Oral Presentation-2

O2-1 DIETARY INTAKE IN ELDERLY TYPE 2 DIABETES SUBJECTS IN TAIWAN

1HSIU-YUEH SU,

2MIN-SU TZENG, 3SHU-TI CHIOU, 4NENG-CHUN YU, 5WAYNE H-H SHEU

1Department of Dietetics, Taipei Medical University Hospital, Taipei, Taiwan, R.O.C.; 2Department of Nutritional Science, Fu Jen Catholic University, Taipei, Taiwan, R.O.C.; 3Health Promotion Administration, Ministry of Health and Welfare, Taiwan, R.O.C.; 4Yu Neng-Chun Diabetes Clinic, I-Lan County, Taiwan, R.O.C.; 5Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.

This was a cross-sectional survey commissioned by Health Promotion Administration, Ministry of Health and Welfare, and conducted by Taiwanese Association of Diabetes Educators in year 2011. In brief, type 2 diabetic subjects who regularly visited the same Diabetes Health Promotion Institute for at least one year were invited by a method of one per every 5 consecutive visitors. Every 5 enrolled subjects were asked to fill the semi-quantitative food frequency questionnaire (FFQ). The categories listed in FFQ included a total of 10 food categories and 83 types of food. We compared elderly group (≥65 years old, n=285, with age 72.6±5.1 years (mean±SEM), and the adult group (<65 years old, n=392, with age 54.4±8.0 years). The body mass index of the elderly group was lower than the adult group (25.3±3.7 vs. 26.4±4.4 kg/m2, p<0.05). Values of SBP, DBP, fasting glucose, PPG, HbA1c, total cholesterol, LDL-cholesterol and triglyceride were not different between elderly and adult diabetes. There were no differences between calorie intake (1856.0±630.8 vs. 1965.1±619.3 kcal/day, p=0.80) and protein intake (59.5±25.0 vs. 64.9±23.9 gm/day, p=0.47) while cholesterol intake were significantly lower in elderly diabetes subjects (158.7±123.6 vs. 206.4±156.5mg/day, p<0.01) than adults diabetes. In general, nutrients intake were lower in women than men with the cholesterol intake reached statistically significant. The percentages of those who attained the ABC goals in the elderly group were 12.3% compared with 8.6% in the adult group (p=0.413). In conclusion, nutrients intake of the elderly diabetic group are lower than the adult group. Further careful monitoring and ensure adequacy nutrients intake while maintain good diabetes control in elderly patients are clearly needed.

O2-2 S ITAGLIPTIN AND RISK OF HEART FAILURE HOSPITALIZATION IN PATIENTS WITH TYPE 2 DIABETES AND END STAGEENAL DISEASE ON DIALYSIS: A POPULATION-BASED COHORT STUDY

1,2YI-CHIH HUNG, 3,4CHE-CHEN LIN, 1,2WEI-LUN HUANG, 5MAN-PING CHANG, 1,6CHING-CHU CHEN

1Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C.; 2BDepartment of Medicine, China Medical University, Taichung, Taiwan, R.O.C.; 3Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan, R.O.C.; 4Department of Public Health, China Medical University, Taichung, Taiwan, R.O.C.; 5Department of Nursing, School of Health, National Taichung University of Science and Technology, Taichung, Taiwan, R.O.C.; 6School of Chinese Medicine, China Medical University, Taichung, Taiwan, R.O.C.

Context: The incidence of heart failure hospitalization (HHF) after taking sitagliptin in type 2 diabetes (T2DM) patients with end stage renal disease (ESRD) on dialysis is unclear because these patients are usually excluded from randomized clinical trials.

Objective: To assess sitagliptin treatment and the risk of HHF among T2DM patients receiving dialysis.

Design and Setting: In this population-based cohort study from the Taiwan National Health Insurance Research Database, we identified individuals taking sitagliptin between 2009 and 2011 and randomly selected a control cohort matched by age, sex, and index year at a 1:4 ratio. Multivariable Cox proportional hazards regression analysis was used to evaluate HHF risk.

Participants: Patients with T2DM and ESRD on dialysis, not taking metformin, acarbose, saxagliptin, vildagliptin, linagliptin, or thiazolidinediones.

Intervention: Taking sitagliptin for the first time.

Main Outcome: HHF

Results: The overall incidence of HHF was higher in the sitagliptin cohort than in the control cohort (1142 vs.806 per 10000 person-years; adjusted hazard ratio (HR): 1.50, 95% CI =1.18-1.89). There was a significant trend towards increased HHF risk associated with increased sitagliptin dose (p for trend < 0.01). Subjects at greater risk of HHF were those without severe hypoglycemia, on ACE inhibitors treatment, having history of heart failure, or receiving hemodialysis.

Conclusions: Use of sitagliptin was associated with an increased risk of HHF in patients with T2DM and ESRD on dialysis, especially in those without severe hypoglycemia, on ACE inhibitors treatment, with prior heart failure, or receiving hemodialysis.

O2-3 ALTERED MITOCHONDRIAL DYNAMICS, BIOGENESIS, AND BIOENERGETICS IN CYBRID CELLS HARBORING A DIABETESSUSCEPTIBLE MITOCHONDRIAL DNA HAPLOGROUP

1CHENG-FENG TSAO, 1PEI-WEN WANG, 1HSIAO-MEI KUO, 1SHAO-WEN WENG, 3JIIN-HAUR CHUANG, 2TSU-KUNG LIN, 2CHIA-WEI LIOU, 1CHING-YI LIN

1Department of Internal Medicine, 2Department of Neurology and 3Department of Surgery , Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

Aims: The advantage of using a cytoplasmic hybrid (cybrid) model to study the genetic effects of mitochondria is that the cells have the same nuclear genomic background. We previously demonstrated the independent role of mitochondria in the pathogenesis of insulin resistance (IR). However, exactly how the mitochondria respond to insulin stimulation in insulin-resistant cells remains unanswered.

Methods: We compared mitochondrial dynamics, biogenesis, and bioenergetics between cybrid cells harboring diabetes-susceptible (B4) and diabetes-protective (D4) mitochondrial haplogroups, especially the responses before and after insulin stimulation.

Results: Diabetes-susceptible cybrid B4 showed a more fragmented mitochondrial network, impaired mitochondrial biogenesis (mtDNA copy number) and bioenergetics (mitochondrial ATP concentrations and Oxygen consumption rate (OCR)), and a high expression of fission-related molecules (mitochondrial fission 1 protein (FIS1) and dynamin-related protein 1 (DRP1)), with a trend towards pro-fission. Upon insulin stimulation, increases in network formation, mitochondrial DNA (mtDNA) content, and ATP production were observed only in the diabetes-protective cybrid D4. Insulin promoted a pro-fusion dynamic status in both cybrids, but the trend was greater in D4 cells than in B4 cells. In cybrid B4, the imbalance between mitochondrial dynamics and impaired biogenesis and bioenergetics were significantly improved in response to antioxidant treatment. Further, the increase in the mitochondrial network and mtDNA content and ATP concentration in response to insulin developed after antioxidant treatment.

Conclusions: Diabetes-susceptible mtDNA variants are themselves resistant to insulin. These genetic variants, mediating ineffective mitochondrial respiration, affect multifarious mitochondrial and cellular functions, including an imbalance in mitofusion and mitofission, decreased biogenesis and impaired bioenergetics.

O2-4 NONFUNCTIONAL PITUITARY MACROADENOMA WITH PANHYPOPITUITARISM AND HYPONATREMIA— REPORT OF TWO CASES

WEI-HSIN HSU, I-MIN PAN

Division of Endocrinology and Metabolism, Tainan Sin-Lau Hospital, Tainan, Taiwan, R.O.C.

Tumor mass effects of headache, visual field defects, and hypopituitarism are main clinical manifestation of nonfunctional pituitary macroadenoma. Usually, various degrees of deficiency in different kinds of pituitary hormones were reported in the cases with hypopituitarism. Here, we reported two cases of nonfunctional pituitary macroadenoma presenting as panhypopituitarism and hyponatremia.

Case 1: A 65 year-old male was sent to ER with persistent vomiting, epigastric dull pain since last night. Other symptoms included chest tightness, vertigo, and headache. Physical examination revealed BP 145/79mmHg, PR 95/min, BT 36.5°C, E4V5M6, BW 76 kg, acute ill-looking, and weakness. Laboratory data showed serum Na: 119 mmol/L, random cortisol: 1.17 ug/dL(N:4.3~22.40), ACTH: 11.7 pg/mL(N:7.9-47.1), Free T4: 0.58 ng/dL (N:0.61-1.48), TSH: 1.35μIU/mL (N:0.34-5.6). Under the impression of adrenal insufficiency with hyponatremia, hydR.O.C.ortisone and intravenous fluid supplement were given. Followed up laboratory data showed cortisol: 14.8 ug/dL, free T4: 0.47 ng/dL, and Na: 139mmol/L. Brain MRI showed a 1.6 cm mass lesion in the sella turcica. He was referred to neurosurgeon for the further management.

Case 2: A 66-year-old female came to OPD f for the chief problem of vomiting for one day. She was currently treated with prednisolone 5 mg 2 # qd and eltroxin 100ug by her doctor in another hospital. At our OPD, the findings of physical examination were unremarkable. Her laboratory data during admission period showed Na110mmol/L, K4.0 mmol/L, Cl87 mmol/L, cortisol(AM): 2.45ug/ dL, ACTH: 22.5pg/mL(N:9~52), TSH: 3.37μIU/mL (N: 0.4~4), T3: 0.73 ng/mL (N: 0.84-1.72), and T4: 3.39μg/dL (N: 4.5-12.5). Other endocrine hormone tests showed LH:0.84 mIU/mL(N:1.1~77), FSH: 5.85 mIU/mL(N:1.2~21), Prolactin: 24.4 ng/mL (N:3~20), E2: 5.04 pg/mL(N:30~330), and progesterone: 0.09 ng/mL(N:0.25~23). Brain MRI showed a pituitary macroadenoma. After operation, she was treated with levothyroxine 100ug qd ac. Baseline serum cortisol (AM) and ACTH level were within normal limit.

In conclusion, hyponatremia may be the main clinical manifestation of patients with nonfunctional pituitary macroadenoma with panhypopituitarism.

O2-5 RETROSPECTIVE ANALYSIS OF DIABETIC KETOACIDOSIS TREATMENT WITH MODIFIED AND SIMPLIFIED REGIMEN: A MEDICAL CENTER EXPERIENCE

SENG-WEI OOI, HUA-FEN CHEN

Department of Metabolism, Far Eastern Memorial Hospital, Taipei, Taiwan

Background and aim: Current diabetic ketoacidosis (DKA) guidelines are sometimes too complicated and it is difficult for the residents to strictly adhere every step of recommendation on duty(no ensuring 0.02U/Kg/hour insulin by adding intravenous glucose, even stopped insulin infusion when near hypoglycemia, resulting ketogenesis recurs and increases cerebral edema risk). In this study, we retrospectively evaluated the outcome of our simplified modification of DKA guideline.

Methods: We give continuous intravenous “12U insulin mix with 50g glucose” (without using pump) to replace insulin pump. Suggested infusion rate is about 4U/hour at initial 6 hours(loading), then 2U/hour for subsequent 24 hours(maintainance), to ensure >0.02U/Kg/hour insulin in most patients. Oral intake is encouraged if no contraindication(give prokinetic if poor intake), so we can inject more subcutaneous insulin to ensure daily insulin ≥0.8U/Kg/day. Oral intake is also for dietary potassium and phosphate supplement. Prophylactic potassium supplement is given to reduce the severity and frequency of hypokalemia, for renal failure patients, can start with empirical safe dose(safe dose[meq] before follow serum K level next time = [5.3 - current serum K] * 0.236 * Body weight[Kg]) to ease the worry of iatrogenic hyperkalemia. We present a typical DKA case who experienced common suboptimal treatment(poor adherence to guideline) prescribed by duty physicians in emergency department for 4 hours, and was shifted to our simplified protocol then.

Results: After one day of treatment, beta-Hydroxybutyric acid was rechecked, DKA already subsided(from>8.0mmol/L to 0.1mmol/L), serum bicarbonate had been normalized too. Her DKA subsided simply due to adequate insulin supplement, without strict glucose control with insulin pump(which need to check one touch per 1~2 hour to titrate infusion rate), thus, patient can sleep well under check one touch only 4 times a day, cost and nursing loading(for check one touch) also become lower. DKA doesn’t recur under daily insulin ≥0.8U/Kg/day as long as adequate oral intake.

Conclusions: The simplified modification ensures the adherence of continuous adequate intravenous insulin by giving intravenous glucose at the same time. DKA subside without insulin pump thus improves patients’ sleep quality, decreases cost and nursing loading.

O2-6 CLINICAL CHARACTER OF PAPILLARY THYROID CANCER WITH HYPERTHYROIDISM

WEI-YU CHOU, SZU-TAH CHEN, JEN-DER LIN

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taiwan, R.O.C.

Background: Whether hyperthyroidism affects clinical outcome of thyroid cancer remains controversial.

Objectives: We retrospectively compare the clinical characters and outcome of thyroid cancer patients with euthyroidism (ETC) or hyperthyroidism (HTC).

Methods: From Oct. 1987 to Nov. 2013, 546 cases of thyroid cancer were retrospectively reviewed in a Northern Taiwan medical center. Clinical outcome was compared according to the histopathological diagnosis and the presence or absence of hyperthyroidism.

Results: Among the 546 thyroid cancer patients, 182 (33.3%) were HTC and 364 (66.7%) were ETC. All patients were confirmed to be papillary thyroid cancer post-operatively. The mean age was 39.1 (range, 22-72) year-old in HTC and 39.2 (range ,15-73) year-old in ETC. Female predominance was found equally in HTC and ETC (86.3% vs 82.4%, P=0.251). The tumor size was significantly smaller in HTC than in ETC ( 1.2 ± 1.2 vs 2.4 ± 1.6 cm, P<0 .001). While cancer mortality rate was low in both HTC and ETC (2.7% vs 4.7%, P=0.281); disease-free rate (DFR) was higher in HTC than in ETC (93.4% vs 84.1%, P=0.002). Persistently elevated anti-thyroglobulin antibody (ATA) was found in 18 of 149 (12.1%) disease-free HTC even after total thyroidectomy.

Conclusions: In this series, papillary cancer was the only cancer type. Although HTC has significantly higher DFR, it can be attributed to the higher incidence of micR.O.C.arcinomas in HTC since no difference of DFR was found when micR.O.C.arcinoma was excluded from both groups. Finally, not a small proportion (12.1%) of HTC has persistently high ATA postoperatively.

O2-7 COMPARISON OF CLINICAL CHARACTERISTICS AND OUTCOME OF MICRO- AND MACRO-ALBUMINURIA IN TYPE 2 DIABETES

WAI-KIN CHAN, SZU-TAH CHEN

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taiwan, R.O.C.

OBJECTIVE: This study retrospectively compared the clinical characteristics and outcome of diabetic nephropathic patients with micro- (30-299 mg/L) or macro- (above 300mg/L) albuminuria.

RESEARCH DESIGN AND METHODS: 56 type 2 diabetic nephro 特 pathic patients were retrospectively reviewed from 2013/01 to 2016/01. All patients were treated with oral anti-diabetes drugs/insulin, angiotensin II receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI). Clinical data including urine albumin creatinine ratio (UACR), glycosylated hemoglobin (HbA1c), systolic blood pressure (SBP) and estimated glomerular filtration rate(eGFR) were analyzed. Patients were divided into micro- and macro-albuminurine groups according to their latest amount of spot urine albumin. All data were analyzed with Generalized Estimating Equation (GEE) to evaluate the changes in SBP, HbA1c, UACR and eGFR.

RESULTS: Our study includes 23 (41%) micro- and 33 (59%) macro-albuminuria patients aged 60.21±10.46 and 66.13±11.27 year-old, respectively. After adjusting age and sex factors, both groups showed a trend of increasing UACR during the 3-year follow-up period. Although both group has similar HbA1c (microalbuminuria: 7.74%±1.85 VS macroalbuminuria: 8.11%±1.45) and SBP, only the macroalbuminuria group showed a statistical significance (B=210.501, SE=88.72, p=0.018) in UACR increment with a significant higher slope (B=540.828, SE=211.88, p=0.011). Deterioration of renal function as demonstrated by decreasing eGFR was found significantly in both groups (microalbuminuria: B=-6.310, SE=1.9212, P=.001; macroalbuminuria: B=-4.879, SE=1.2949, P<0.0001) without significant difference in their decreasing slope (B=-12.06, SE=9.30, p=0.195).

CONCLUSIONS: Although the rate of exacerbated urinary protein excretion was enhanced in the macroalbuminuria group, the rate of decreasing eGFR was similar in both micro- and macroalbuminuria groups during the 3-year follow-up period.

O2-8 INTERACTION BETWEEN STRA6 SIGNALING SUPPRESSION AND MITOCHONDRIAL DYSFUNCTION INDUCES KIDNEY APOPTOSIS AND FIBROSIS IN DIABETES

1CHAO-HUNG CHEN, 2KUN-DER LIN, 3TUSTY-JIUAN HSIEH, 2YU-LI LEE, 2MEIYUEH LEE, 2,4PI-JUNG HSIAO, 2,4SHYI-JANG SHIN

1Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 2Division of Endocrinology and Metabolism, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 3Department of Medical Genetics, School of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 4Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

Mitochondrial dysfunction and oxidative stress are shown as an initiating trigger to induce diabetic nephropathy. We recently reported that the suppression of RBP4 receptor cascades involves dyslipidemia-induced arterial and renal damage. We thus investigated whether the suppression of RBP4 receptor signaling could interact with mitochondrial dysfunction to cause apoptosis and fibrosis in diabetes. In the kidneys of streptozotocin(STZ)-induced diabetes and high glucose(HG)cultured HEK cells, RBP4 receptor(STRA6), MnSOD, caspase 3 and collagen 1 protein as well as apoptotic cells increased, but CRBP1, RARα, ATP synthase, and cytochrome c expression as well as mitochondrial potential decreased. By immunoprecipitation method using STRA6 antibody, we found the binding activity of RBP4 on STRA6 in diabetes and HG-cultured cells were markedly reduced. ROS inhibitor and MnSOD gene transfection reversed above alterations in HG-cultured cells. MnSOD silencing significantly reversed STRA6, CRBP1 and RARα expression but didn’t affect caspase3 and collagen 1 in HG-cultured cells. Interestingly, CRBP1 gene transfection reversed the suppression of ATP synthase, cytochrome c, the increase of caspase 3 and collagen 1 protein and mRNA expression, but increased binding activity of RBP4 with STRA6, and expression of RARα in HG-cultured cells. This study indicates that interaction between the suppression of RBP4 Receptor signaling and mitochondrial dysfunction induces kidney apoptosis and fibrosis in diabetes.

KEY WORDS: RBP4; STRA6; MnSOD; MITOCHONDRIAL DYSFUCTION; KIDNEY

O2-9 SULFONYLUREA THERAPY IMPROVED DIABETIC CONTROL IN A MAN WITH NEONATAL DIABETES AND AN ACTIVATING KCNJ11 MUTATION

1,2,3,4,5YANN-JINN LEE, 1,6CHI-YI HUANG, 1,6WEI-HSIN TING, 2CHIUNG-LING LIN, 1CHON-IN CHAN

1Department of Pediatric Endocrinology, MacKay Children’s Hospital; 2Department of Medical Research, MacKay Memorial Hospital Tamsui District; 3Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University; 4Institute of Biomedical Sciences, MacKay Medical College; 5Department of Medicine, MacKay Medical College; 6Department of Nursing, MacKay Medicine, Nursing and Management College

Neonatal diabetes, defined as hyperglycemia occurring in the first few months of life and requiring insulin therapy, is a rare disorder with an estimated incidence of 1 in 400,000 to 500,000 neonates. It may be transient, resolving in a median of 3 months, or permanent, requiring lifelong insulin therapy. A heterozygous activating mutation in the KCNJ11 gene has been identified as a cause of permanent neonatal diabetes (PND). It has been implicated in 30% to 58% of cases of PND in infants under the age of six months.

The KCNJ11 gene encodes the Kir6.2 subunit of an ATP-dependent potassium channel (KATP channel) which is critical in regulating insulin secretion in islet β cells. The KATP channel consists of the Kir6.2 pore-forming subunit and SUR (sulfonylurea receptor), the regulatory subunit. Activating mutations of the genes encoding either Kir6.2 or SUR impair KATP channel closure and inhibit insulin secretion, thus causing neonatal diabetes. Sulfonylureas close the KATP channel by an ATP-independent pathway. Their specificity for this molecular defect has led to these agents replacing insulin as the first line therapy in most patients with KCNJ11 mutations.

We have reported our experience with successful sulfonylurea treatment in two patients with PND caused by KCNJ11 mutation. Here we reported one more case in whom sulfonylurea therapy could not completely replace insulin treatment.

Patient: A 35-year-old man had PND diagnosed at 4 month of age. He was born to a healthy G5P3 mother at 36 weeks of gestation by normal spontaneous delivery. His birth weight was 2400 gm. At 4 months of age he had fever and vomiting and was diagnosed to have juvenile diabetes. Insulin injection was started but parents discontinued it in 2 weeks. At 1 8/12 years of age he was 7.8 kg and had polyuria, polydipsia, polyphagia, constipation, oral ulcer and carbuncle. His urine sugar was 4+ by Benedict test and ketones 3+, and blood glucose 400 mg/dl. Then he was hospitalized and insulin therapy with NPH and regular insulin before breakfast was restarted. One episode of diabetic ketoacidosis when he was 3 1/12 years old because of stop of insulin for 20 days.

On insulin therapy, his growth was appropriate for age (50th percentile). He had mild

developmental delay and psychomotor retardation but no seizures. His HbA1c levels were between 7.6% and 9.6% without obvious hypoglycemia. At the age of 35 years, genetic testing confirmed a c.602G>A (R201H) mutation in the KCNJ11 gene. The insulin dose at that time was 0.81 U/kg/day. A glucose tolerance test showed a C-peptide of 0.29 ng/ml at the peak level. Glibenclamide was started and the dose increased according to Pearson’s switching protocol. The C-peptide concentration was 2.27 ng/ml on the 30th day and 2.44 ng/ml in 1.5 years of glibenclamide therapy. His recent HbA1c was 7.5% at 1.9 mg/kg/day tid of glibenclamide and Novomix 8 U/day.

Except 3 bowel movement with soft formed stool, no hypoglycemia had been detected. Hemogram, ALT, AST, BUN, and Cr were within normal limits.

Genetic detection of mutation of the KCNJ11 gene: Genomic DNA was isolated from the buffy coat of blood using standard pR.O.C.edures. We first amplified the KCNJ11 gene from 5’ UTR to 3’ UTR, then sequenced the PCR product in both directions through 3 overlapping fragments with 3 nested primer pairs. The primers and PCR conditions were according to Ting et al [PMID 19774848]. The results were compared with data in Genbank (NCBI). The position of a nucleotide is denoted with reference to the A of the starting codon ATG which is +1.

Conclusion: Sulfonylurea therapy could improve diabetic control in our patient with PND but not completely replace insulin therapy.