from a few mSv to several Sv. The purpose of this work was to reconstruct more reliable individual doses for epidemiologic and medical uses. This reconstruction provided the best estimated doses as well as conceivable upper and lower bounds. The variation of residential day-life activities by individual members in a family was considered according to their sex, age, profession, etc. Intensive data on exposure rates were collected using thermoluminescent dosimeters positioned at 1 m height and 1 m x 1 m intersections with additional measurements at special locations such as bed, sofa, dining table, etc. Thermoluminescent dosimeter measurements were performed in all 24 residences studied in this work. This showed that the Atomic Energy Council maximal doses were 2-6 times higher than the present best estimated doses. Among all family members, elders and housewives received the highest doses; children received the lowest doses. The difference in doses among all family members belonging to different cohort categories is within a factor of two.