2016 Award

AP-01 IMPROVE GLYCEMIC CONTROL IN PATIENTS WITH TYPE 2 DIABETES

HARN-SHEN CHEN

Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taiwan, R.O.C.

The U.K. Prospective Diabetes Study demonstrated thatgood glycemic control in type 2 diabetes is associated witha reduced risk of diabetes complications. However, achievingand maintaining tight glycemic targets represent a major challenge, especially in insulin treated patients.

We first demonstrated an influence of winter holiday on the glycemic control of patients who had type 2 diabetes. Then, we designed a study to investigate whether the effects of regular diabetes health education or a holiday-specific paper pamphlet before the Chinese New Year’s holidays could improve glycemic control during the winter holidays among type 2 diabetics.

Self-monitoring blood glucose (SMBG) is important for patients treated with insulin to guide patients toward reaching blood glucose goal. We designed a study to improve glycemic control by a structured education package for SMBG in poorly-controlled type 2 diabetic subjects. This study reveals that a constructed education package for SMBG could improve glycemic control in type 2 diabetic subjects. We designed another pilot study to evaluate the kinetics of HbA1c levels in response to blood glucose change in type 2 diabetic patients with chronic kidney disease. We wanted the HbA1c to be able to decrease about 1.5 to 2.0% in order to see the kinetic change of HbA1c.

When a patient presents with new-onset type 2 diabetes with severe hyperglycemia, the optimal treatment is aggressive insulin therapy. We designed an interventional trial to compare the effects of a further 6-month insulin therapy and oral anti-diabetic drugs on long-term glycemic control. Our main finding is that A 6-month course of insulin therapy could more effectively achieve adequate glycemic control and significant improvement of beta-cell function. A 6-month course of insulin therapy led to better 5 year glycemic control than did oral antidiabetic agent therapy in these patients.

We provide health education, diabetes management, adjust insulin dose from SMBG, and encourage early insulin therapy to improve glycemic control in patients with type 2 diabetes. These serial studies not only proof some concepts but also translate these results to clinical practice.

AP-02 GENETIC DETERMINANTS OF ANTITHYROID DRUG-INDUCED AGRANULOCYTOSIS BY HUMAN LEUKOCYTE ANTIGEN GENOTYPING AND GENOME-WIDE ASSOCIATION STUDY

1,2,3,4P-L CHEN, 1,5S-R SHIH, 6P-W WANG, 7Y-C LIN, 8C-C CHU, 7,9,10J-H LIN, 1,11S-C CHEN, 1,12,13C-C CHANG, 1,5,14T-S HUANG, 1,15K S TSAI, 1F-Y TSENG, 1C-Y WANG, 1J-Y LU, 1W-Y CHIU, 7C-C CHANG, 9Y-H CHEN, 7,16Y-T CHEN, 7C S-J FANN, 1,3,4,5W-S YANG & 1,5T-C CHANG

1Division of Endocrinology and Metabolism, Department of Internal Medicine, 2Department of Medical Genetics, National Taiwan University Hospital, 3Graduate Institute of Medical Genomics and Proteomics, 4Graduate Institute of Clinical Medicine, 5Department of Medicine, College of Medicine, National Taiwan University, 6Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 7Institute of Biomedical Sciences, Academia Sinica, 8Immunogenetics Laboratory, Medical Research Department, Mackay Memorial Hospital, 9School of Pharmacy, National Taiwan University, 10Research Center for Applied Sciences, Academia Sinica, 11Department of Internal Medicine, New Taipei City Hospital, 12Department of Internal Medicine, China Medical University Hospital, 13Department of Internal Medicine, China Medical University, 14Department of Social Medicine, 15Department of Laboratory Medicine, College of Medicine, National Taiwan University, 16Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27708, United States of America

Graves’ disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Anti-thyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves’ disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined = 6.75 × 10-32) and HLA-DRB1*08:03 (Pcombined = 1.83 × 10-9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval = 11.13-41.48) and 6.13 (95% confidence interval = 3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLADRB1*08:03 increases odds ratio to 48.41 (Pcombined = 3.32 × 10-21, 95% confidence interval = 21.66108.22). Our results could be useful for anti-thyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

AP-03 Glucose Variability and beta- Cell Response by GLP-1 Analogue added-on CSII for Patients with Poorly Controlled Type 2 Diabetes

1,2C-H LIN, 1S-H HSIEH, 1J-H SUN, 3J-S TSAI, 1Y-Y HUANG

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan; 2Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan,Taiwan; 3Sun Yat-Sen Cancer Center, Taipei, Taiwan

Introduction: The purpose of this study was to test the effects of twice-daily exenatide injections added on continuous subcutaneous insulin infusion in patients with poorly controlled type 2 diabetes (T2DM).

Methods: Patients with poorly controlled (A1C 8-12%) T2DM were randomized to receive a 6-day course of continuous subcutaneous insulin infusion (CSII) during hospitalization. After optimization of blood glucose in the first 3 days, patients were randomized to receive CSII combined with injections of exenatide for another 3 days or placebo. Biomarkers and 75 g oral glucose tolerance test (OGTT) were performed at baseline (day 0) and endpoint (day 7).

Results: A total of 51 patients (30 in exenatide and 21 in placebo groups) with mean A1C 11 % were studied. At endpoint, the mean glucose was 143.93±4.15 and 153.36±5.13 mg/dl in exenatide and placebo groups, respectively (p = 0.167). There was no difference in daily insulin dose but a significant higher standard deviation of plasma glucose (SDPG) was found in the exenatide group (50.51±2.43 vs. 41.49±3.00 mg/dl, p = 0.027). The improvement of incremental area under the curve (AUC) of glucose and insulinogenic index (Insulin0–peak/ Glucose0–peak) was prominent in the exenatide group (p < 0.01). The adiponectin level was significantly increased with exenatide added on (0.39 ± 0.32 vs. -1.62 ± 0.97 μg/mL, in exenatide and placebo groups, respectively, p = 0.045).

Conclusions: The add-on of GLP-1 analogue to CSII increased glucose variability and the β cell response in patients with poorly controlled T2DM.

Keywords: GLP-1 analogue, CSII, type 2 diabetes

AP-04 THE ASSOCIATION BETWEEN BODY MASS INDEX AND ALL-CAUSE MORTALITY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: A 5.5-YEAR PRPPECTIVE ANALYSIS

1J-F KUO, 2Y-T HSIEH, 1I-C MAO, 1S-D LIN, 1S-T TU, 1,3M-C HSIEH

1Department of Internal Medicine, Division of Endocrinology and Metabolism, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.; 2Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan, R.O.C.; 3Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan

OBJECTIVE: Abundances of study in different population have noted that obese cardiovascular disease (CVD) patients have a better prognosis than leaner patients, which refer to the phenomenon of obesity paradox. However, data on the association between body mass index (BMI) and mortality among Asian patients are limited, especially in patients with type 2 diabetes mellitus (T2DM). We investigate the association between BMI and all-cause mortality in Taiwanese patients with T2DM to define the optimal body weight for health.

METHOD: We conducted a longitudinal cohort study of 2161 T2DM patients with a mean follow-up period of 66.7±7.5 months. Using Cox regression models, BMI was related to the risk of allcause mortality after adjusting all confounding factors.

RESULT: A U-shaped association between BMI and all-cause mortality was observed among all participants. Those with BMIs <22.5 kg/m2 had a significantly elevated all-cause mortality as compared with those with BMIs 22.5 to 25.0 kg/m2, (BMIs 17.5–20.0 kg/m2: hazard ratio 1.989, p<0.001; BMIs 20.0–22.5 kg/m2: hazard ratio 1.286, p=0.02), as did those with BMIs >30.0 kg/m2 (BMIs 30.0–32.5 kg/m2: hazard ratio 1.670, p<0.001; BMIs 32.5–35.0 kg/m2: hazard ratio, 2.632, p<0.001). This U-shaped association remained when we examined the data by sex, age, smoking, and kidney function.

CONCLUSION: Our study found a U-shaped relationship between all-cause mortality and BMI in Asian patients with T2DM, irrespective of age, sex, smoking, and kidney function. BMI <30 kg/m2 should be regarded as a potentially important target in the weight management of T2DM.

AP-05 Genetic Polymorphisms of PCSK2 are Associated with Glucose Homeostasis and Progression to Type 2 Diabetes in a Chinese Population.

1TJ CHANG,

2YF CHIU, 3WH SHEU, 4KC SHIH, 5,6CM HWU, 7QUERTERMOUS T, 8YS JOU, 1SS KUO , 1,9 YC CHANG, 1,10LM CHUANG

1Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; 2Department of Bioinformatics and Biostatistics, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan; 3Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; 4Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei 11217, Taiwan; 5Section of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11127, Taiwan; 6Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan; 7Division of Cardiovascular Medicine, Falk Cardiovascular Research Building, Stanford University School of Medicine, Stanford, CA 94305, USA; 8Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; 9Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei 10055 Taiwan; 10Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan.

Proprotein convertase subtilisin/kexin type 2 (PCSK2) is a prohormone processing enzyme involved in insulin and glucagon biosynthesis. We previously found the genetic polymorphism of PCSK2 on chromosome 20 was responsible for the linkage peak of several glucose homeostasis parameters. The aim of this study is to investigate the association between genetic variants of PCSK2 and glucose homeostasis parameters and incident diabetes. Total 1142 Chinese participants were recruited from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study, and 759 participants were followed up for 5 years. Ten SNPs of the PCSK2 gene were genotyped. Variants of rs6044695 and rs2284912 were associated with fasting plasma glucose, and variants of rs2269023 were associated with fasting plasma glucose and 1-hour plasma glucose during OGTT. Haplotypes of rs4814605/rs1078199 were associated with fasting plasma insulin levels and HOMA-IR. Haplotypes of rs890609/rs2269023 were also associated with fasting plasma glucose, fasting insulin and HOMA-IR. In the longitudinal study, we found individuals carrying TA/AA genotypes of rs6044695 or TC/CC genotypes of rs2284912 had lower incidence of diabetes during the 5-year follow-up. Our results indicated that PCSK2 gene polymorphisms are associated with pleiotropic effects on various traits of glucose homeostasis and incident diabetes.

AP-06 CLINICAL CHARACTERISTICS AND RISK FACTOR ANALYSIS FOR LOWER-EXTREMITY AMPUTATIONS IN DIABETIC PATIENTS WITH FOOT ULCER COMPLICATED BY NECROTIZ FASCIITIS

1I-WEN CHEN, 1HUI-MEI YANG, 2CHENG-HSUN CHIU, 3JIUN-TING YEH, 1CHUNG-HUEI HUANG, 1YU-YAO HUANG

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taiwan; 2Molecular Infectious Disease Research Center, Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University, Taiwan; 3Division of Trauma Plastic Surgery, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taiwan.

Patients with diabetes are at a higher risk of having diabetic foot ulcers (DFU) or necrotizing fasciitis (NF). The present study aims to examine the clinical characteristics and associated risk factors for lower-extremity amputation (LEA) in patients with DFU complicated by NF.

We retrospectively reviewed patients treated at a major diabetes center in Taiwan between 2009 and 2014. Of the 2,265 cases 110 had lower-extremity NF. Limb preservation outcomes were classified as major LEA, minor LEA or limb-preserved. Clinical characteristics, laboratory data, and bacterial culture results were collected for analysis.

Of the 110 patients with NF, 100 had concomitant diabetic foot ulcers (NF with DFU) and the remaining 10 had no DFU (NF without DFU). None of the NF patients without DFU died nor had their leg amputated. Two NF patients with DFU died of complications. The amputation rate in the surviving 98 NF patients with DFU was 72.4% (46.9% minor LEA and 25.5% major LEA). Seventy percent of the NF patients without DFU had monomicrobial infections (60% with Streptococcus species), and 81.4% NF patients with DFU had polymicrobial infections. Anaerobic organisms were identified in 66% of the NF patients with DFU. Multinomial logistic regression analysis revealed an association between high-grade Wagner wound classification (Wagner 4 and Wagner 5) and LEA (adjusted odds ratio [aOR]= 21.856, 95% confidence interval [95% CI] =1.625–203.947, P = 0.02 and aOR= 20.094, 95% CI = 1.968–205.216, P = 0.01 for major and minor LEA, respectively) for NF patients with DFU. In addition, a lower serum albumin level was associated with major LEA (OR = 0.066, P = 0.002).

In summary, once diabetic foot ulcers were complicated by NF, the risk of amputation increased. Empirical treatment for NF patients with DFU should cover polymicrobial infections, including anaerobic organisms. The high-grade wound classification and low serum albumin level were associated with LEA.