AP：2018 Award

AP-1 THE HEPATIC PROTECTION EFFECTS OF HEPASSOCIN IN HYPERGLYCEMIC CRISIS

HORNG-YIH OU

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

Background: High glucose generates reactive oxygen species (ROS) and contributes to glucotoxicity in hepatocytes, and hyperglycemia causes structural and functional damage to the liver. However, only a mild hepatic dysfunction was observed in subjects with hyperglycemic crisis, implying a factor exists to exert a hepatic protective effect. Hepassocin is a hepatokine that modulates the proliferation and metabolism of hepatocytes and also exerts protective activity in liver injury. However, its role in hyperglycemic crisis-induced hepatic dysfunction remains unknown.

Objective: To investigate the possible hepatic protection effects of hepassocin in hyperglycemic crisis.

Methods: Plasma hepassocin concentrations and routine biochemistry were measured in 21 patients with hyperglycemic crisis before and after standard treatments. The effects of hepassocin on hepatic functions were evaluated in streptozotocin-induced hyperglycemic mice (STZ mice). HepG2 cells were used to clarify the possible mechanisms regulating hepassocin expression.

Results: Plasma hepassocin concentrations decreased significantly in subjects with hyperglycemic crisis after standard treatment accompanied by improved hepatic functions. Correction of hyperglycemia in STZ mice also decreased the hepatic hepassocin expression. Injection of recombinant hepassocin improved hepatic functions and histologic changes and increased the expression of antioxidative stress proteins, including superoxide dismutase 1 (SOD1). In HepG2 cells, high glucose increased hepassocin expression through signal transducer and activator of transcription 3 and hepatocyte nuclear factor-related pathways. We also demonstrated that hepassocin increased SOD1 expression through an extracellular signal-regulated kinase 1/2 nuclear factor erythroid-2-related factor 2 pathway, decreasing ethyl acetate-induced ROS production and improving cell viability.

Conclusions: Increased hepassocin secretion in hyperglycemic crisis might offset the deleterious effects of hyperglycemia on hepatocytes.

AP-2 EFFICACY OF AN HSP90 INHIBITOR, GANETESPIB, IN PRECLINICAL THYROID CANCER MODELS

1SHU-FU LIN, 1JEN-DER LIN, 2CHUEN HSUEH, 3,7TING-CHAO CHOU, 4CHUN-NAN YEH, 5MING-HUANG CHEN,6RICHARD J. WONG

1Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. 2Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 3Laboratory of Preclinical Pharmacology Core, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 4Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 5Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 6Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 7Current address: PD Science, Inc., Paramus, NJ, USA

Heat shock protein 90 is a molecular chaperon that maintains the correct foldingand function of multiple client proteins. The inhibition of heat shock protein 90, whichleads to the simultaneous degradation of multiple proteins involved in oncogenicsignaling pathways, has revealed an innovative strategy to treat a variety of cancertypes. We evaluated the therapeutic effects of ganetespib, a heat shock protein 90inhibitor, in treating thyroid cancer. Ganetespib effectively inhibited cell proliferationin a dose-dependent manner in eight cell lines originating from four major histologictypes of thyroid cancer (papillary, follicular, anaplastic and medullary). Ganetespibdecreased cyclindependent kinase 1 and arrested cell cycle progression in G2/Mphase. The expression of proteins involved in RAS/RAF/ERK and PI3K/AKT/mTORsignaling pathways was also inhibited. The RET level was decreased in a medullarythyroid cancer cell line. Ganetespib increased Bim expression, activated caspase-3 andinduced apoptosis. In vivo, ganetespib retarded the tumor growth of anaplastic andmedullary thyroid cancer xenografts with acceptable safety profiles. These findingsindicate that ganetespib has potential in the treatment of patients with thyroid cancer

AP-3 LOWER RISK OF DEMENTIA WITH PIOGLITAZONE,COMPARED WITH OTHER SECOND-LINE TREATMENTS,IN METFORMIN-BASED DUAL THERAPY:A POPULATION-BASED LONGITUDINAL STUDY

1,2,3CHIEH-HSIANG LU, 4CHEN-YI YANG, 5,6CHUNG-YI LI,7CHENG-YANG HSIEH, 4,8,9HUANG-TZ OU

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City, Taiwan. 2College of Chinese Medicine, China Medical University, Taichung, Taiwan. 3Department of Biotechnology, Asia University, Taichung, Taiwan. 4Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University. 5Department of Public Health, College of Medicine, National Cheng Kung University. 6Department of Public Health, China Medical University, Taichung, Taiwan. 7Department of Neurology, Tainan Sin Lau Hospital, Tainan. 8Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan. 9Department of Pharmacy, National Cheng Kung University Hospital, Tainan.

OBJECTIVE: The effect of pioglitazone was compared with that of other second-line glucoselowering drugs on the risk of dementia among individuals with type 2 diabetes receiving metforminbased dual therapy.

METHODS: A total of 204,323 individuals with type 2 diabetes aged ≥18 years who were stable metformin users and dementia-free before the initiation of second-line glucose-lowering medication were identified in the period 2000-2011 from Taiwan’s National Health Insurance Research Database and followed to the end of 2013. Primary analyses included 51,415 individuals aged ≥65 years without dementia events in the first year of second-line glucose-lowering treatment. Study subjects were classified into mutually exclusive groups according to various second-line glucose-lowering drugs to metformin. Cox proportional hazards models were applied to assess the time-to-event between propensity score-matched glucose-lowering treatment groups.

RESULTS: Individuals aged ≥ 65 years on metformin + pioglitazone had a significantly lower risk of dementia compared with those on metformin + sulfonylurea (HR 0.56; 95% CI 0.34, 0.93), and a lower, but insignificant, risk of dementia compared with those on other metformin-based dual regimens (i.e. metformin + acarbose, metformin + meglitinide, metformin + insulin or metformin + dipeptidyl peptidase 4 inhibitors). Among individuals aged ≥18 years, there was also a decreased risk of dementia in those taking pioglitazone compared with those taking other second-line glucoselowering drugs. A lower incidence of dementia was found in users of metformin + pioglitazone compared with users of metformin + rosiglitazone.

CONCLUSION: Pioglitazone as a second-line treatment after metformin might provide a protective effect on dementia risk among individuals with type 2 diabetes.

AP-4 USEFULNESS OF THE PLASMA GLUCOSE CONCENTRATIONTO-HBA1C RATIO IN PREDICTING CLINICAL OUTCOMES DURING ACUTE ILLNESS WITH EXTREME HYPERGLYCEMIA

Y-W SUa, C-Y HSUb, Y-W GUOc, H-S CHENa

a Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; b Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwna; c Department of Medicine, Taipei City Hospital, Zhongxing Branch, Taipei, Taiwan

Aims- To evaluate the correlation between the plasma glucose-to-glycated haemoglobin ratio(GAR) and clinical outcome during acute illness.

Methods- This retrospective observational cohort study enrolled 661 patients who visited the emergency department of our hospital between 1 July 2008 and 30 September 2010 with plasma glucose concentration > 500mg/dL. Systolic blood pressure, heart rate, white blood cells, neutrophils, haematocrit, blood urea nitrogen, serum creatinine, liver function and plasma glucose concentration were recorded at the initial presentation to the emergency department. Data on glycated haemoglobin over the preceding 6 months were reviewed from our hospital database. The glucose-to-HbA1c ratio (GAR)was calculated as the plasma glucose concentration divided by glycated haemoglobin.

Results- The GAR of those who died was significantly higher than that of the survivors (81.0 ± 25.9 vs. 67.6 ± 25.0; p < 0.001 ). There was a trend toward a higher 90-day mortality rate in patients with higher GARs (log-rank test p < 0.001 for trend). On multivariate Cox regression analysis, the GAR was significantly related to 90-day mortality (hazard ratio[HR] for 1 standard deviation [SD] change:1.41, 95% confidence interval [CI]:1.22-1.63; p < 0.001), but not to plasma glucose. Rates of intensive care unit admission and mechanical ventilator use were also higher in those with higher GARs.

Conclusion- GAR independently predicted 90-day mortality, ICU admission and use of patient outcomes than plasma glucose alone in patients with extremely high glucose levels.