9 minute read
2015 Award
from 104年會論文摘要集
by Endo 電子書上傳區
AP-01
The Studies of Gas6/AxL and Glucose Metabolism, Atherosclerosis, Obestiy and Sex Hormones
1CHANG-HSUN HSIEH
1Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, Taipei, Taiwan
Protein growth arrest–specific 6 (Gas6) was the last addition to the family of plasma vitamin K–dependent proteins. Gas6 was cloned and characterized in 1993 and found to be similar to plasma anticoagulant protein S. It was recognized as a growth factor–like molecule, as it interacted with receptor tyrosine kinases of the TAM (Tyro-3, Axl, Mer) family. The Gas6/TAM system regulates an intriguing mix of processes, including cell survival and proliferation, cell adhesion and migration, blood clot stabilization, and inflammatory cytokine release. The role of the Gas6/TAM system has been found to be important in inflammation; hemostasis; autoimmune disease; nervous, reproductive, and vascular systems; and cancer.
In our study, plasma Gas6 is associated with altered glucose tolerance, inflammation, and endothelial dysfunction. It may represent a novel independent risk factor of type 2 diabetes and a potential surrogate marker of inflammation and endothelial dysfunction. The Gas6 c.843+7AA genotype and A allele are less prevalent in type 2 diabetes, which may have a protective role for type 2 diabetes. Otherwise, in cellular study, we also found that high glucose can alter Gas6/Axl signaling and may through Akt and VEGF/VEGFR2 downstream molecules and suggests that Gas6/Axl may involve in high glucoSE-induced endothelial cell dysfunction.
Gas6 expression is widespread in many tissues, including immune cells, endothelial cells, vascular smooth muscle cells, and adipocytes. Preclinical studies indicate that Gas6 and its receptors of the TAM family may be involved in the pathogenesis of obesity and its complications. Therefore, our data showed that circulating Gas6 and sAxl were significantly higher in overweight and obese adolescents. Circulating Gas6 levels were significantly positively correlated with body mass index Z-score, waist circumference, body fat mass, among overweight and obese adolescents. GAS6 and AXL polymorphisms are associated with adiposity, systemic inflammation, and insulin resistance in adolescents, especially in boys.
In addition, we also found that significantly higher Gas6 concentrations were observed in adult male rather than female and lower Gas6 levels in the postmenopausal compared to the premenopausal women. Plasma Gas6 levels were positively correlated with estradiol levels in the pre- and postmenopausal women. Plasma Gas6 is associated with sex hormones in female and ages in male, indicating a potential role of sex hormones and ages involving the Gas6/TAM system. How the Gas6/ TAM pathway is regulated by sex hormones or ages in cellular concentrations, whether the activation of GAS6 gene by estrogen and androgen. It still needs further studies to elucidate.
AP-02
Three-Dimensional Islet Graft Histology: Panoramic Imaging of Neural Plasticity in Sympathetic Reinnervation of Transplanted Islets Under the Kidney Capsule
1,2JYuHn-Huarng Juang, 3,4SHIH-JUNG PENG, 5CHIEN-HUNG KUO,
3,4,6SHIUE-CHENG TANG
1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taiwan, R.O.C; 2Department of Medicine, College of Medicine, Chang Gung University, Taiwan, R.O.C.; 3Connectomics Research Center, National Tsing Hua University, Taiwan, R.O.C.; 4Institute of Biotechnology, National Tsing Hua University, Taiwan, R.O.C.; 5Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Taiwan, R.O.C.; 6Department of Medical Science, National Tsing Hua University, Taiwan, R.O.C.
Microscopic examination of transplanted islets in an ectopic environment provides information to evaluate graft adaption. However, because of the dispersed nature of blood vessels and nerves, global visualization of the graft neurovascular network has been difficult. In this research we prepared transparent mouse islet grafts under the kidney capsule with optical clearing to investigate the sympathetic reinnervation via three-dimensional confocal microscopy. Nondiabetic and streptozotocindiabetic mice were used in syngeneic islet transplantation, with both groups maintaining euglycemia after transplantation. Triple staining of insulin/glucagon, blood vessels, and tyrosine hydroxylase was used to reveal the graft microstructure, vasculature, and sympathetic innervation. Three weeks after transplantation, we observed peri-graft sympathetic innervation similar to that in the pancreas. Six weeks after transplantation, prominent intra-graft, perivascular sympathetic innervation was achieved, resembling the pancreatic sympathetic innervation in situ. Meanwhile, a higher graft sympathetic nerve density in diabetic recipients compared with nondiabetic recipients, indicating the graft neural plasticity in response to the physiological difference of the recipients and the resolving power of this imaging approach. Overall, this new graft imaging method provides a useful tool to identify the islet neurovascular complex in an ectopic environment.
AP-03
High Glucose Induces Human Endothelial Dysfunction Through an Axl-Dependent Mechanism
4CHIH-YUAN LIN, 1CHANG-HSUN HSIEH, 1YI-JEN HUNG
1Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2School of Dentistry, National Defense Medical Center, Taipei, Taiwan; 3Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, Taipei, Taiwan; 4Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
obJeCTIve:
The receptor tyrosine kinase Axl and its ligand growth arrest-specific protein 6 (Gas6) are involved in the diabetic vascular disease. The aim of this study was to explore the role of Gas6/Axl system in high glucose (HG)-induced endothelial dysfunction.
MeTHods:
We investigated the effect of various glucose concentrations on Axl signaling in human microvascular endothelial cells (HMEC-1 s).
resuLTs:
Human plasma Gas6 value inversely correlated with glucose status, endothelial markers. HG decreased Gas6/Axl expression and increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1) expression in HMEC-1 s. HG significantly decreased HMEC-1 s cell viability and tube formation and promoted monocyte-EC adhesion. Down-regulation of Akt phosphorylation was found in HG culture. Axl transfection significantly reversed HG-induced Akt phosphorylation, VCAM-1 expression and endothelial dysfunction. We also found additive changes in Axl-shRNA-infected HMEC-1 cells in HG culture. Furthermore, Axl overexpression in HMEC-1 s significantly reversed HG-induced vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. In addition, significantly lower Axl and VEGFR2 expression in arteries were found in diabetic patients as compared with non-diabetic patients.
ConCLusIons:
This study demonstrates that HG can alter Gas6/Axl signaling and may through Akt and VEGF/ VEGFR2 downstream molecules and suggests that Gas6/Axl may involve in HG-induced EC dysfunction.
AP-04
Cardiac Metabolism, Inflammation, and Peroxisome ProliferatorActivated Receptors Modulated by 1,25-Dihydroxyvitamin D3 in Diabetic Rats
1,2TIng-I Lee, 3,4YU-HSUN KAO, 5YAO-CHANG CHEN, 6WEN-CHIN TSAI,
4,7CHENG-CHIH CHUNG, 4,7*YI-JEN CHEN
1Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 2 Department of General Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 3Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 5 Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan; 6 Division of Cardiology, Tzu-Chi General Hospital, Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan; 7 Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
background: High free fatty acid with reduced glucose utilization in diabetes mellitus (DM) impairs cardiac function. Peroxisome proliferator-activated receptors (PPARs) modulate myocardial lipid and glucose homeostasis. The active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates oxidative stress and inflammation, which may play a key role in the modulation of PPARs. The aim of this study was to investigate whether 1,25(OH)2D3 can modulate the cardiac PPARs and fatty acid metabolism.
Methods: Electrocardiogram, echocardiogram, and Western blot analysis were used to evaluate cardiac fatty acid metabolism, inflammation, and PPAR isoform expression in Wistar-Kyoto (WKY) rats, DM rats, and DM rats treated with 1,25(OH)2D3. results: Compared to healthy rats, DM and 1,25(OH)2D3-treated DM rats had lower body weight. DM rats has larger left ventricular end-diastolic diameter, and longer QT interval than healthy or 1,25(OH)2D3-treated DM rats. Moreover, compared to healthy or 1,25(OH)2D3-treated DM rats, DM rats had fewer cardiac PPAR-α and PPAR-δ protein expressions, but had increased cardiac PPAR-γ protein levels, tumor necrosis factor-α, interleukin-6, 5’adenosinemonophosphate-activated protein kinaseα2, phosphorylated acetyl CoA carboxylase, carnitine palmitoyltransferase 1, PPAR-γ coactivator 1-α, cluster of differentiation 36, and diacylglycerol acyltransferase2 protein expressions.
Conclusions: 1,25(OH)2D3 significantly changed the cardiac function and fatty acid regulations in DM hearts, which may be caused by its regulations on cardiac PPARs and proinflammatory cytokines.
AP-05
Effects of Pitavastatin Versus Atorvastatin on the Peripheral Endothelial Progenitor Cells and Vascular Endothelial Growth Factor in High-Risk Patients: a Pilot Prospective, Double-Blind, Randomized Study
1,2LIang-Yu LIn, 3CHIN-CHOU HUANG, 4 JIA-SHIONG CHEN, 3TAO-CHENG WU,
3HSIN-BANG LEU, 3PO-HSUN HUANG, 2TING-TING CHANG, 3 SHING-JONG LIN,
2,3JAW-WEN CHEN
1Division of Endocrinology and Metabolism, 3Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 2Institute of Pharmacology, 4Cardiovascular Research Center, National YangMing University, Taipei, Taiwan
background: Circulating endothelial progenitor cells (EPCs) reflect endothelial repair capacity and may be a significant marker for the clinical outcomes of cardiovascular disease. While some highdose statin treatments may improve endothelial function, it is not known whether different statins may have similar effects on EPCs. This study aimed to investigate the potential class effects of different statin treatment including pitavastatin and atorvastatin on circulating EPCs in clinical setting.
Methods: A pilot prospective, double-blind, randomized study was conducted to evaluate the ordinary dose of pitavastatin (2 mg daily) or atorvastatin (10 mg daily) treatment for 12 weeks on circulating EPCs in patients with cardiovascular risk such as hypercholesterolemia and type 2 diabetes mellitus (T2DM). Additional in vitro study was conducted to clarify the direct effects of both statins on EPCs from the patients. results: A total of 26 patients (19 with T2DM) completed the study. While the lipidlowering effects were similar in both treatments, the counts of circulating CD34+KDR+EPCs were significantly increased (from 0.021±0.015 to 0.054±0.044% of gated mononuclear cells, P<0.05) only by pitavastatin treatment. Besides, plasma asymmetric dimethylarginine level was reduced (from 0.68±0.10 to 0.53±0.12 μmol/L, P<0.05) by atorvastatin, and plasma vascular endothelial growth factor (VEGF) level was increased (from 74.33±32.26 to 98.65±46.64 pg/mL, P<0.05) by pitavastatin. In the in vitro study, while both statins increased endothelial nitric oxide synthase (eNOS) expression, only pitavastatin increased the phosphorylation of eNOS in EPCs. Pitavastatin but not atorvastatin ameliorated the adhesion ability of early EPCs and the migration and tube formation capacities of late EPCs.
Conclusions: While both statins similarly reduced plasma lipids, only pitavastatin increased plasma VEGF level and circulating EPCs in high-risk patients, which is probably related to the differential pleiotropic effects of different statins.
AP-06
Diabetes and Non-Hodgkin’s Lymphoma: Analyses of Prevalence and Annual Incidence in 2005 Using the National Health Insurance Database in Taiwan
CHIn HsIao Tseng
Department of Internal Medicine, National Taiwan University College of Medicine; Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital
background: The association between diabetes and non-Hodgkin’s lymphoma (NHL) is rarely studied and the risk associated with insulin use is not known.
Materials and Methods: The crude and age-standardized trends of NHL incidence in the general population from 1979 to 2007 were first calculated. NHL prevalence and annual incidence in 2005 were calculated in 329,198 insurants aged ≥45 years from a random sample of 1,000,000 insurants of the National Health Insurance. Logistic regression evaluated the risk factors. results: NHL incidence trends increased significantly in either sex. A total of 1,079 and 148 NHL cases were identified for prevalence and incidence analysis, respectively. The respective prevalence (per 100,000) for diabetic and non-diabetic subjects was 480.2 and 269.9 (P<0.01); and the respective incidence (per 100,000) was 70.9 and 35.3 (P<0.01). Odds ratio for diabetic versus non-diabetic subjects after adjustment for age, sex, occupation and living region was 1.51 (1.33-1.71) for prevalence and 1.48 (1.06-2.06) for incidence. In diabetic patients, the adjusted odds ratio for insulin users versus non-users was 1.63 (1.23-2.15) for prevalence and 2.52 (1.37-4.64) for incidence. Conclusions: NHL incidence is increasing in Taiwan. Diabetes and insulin use are associated with a higher risk.
Abstract
