AP：2021 Award

AP-1 SERUM ANGIOPOIETIN-LIKE PROTEIN 6, RISK OF TYPE 2 DIABETES, AND RESPONSE TO HYPERGLYCEMIA: A PROSPECTIVE COHORT STUDY

1,2KANG-CHIH FAN, 3HUNG-TSUNG WU, 4JUNG-NAN WEI, 5LEE-MING CHUANG,

1CHIH-YAO HSU, 1I-WENG YEN,

1CHIA-HUNG LIN, 5MAO-SHIN LIN,

5SHYANG-RONG SHIH,

6SHU-HUEI WANG, 5TIEN-JYUN CHANG,

AND 5HUNG-YUAN LI

1Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan; 2Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan; 4Chia Nan University of Pharmacy and Science, Tainan, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 6Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan

Purpose Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine that improves insulin sensitivity in animals. However, serum ANGPTL6 concentration was found to be higher in human participants with diabetes or metabolic syndrome in cross-sectional studies, implying that ANGPTL6 may be induced to counteract hyperglycemia.

To investigate whether serum ANGPTL6 can predict incident diabetes and explore whether glucose or insulin can regulate ANGPTL6 expression and secretion.

Method This cohort study included adults without diabetes at baseline who were followed every 2 years for incident diabetes. Serum ANGPTL6 concentrations were measured at baseline and during oral glucose tolerance tests (OGTTs). A hepatic cell line, HepG2, and diet-induced obesity mouse model were used to evaluate the response of ANGPTL6 expression and secretion to hyperglycemia and the metabolic syndrome.

Result We recruited 1103 participants without diabetes at baseline. During the 4.22-year followup, 113 (10.2%) participants developed incident diabetes. Serum ANGPTL6 was negatively associated with the incidence of diabetes (adjusted hazard ratio, 0.77; P = 0.042). However, serum ANGPTL6 level was higher in participants with prediabetes (P = 0.018) and was elevated during OGTT. In HepG2 cells, treatment with glucose, but not insulin, induced ANGPTL6 expression. Hepatic ANGPTL6 expression and serum ANGPTL6 concentrations were significantly higher in mice fed with a high-fat diet than in those fed with a standard chow (both P < 0.05).

Conclusion A high serum ANGPTL6 level is associated with a low incidence of diabetes in humans. ANGPTL6 is expressed and secreted in response to hyperglycemia to maintain glucose homeostasis.

AP-2 PROTHYMOSINΑ ACTIVATES TYPE I COLLAGEN TO DEVELOP A FIBROTIC PLACENTA IN GESTATIONAL DIABETES

1WU, H-T, 2KANG, L, 3SU, Y-C, 4OU, H-Y, 5CHAN, F-Y, 6CHEN, Y-C, 7SU, B-H, 5WANG,

Y-S, 6WU, C-L, 5SHIAU, A-L AND

2,8,9WU, P 1Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan; 2Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 6Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; 8Academic Unit of Obstetrics and Gynecology, University Hospital of North Midlands, Stoke-on-Trent, United Kingdom; 9Keele Cardiovascular Research Group, Centre for Prognosis Research, School of Medicine, Keele University, Stoke-on-Trent, United Kingdom

Purpose High-risk pregnancies, such as pregnancies with gestational diabetes mellitus (GDM), are becoming more common and as such, have become important public health issues worldwide. GDM increases the risks of macrosomia, premature infants, and preeclampsia. Although placental dysfunction, including fibrosis is associated with the development of GDM, factors that link these observations remain unknown. Prothymosin α (ProTα) is expressed in the placenta and is involved in cell proliferation and immunomodulation. It also plays an important role in insulin resistance and fibrosis. However, the role of ProTα in GDM is still unclear.

Methods A total of 141 participants with or without GDM were recruited and the blood and placentae samples were collected for a cross-sectional study. Plasma ProTα concentrations were measured by ELISA, and the expressions of ProTα placenta were determined by Western blots.The causal relationship between ProTα and GDM was then investigated in animal and cell models. ProTα transgenic mice were generated to investigate the role of ProTα in placenta. Streptozotocin-induced GDM mouse model was used to clarify the role of ProTα in the development of GDM. 3A-sub-E trophoblasts were used to clarify the possible mechanism of ProTα-induced fibrosis in placenta.

Result In the present study, we found that fibrosis-related protein expressions, such as type I collagen (Col-1) were significantly increased in the placentae of ProTα transgenic mice. With elevated fibrosis-related protein expressions, placental weights significantly increased in GDM group. In addition, placental and circulating ProTα levels were significantly higher in patients with GDM (n = 39), compared with the healthy group (n = 102), and were positively correlated with Col-1 expression. Mice with streptozotocin (STZ)-induced GDM had increased ProTα, fasting blood glucose, Col-1, and placental weight, whereas plasma insulin levels were decreased. ProTα overexpression enhanced

nuclear factor κB (NFκB) activation to increase fibrosis-related protein expressions in 3A-Sub-E trophoblasts, while treatment with an NFκB inhibitor reversed the effect of ProTα on fibrosis-related protein expressions. We further investigated whether ProTα is regulated by hyperglycemia-induced reactive oxygen species (ROS).

Conclusion In conclusion, ProTα increases the amount of placental connective tissue and thus contributes to the pathogenesis of placental fibrosis in GDM. Therefore, ProTα may be a novel therapeutic target for GDM.

AP-3 ABERRANT EXPRESSION OF ANDROGEN RECEPTOR ASSOCIATED WITH HIGH CANCER RISK AND EXTRATHYROIDAL EXTENSION IN PAPILLARY THYROID CARCINOMA

1CHEN-KAI CHOU, 2SHUN-YU CHI, 2FONG-FU CHOU,

3SHUN-CHEN HUANG,

1JIA-HE WANG, 1CHUEH-CHEN CHEN AND 4,5HONG-YO KANG

1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Chang GungMemorial Hospital, Chang Gung University College of Medicine; 2 Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine; 3 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine; 4 Graduate Institute of Clinical Medical Sciences, Chang Gung University; 5 Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine

Purpose Male gender is a risk factor for mortality in patients with papillary thyroid carcinoma (PTC). This study investigated the impact of androgen receptor (AR) gene expression on the clinical features and progression of PTC.

Method The levels of AR mRNA and protein in frozen, formalin-fixed, parafin-embedded tissue samples from PTC and adjacent normal thyroid tissue were assessed by quantitative real-time polymerase chain reaction and immunohistochemical staining, respectively, and the relationships between AR expression and clinical features were analyzed. The thyroid cancer cell lines, BCPAP and TPC-1, were used to evaluate the efects of AR on the regulation of cell migration, and key epithelial–mesenchymal transition (EMT) markers.

Result AR mRNA expression was significantly higher in normal thyroid tissue from men than women. The sex difference in AR mRNA expression diminished during PTC tumorigenesis, as AR mRNA expression levels were lower in PTC than normal thyroid tissues from both men and women. AR mRNA expression was significantly decreased in PTC patients with higher risk and in those with extrathyroidal extension. Overexpression of AR in BCPAP cells decreased cell migration and repressed the EMT process by down-regulating mRNA expression of N-cadherin, Snail1, Snail2, Vimentin, and TWIST1 and up-regulating E-cadherin gene expression.

Conclusion These results suggest that suppression of the androgen–AR axis may lead to aggressive tumor behavior in patients with PTC.

AP-4 HLA-DQ GENOTYPE AND BIOCHEMICAL CHARACTERIZATION OF ANTI-TRANSGLUTAMINASE 2 ANTIBODIES IN PATIENTS WITH TYPE 1 DIABETES MELLITUS IN TAIWAN

1,2,4,6,10LEE YJ, 2,3,4TING WH,

1YANG YW, 5LIN CJ, 1,7HSIEH YT, 2,3,4HUANG CY, 8.9LO FS,

6CHU CC, 6LIN CL, 6LIN WS, 1LAI TS

1 Institute of Biomedical Sciences, Mackay Medical College, New Taipei; 2 Department of Medicine, Mackay Medical College, New Taipei; 3 MacKay Junior College of Medicine, Nursing, and Management, Taipei; 4 Department of Pediatric Endocrinology, MacKay Children's Hospital, Taipei; 5 Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei; 6 Department of Medical Research, MacKay Memorial Hospital Tamsui District, New Taipei; 7 Department of Clinical Laboratory, MacKay Memorial Hospital, Taipei; 8 College of Medicine, Chang Gung University, Taoyuan; 9 Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan; 10 Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC

Purpose Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 are genetic risk factors for Type 1 Diabetes Mellitus (T1DM) and Celiac disease (CD) in Caucasians, but their association with Taiwanese Han population is unknown.

Method We screened 532 Taiwanese T1DM patients for CD biomarkers including anti-tissue transglutaminase (TGM2), anti-gliadin and anti-neoepitope antibodies (Abs), sequencing DQB1 genotypes, and characterized the TGM2 Abs.

Results 3.76% of Taiwanese patients had TGM2-Abs and all had no CD's symptoms. In contrast to Caucasian's CD patients, DQ2/DQ8 only constituted ~4/5 of TGM2-Abs positive patients, while the other ~1/5 patients belonged to different HLA genotypes. Either anti-gliadin or anti-neoepitope Abs coexisted with ~3/4 of TGM2-Abs positive patients that were likely due to gluten-ingestion, while the cause of TGM2-Abs production for other ~1/4 of patients was unknown.

Purified anti-TGM2 IgA (TGA) and anti-TGM2 IgG (TGG) could bind on endothelial cells surface, recognized native better than denatured forms of TGM2, and TGA inhibited TGM2’s transamidation activity by up to 80% but TGG had no effects.

Epitope mapping of all TGM2-Abs positive sera demonstrated that TGM2-Abs had heterogeneity in specificities.

Conclusion This is the first study on Taiwanese Han T1DM patients and demonstrated the differences between our patients and Caucasian ones in HLA genotypes and properties of anti-TGM2-Abs.