Impact of diabetes and Intercellular adhesion molecule-1 genetic polymorphism on coronary artery disease susceptibility in Taiwan

Poster Presentations / Diabetes Research and Clinical Practice 120S1 (2016) S65–S211

594 individuals with diabetes were recruited, including 201 with diabetic retinopathy and 393 with diabetes of ≥5 years duration but without retinopathy. GCKR rs780094 genotyping was conducted with Sequenom. The diagnose and grading of diabetic retinopathy were according to fundus examination. 24-hour urinary albumin excretion rate and estimated glomerular filtration rate were used to evaluate diabetic nephropathy. Results: In the first stage, rs10010131 was significantly associated with diabetic retinopathy (OR = 1.629, 95% CI 1.019–2.606, P = 0.0416) after adjusting for duration of diabetes, HbA1c, blood pressure and body mass index. However, rs10010131 did not show association with Diabetic nephropathy (OR = 0.991, 95% CI 0.619–1.586, P = 0.970). In the second stage, no significant association of rs10010131 and DR was observed (OR = 0.837, 95% CI 0.408–1.716, P = 0.627). The metaanalysis showed that rs10010131 was not significantly associated with DR (OR = 1.334, 95% CI 0.901–1.977, P = 0.150). Conclusion: WFS1 rs10010131 was not associated with diabetic nephropathy and diabetic retinopathy in the Chinese individuals with type 2 diabetes. PB-11 In type 2 diabetes, smoking cessation is associated with deterioration in glycemic control and this is unrelated to weight gain Takako KIKUCHI1*, Kenichiro ENOOKU2, Akifumi KUSHIYAMA1, Yoko YOSHIDA1, Sayaka WAKABAYASHI1, Yasuhiko IWAMOTO1. 1The Institute for Adult Diseases, Asahi Life Foundation, 2University of Tokyo, Japan Background/aims: Diabetes mellitus (DM) are closely associated with the development of cardiovascular diseases. Smoking represents one of the most important preventable risk factors for the development of atherosclerosis. In patients with DM, smoking works synergistically in increasing the risk of cardiovascular events and death. There are some studies suggesting that diabetes control deteriorates temporarily during the first year after smoking quitting. The aims of this study were to examine whether or not quitting smoking was associated with altered diabetes control, and whether or not this association was mediated by weight change. Patients and methods: From May 2010 to October 2014, we recruited 131 patients on medication for DM and in hope to use Varenicline for smoking cessation at the Institute for Adult Diseases, Asahi Life Foundation. Physical examinations and blood samples were taken on the day of starting administration, and every two weeks thereafter. Varenicline were administered for three months. All patients gave informed written consent. We investigated the association between a quit event, smoking abstinence duration, change in HbA1c, and the mediating effect of weight change. Results: 97 (74.0%) quit smoking and remained abstinent for at least 1 year. The majority (89.7%) was male and the median body mass index (BMI) was 24.2 kg/m2 (IQR 21.8–26.9). BMI and HbA1c level showed a significant increase during smoking cessation. But this increase in HbA1c was not mediated by weight change. The changes in HbA1c during smoking cessation were not correlated with the changes in BMI, and HbA1c level increased in 75.0% of patients who decreased BMI during smoking cessation. In patients who were treated with insulin, HbA1c level increased higher than in those who were treated with oral drugs only. Patients who increased BMI during smoking cessation gained significantly more weight within the first year after quitting than those who decreased BMI during smoking cessation. Spearman’s rank correlation revealed that the white blood cell count and neutrophil to lymphocyte ratio (NLR) significantly improved immediately after smoking cessation. High-density

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lipoprotein cholesterol levels increased after smoking cessation, although BMI also significantly increased. Conclusions: In type 2 diabetes, smoking cessation is associated with deterioration in glycemic control and this is unrelated to weight gain, although smoking cessation significantly and immediately decreased systemic inflammation and increased serum HDL cholesterol level in diabetic patients. PB-12 New findings of genetic determinants of sulfonylurea efficacy from next-generation sequencing in sulfonylurea sensitive patients Qian REN1, Xueyao HAN1, Siqian GONG1, Yumin MA1, Linong JI1*. 1Peking University People’s Hospital, China Background: The genetic determinants for sulfonylureas efficacy has not been well understood until now. Methods: This pharmacogenetic study was divided into three stages. In the First stage, we screened a total of 747 patients with type 2 diabetes enrolled from the Xiaoke Pills Clinical Trial to select patients with extreme phenotype. We regarded “very sensitive to sulfonylurea” as an extreme phenotype, including two conditions (1) sulfonylurea treatment best responders: HbA1c level was decreased by more than 1%, and body weight increased by more than 5% during the first three months of follow up. (2) hypoglycemia occurred so frequently that the dose of glybeclamide was 1.25 mg/d during the whole follow up period as initial dose or the patient lost follow up because of hypoglycemia. In the second stage, next-generation sequencing was performed in patients with extreme phenotype. Variants with prediction of harmful were selected and validated by first-generation sequencing and re-sequenced them in subjects with normal glucose metabolism. In the third stage, we did case-control study in 340 patients treated with glybenclamide to investigate if the selected variants could really influence sulfonylurea efficacy. Results: We selected 32 “sulfonylurea very sensitive patients’. After next-generation sequencing, we selected 48 variants (39 genes), which seem to be harmful in prediction. Then 26 variants were successfully validated by first-generation sequencing and were re-sequenced in 20 normal glucose metabolism subjects to compare genotype between patients and controls. The genotypes were similar between patients and normal glucose metabolism subjects, except rs56743379. Rs56743379 was an insert/delete mutation in exon 5 of DMKN gene. So we did case-control study in 340 patients treated with glybenclamide to investigate the association between rs56743379 and sulfonylurea efficacy. There were 35 (10.3%) homozygous with insert mutation (Ins group), 50 (14.7%) homozygous with delete mutation (Del group). And because there were 58 SNPs downstream to the rs56743379, including 3 SNPs hit on the same contig position of rs56743379. So we regarded 255 (75%) subjects as heterozygous with varying degrees of insert/delete mutation (Hetero group). There were no significant difference between genotypes and treatment failure of glybenclamide (OR = 1.488, 95%CI 0.937– 2.361, P = 0.092). However, Logistic regression analysis showed that rs56743379 were significantly associated with proportion of patients with FPG < 7 mmol/L after adjustment of age and sex (OR = 0.630, 95% CI 0.405–0.979, P = 0.040). Conclusions: Rs56743379 in DMKN gene may be associated with sulfonylurea efficacy. Further pharmacogenetic and functional studies are needed to confirm this observation. PB-14 Impact of diabetes and Intercellular adhesion molecule-1 genetic polymorphism on coronary artery disease susceptibility in Taiwan Chihung CHOU1,2 *, Kwo-Chang UENG3,4, Shun-Fa YANG1,5, Po-Hui WANG1,4,6. 1Institute of Medicine, Chung Shan Medical University, Taichung, 2Division of Cardiology, Department of Internal

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Poster Presentations / Diabetes Research and Clinical Practice 120S1 (2016) S65–S211

Medicine, Yuan-Sheng Hospital and Changhua Christian Hospital, Yuanlin Branch, Yuanlin, 3Department of Internal Medicine, Chung Shan Medical University Hospital, 4School of Medicine, Chung Shan Medical University, 5Department of Medical Research, Chung Shan Medical University Hospital, 6Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan Objectives: The aim of the study was to evaluate impact of diabetes and Intercellular adhesion molecule-1 (ICAM-1) genetic polymorphism on coronary artery disease (CAD) in patients received coronary angiography to assess the genetic risks and conventional risks. Background: The prevention of CAD might be facilitated by identifying genes that confer susceptibility, as defined by conventional risk factors. The pathogenesis of CAD is atherosclerosis which is a chronic inflammatory disease on the vessel walls. Genetic variants in ICAM-1 gene have been shown to have association with a range of inflammatory diseases. Therefore, we conducted a study to investigate the association of the single nucleotide polymorphisms (SNPs) of ICAM-1with CAD. Methods: The study population comprised 525 unrelated Taiwanese individuals who received elective coronary angiography in Chung Shan Medical University. Among all study subjects, 207 had diabetes mellitus, 364 individuals had hypertension, 183 had hypercholesterolemia, and 219 were active smokers. The single nucleotide polymorphismsof ICAM-1 were determined by real time-PCR and genotyping. Results: Diabetes and other conventional risks were significantly associated with CAD. Our study showed that rs281432 (C8823G) was the only ICAM-1 SNP which affect the development of CAD. Multivariate analysis revealed that ICAM-1 SNP rs281432 CC/CG [p = 0.016; odds ratio (OR): 2.56, 95% confidence interval (CI): 1.19–5.56], male gender (p = 0.018; OR: 1.66, 95% CI: 1.09–2.51), aspirin use in the past 7 days ( p = 0.001; OR: 2.05, 95% CI: 1.33–3.14), hypertension (p < 0.001; OR: 2.15, 95% CI: 1.42–3.25), serum cardiac troponin I elevation ( p < 0.001; OR: 2.14, 95% CI: 1.47–3.24) and severe angina in recent 24 hours (p = 0.001; OR: 1.97, 95% CI: 1.31–2.95) increase the risk of CAD. Conclusions: In conclusion, diabetes remains one of the strongest risks of CAD. And ICAM-1 SNP rs281432 is an independent factor to predict the development of CAD. ICAM-1 SNP rs281432 homozygotic mutant GG can reduce the susceptibility to the CAD in Taiwanese subjects. Genotyping of polymorphisms may prove informative for assessment of the risks of CAD. PB-15 Gain of muscle strength in mitochondrial diabetes treated with SGLT2 inhibitors Yoshihiko SUZUKI1*, Junichiro IRIE2, Motoaki SANO3, Toshihide KAWAI4, Shu MEGURO2, Nobuhiro IKEMURA3. 1HDC Atlas Cliniv, 2Department of Internal Medicine, Keio University School of Medicine, 3Department of Cardiology, Keio University School of Medicine, 4Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan In 1996, we reported the first identified case of mitochondrial diabetes caused by a T-to-C transition at position 3271. The proband was a 58-year-old male. Heteroplasmy of the 3271 mutation, strongly maternal inheritance of diabetes and other evidences associated with mitochondrial dysfunction suggested this 3271 mutation to be pathogenic. During a 20 year follow-up, in 2014, he received SGLT2 inhibitor (Sodium glucose transporter 2 inhibitor: SGLT2i), first ipragliflozin 50 mg/day for 6 weeks, subsequently luseogliflozin 2.5 mg/day for 4 weeks, dapagliflozin 10 mg/day for 4 weeks, tofogliflozin 20 mg/day for 2 weeks, and again dapagliflozin 10 mg/day for 4 weeks. The four different products of SGLT2i seemingly had similar effect on weight loss and the decrease

of HbA1c. Then, he lost weight and attained improvement of glycemic control with HbA1c from 6.5% to 6.3%. Concurrently, the dose of glimepiride was adjusted to decrease from 6 mg to 1mg daily. Body weight decreased from 64.7 to 58.7 kg within three months (height 174 cm. BMI: from 21.4 to 19.4). These phenomena suggested that he relieved insulin resistance. The patients with sarcopenia have been believed to suffer from loss of muscle power and frailty. Therefore, it is noteworthy that, in this patient, his grip strength (GS) and back strength (BS) got stronger despite robust weight loss. Before SGLT2i treatment, GS was 37.6 kg in right hand and 30.5 kg in left hand, respectively. BS was 82 kg. After three months of SGLT2i, GS of right hand grew stronger to 39.4 kg (+1.8 kg) and left hand to 32.2 kg (+1.7 kg). BS also grew stronger to 105 kg (+23 kg). Thus the case provides a novel information in diabetes treatment and the role of mitochondria. Caloric restriction that reduces oxidative damage improves mitochondrial function. In our previous study, defective insulin secretion as well as insulin resistance is a salient feature of mitochondria diabetes. Reduced glucose flux in muscles with SGLT2i treatment possibly mitigates insulin resistance via decreased oxidative stress. Insulin resistance is one of risk factors of sarcopenia. Hence, the recovery of muscle strength after SGLT2i treatment in our patient is attributed to regained energy from restored mitochondria. Conclusion: SGLT2i upon the patient of mitochondrial diabetes could induce remarkable weight loss within short time and decrease of insulin resistance, which seemingly compensated genetic deficit of mitochondrial DNA. This supports our previous published study. PB-16 Mitochondrial diabetes and subjective hypoglycemia unawareness Yoshihiko SUZUKI1 *, Junichiro IRIE2, Motoaki SANO3, Toshihide KAWAI4, Shu MEGURO2, Nobuhiro IKEMURA3. 1HDC Atlas Clinic, 2Department of Internal Medicine, Keio University School of Medicine, 3Department of Cardiology, Keio University School of Medicine, Tokyo, 4Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan Mitochondrial diabetes (MtDM) usually lacks endocrinal insulin secretion from pancreas. Therefore, most patients are on insulin injection therapy. Hence, among MtDM, rare patients are free of insulin injection. We experienced two MtDM patients without insulin therapy, both of whom had never noticed subjective hypoglycemia. Case 1: 26 y/o. women (at 2006). She was diagnosed as having diabetes at age 12 y/o. During 14 years observation, she never noticed hypoglycemia under sulfonylurea treatment. As examination, we injected rapid insulin to induce absolute hypoglycemia. In result, she never noticed symptoms even when the plasma glucose level became lower than 30 mg/dL. She was afterward diagnosed to have mitochondrial DNA (mitDNA) mutation at position 3243. Her detailed profile are described already (Diabetologia 47:592–3, 2004). Case 2: 59 y/o. men (at 2018). He was diagnosed as having MtDM diabetes at age 33 y/o. During 26 years observation, he never noticed hypoglycemia. Though he was under glimepiride 6 mg daily treatment, he had never experience of hypoglycemia. His detailed profile are already described (Diabetes Care 19: 1304–1305, 1996). Discussion: Some cases of Kearns-Sayre syndrome (KSS), resulting from a mitochondrial DNA deletion, associated with diabetes that presented with hyperosmolar hyperglycemia with minimal ketosis were reported. Some cases of MtDM and MELAS were reported with ketoacidosis in literature. Ketone bodies are produced in liver, mainly from the oxidation of fatty acids, and exported to peripheral tissues for use as an energy source. They are particularly important for the brain, which has no other substantial non-glucose-derived energy