AP 2019 Award

AP-1

THE DIVERSIFIED ROLE OF LIVER FAT AND HEPATOKINES IN METABOLIC DISEASES

HORNG-YIH OU

Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Taiwan.

Metabolic diseases such as obesity, diabetes, and cardiovascular diseases are increasingly public health issues in modern society. The accumulation of ectopic fat plays an important role in the pathogenesis of these diseases. During the past years, my research interest has been focused on the diverse roles of liver fat accumulation (fatty liver) and hormones secreted by liver (hepatokines) in metabolic diseases.

In this talk, I will first present our researches on the hepatokines, fetuin-A. We found hyperglycemia-related endoplasmic reticulum stress induced the expression of fetuin-A to develop insulin resistance. In humans, serum fetuin-A concentrations are elevated in impaired glucose tolerance and newly-diagnosed type 2 diabetes, and the presence of NAFLD significantly increases fetuin-A levels in normoglycemia and prediabetes. Both diabetes and fetuin-A are independently associated with increased risk of arterial stiffness. Furthmore, pharmacologic treatment with a selective G proteincoupled receptor 40 agonist, GW-9508, decreases the hepatic expression of fetuin-A to improve insulin sensitivity and hepatic steatosis in diabetic mice.

Then, I will discuss another hepatokine, hepassocin. We found that subjects with NAFLD and prediabetes/diabetes have a higher serum hepassocin level than those without it. Overexpression of hepassocin induces hepatic steatois and steatohepatitis through an ERK1/2-dependent pathway. Hepassocin also induces insulin resitance in mice model. Furtheromore, in subjects with hyperlgycemic crisis, we demonstrated that increased hepassocin secretion might offset the deleterious effects of hyperglycemia on hepatocytes.

Finally, I will show our collaborative work with NTUH on fatty liver and fatty pancreas. We found the prevalence of fatty pancreas is high in the general population. Both diabetes and NAFLD are important independent associated factors of fatty pancreas. With an increase in glycemia, a and fatty pancreas are associated with diabetes independent of age, gender, adiposity, and other cardiometabolic risk factors.

Taken together, our research suggests that hepatokines play an important role in the development of fatty liver, pathogenesis of insulin resistance and arterial stiffness, and protection from hyperglycemia-related hepatic injury. In addition, fatty liver and fatty pancreas have a synergistic effect in the pathogenesis of diabetes.

AP-2

GENETIC VARIATION OF SORBS1 GENE IS ASSOCAITED WITH GLUCOSE HOMEOSTASIS AND AGE AT ONSET OF DIABETES: A SAPPHIRE COHORT STUDY

CHANG TJ1, WANG WC2,3, HSIUNG CA3, HE CT4, LIN MW5,6, SHEU WHH7,8,9 , CHANG YC1,10,11 12, CHEN YDI13, ROTTER JI13,14, CHUANG LM1,15 & SAPPHIRE STUDY GROUP*

1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 2The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. 3Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. 4Department of Endocrinology and Metabolism, Tri-Service General Hospital, Taipei, Taiwan. 5Institute of Public Health, National Yang-Ming University, Taipei, Taiwan. 6Department of Medical Research & Education, Taipei Veterans General Hospital, Taipei, Taiwan. 7Department of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung, Taiwan. 8School of Medicine, National Yang-Ming University, Taipei, Taiwan. 9School of Medicine, National Defense Medical Center, Taipei, Taiwan. 10Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Medical College, Taipei, Taiwan. 11Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan. 12Division of Cardiovascular Medicine, Falk CVRC, Stanford University School of Medicine, Stanford, CA, USA. 13Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. 14Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA. 15Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan. 16Section of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan. 17Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. 18Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. 19Department of Social Work, Tunghai University, Taichung, Taiwan. 20School of Medicine, Chung Shan Medical University, Taichung, Taiwan. * The SAPPHIREe Study Group: Hwu CM16,17, Hung YJ4,9, Lee WJ18,19, Lee IT7,8,20

Purpose: The SORBS1 gene plays an important role in insulin signaling. We aimed to examine whether common single-nucleotide polymorphisms (SNPs) of SORBS1 are associated with prevalence and incidence of diabetes, age at onset of diabetes, and the related traits of glucose homeostasis.

Method: A total of 1135 siblings from 492 ethnic Chinese families were recruited at baseline, and 630 were followed up for 5.19 ± 0.96 years. Nine SNPs including rs7081076, rs2281939, rs3818540, rs2274490, rs61739184, rs726176, rs2296966, rs17849148, and rs3193970 were genotyped and examined. To deal with correlated data of subjects within the same families, the generalized estimating equations approach was applied throughout all association analyses.

Result: The GG genotype of rs2281939 was associated with a higher risk of diabetes at baseline, an earlier onset of diabetes, and higher steady-state plasma glucose levels in the modified insulin suppression test. The minor allele T of rs2296966 was associated with higher prevalence and incidence of diabetes, an earlier onset of diabetes, and higher 2-h glucose during oral glucose tolerance test.

These two SNPs revealed independent associations with age of diabetes onset as well as risk of diabetes at baseline.

Conclusion: These findings supported that SORBS1 gene participates in the pathogenesis of diabetes.

AP-3

TRANSCRIPTOME ANALYSIS OF PAPILLARY THYROID CANCER HARBORING TELEMERASE REVERSE TRANSCRIPTASE PROMOTER MUTATION

1M-N CHIEN, 2P-S YANG, 3Y-C HSU, 2,4T-P LIU, 2,5J-J LEE, 2,5S-P CHENG

1Division of 1Endocrinology and Metabolism, Department of Internal Medicine, 2Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan. 3Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan. 4Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan. 5Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Purpose: Telomerase reverse transcriptase (TERT) promoter mutations have recently been noncanonical functions beyond telomere maintenance.

Method: Clinicopathological information and transcriptome data for papillary thyroid carcinoma (PTC) samples were obtained from The Cancer Genome Atlas (TCGA). Propensity score matching was performed to adjust for potential confounding variables between the TERT promoter wild-type group and the mutant group. Gene expression data of 36 patients in the mutant group were systemically compared to those of 72 patients in the wild-type group.

Result: Tumors with TERT promoter mutations had a higher TERT expression. Pathways central genes. Transporter and metabolic activities were overrepresented among 799 downregulated genes. There was no difference in the expression of most of the thyroid differentiation genes.

Conclusion: The TERT promoter mutations were associated with proliferative and metabolic alterations in PTC.