bluuebunny/crossref_metadata_2025 huggingface dataset:
2405-PUB: Minimed 640G vs. Minimed 670G, a Comparison in Children and Adolescents with Diabetes Type 1
Authors: SCARAMUZZA ANDREA E. , RABBONE IVANA , BONFANTI RICCARDO
Published: June 2019

Introduction: After a long lead-in period, artificial pancreas (AP) technology is well on its way to revolutionizing the treatment of diabetes, but no AP is currently approved. Recently data about the use of a hybrid closed-loop (CL) insulin delivery has been presented.

Aim: We compared two devices, Minimed 640G system, (Medtronic, CA, U.S.) in the market in Italy since mid-2015 vs. Minimed 670G system (Medtronic, CA, U.S.), just entered the market on October 24th, 2018, used by the same patients.

Methods: We prospectively analyzed data of 19 patients using 640G three months before switching to 670G. Main outcome is the time in range (TIR) compared to TIR while using 640G. Secondary outcomes are predicted A1c, time in hypo, time in hyper (>160 mg/dl), insulin total daily dose (TDD), %bolus and %basal rate, coefficient of variation (CV).

Results: The 19 patients (mean age 13±4 years, range 7-20 years, diabetes duration 7±4 years) who switched to 670G, after 2 months observation had a TIR significantly lower when compared while using 640G (62.9±6.6% vs. 76.6±16.3%, p=0.03), with similar predicted A1c (6,8±0.3% vs. 6.8±0.7%, p=0.89). Time in hypo significantly increased (3.4±2.3% vs. 0.5±0.6%, p=0.001), while no difference has been observed about time in hyper (34.7±5.9% vs. 22.9±16.1%, p=0.38) and CV (40.4±8.5% vs. 43.2±6.5%, p=0.25). Interestingly, TDD is slightly, but not significantly, lower when using 670G, with a higher percentage of insulin given as bolus than as basal rate.

Conclusions: 670G system seems less effective than 640G system to achieve a higher TIR, at the expenses of a higher time in hypo. A systematic educational pathway, as the one used by 640G users, could help reach these results, as well as some constrains 670G system has (fixed glycemic target at 120 mg/dl, only simple bolus, etc.). It is solacing to know that we already have useful tools for the best possible care of our patients with type 1 diabetes while we wait for the commercial availability of an AP or a more performant hybrid CL system.

Disclosure

A.E. Scaramuzza: None. I. Rabbone: None. R. Bonfanti: Advisory Panel; Self; Abbott, Lilly Diabetes, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi.
2410-PUB: Insulin Pumps Accessed through Provincial Funding and Quality of Life: A Qualitative Study
Authors: HAYNES EMILY J. , LEY MARISSA N. , TALBOT PAM J. , DUNBAR MARGARET , CUMMINGS ELIZABETH A.
Published: June 2019

The Nova Scotia Insulin Pump Program (NSIPP) subsidizes the cost of insulin pump (CSII) therapy for patients aged 25 and under with type 1 diabetes. Its medical eligibility criteria ensure structured care and follow-up with focused diabetes teams according to provincial guidelines. Studies on CSII and quality of life are mostly survey-based, thus first voice patient experiences are limited. This qualitative study examined patient/parent perspectives on how CSII affects quality of life and is unique in the context of provincial funding. A phenomenological approach was used. In-depth semi-structured telephone interviews averaging 36 minutes were completed with NSIPP enrollees and/or their parents, depending on age. Saturation was reached after 23 interviews. Verbatim transcripts were coded independently by two researchers using NVivo. Analysis began with a discussion of coding discrepancies, which were resolved using concept mapping to clarify relationships between codes and identify main themes. More freedom in daily life, feelings of control over life and diabetes, less worry and more positive intra/interpersonal social experiences were main themes, but how they were expressed depended on the patient’s stage of life. CSII facilitated precise insulin delivery, allowing more freedom in daily activities. This freedom led to feelings of control, less worry and improvements in social life. These outcomes manifested in how common life events were experienced. For example, parents often saw CSII as enabling their teen to gain independence, while young adults focused on CSII supporting them to function at work, school, and in relationships. Finally, NSIPP’s financial help was necessary for those without private insurance and experiences with NSIPP’s defined, structured care and follow-up were positive for all. Overall, NSIPP’s financial support to access CSII therapy and its structured care and follow-up improved quality of life, and the exact ways depended on the patients’ stage of life.

Disclosure

E.J. Haynes: None. M.N. Ley: None. P.J. Talbot: None. M. Dunbar: None. E.A. Cummings: None.

Funding

Dalhousie Medical Research Foundation
2423-PUB: Rosiglitazone Has a Neutral Effect on the Risk of Dementia in Type 2 Diabetes Patients
Authors: TSENG CHIN-HSIAO
Published: June 2019

Background: This study investigated whether rosiglitazone might affect dementia risk.

Methods: The Taiwan’s National Health Insurance database was used to enroll a cohort of 1:1 matched-pairs of ever and never users of rosiglitazone based on propensity score from patients with new onset type 2 diabetes during 1999-2006. The patients were alive on January 1, 2007 and were followed-up for dementia until December 31, 2011.

Results: A total of 5048 pairs of never users and ever users were identified. The incident case numbers were 127 and 121, respectively. The overall hazard ratio was 0.895 (95% confidence interval: 0.696-1.151) for ever versus never users. The hazard ratios for the first (<12.1 months), second (12.1-25.1 months) and third (>25.1 months) tertiles of cumulative duration were 0.756 (0.509-1.123), 0.964 (0.685-1.357) and 0.949 (0.671-1.341), respectively. When cumulative duration was treated as a continuous variable, the hazard ratio was 1.000 (0.992-1.008). Subgroup analyses conducted in ever users and never users of metformin and in patients whose diabetes was diagnosed during three different periods of time, i.e., 1999-2000, 2001-2003 and 2004-2006, all supported a neutral effect of rosiglitazone.

Conclusions: Rosiglitazone has a neutral effect on dementia risk in patients with type 2 diabetes mellitus.

Disclosure

C. Tseng: None.
2430-PUB: Analysis of Transient Elastography Data and the Risk of Metabolic Syndrome
Authors: HUANG ZHIMIN , DENG WANPING , CHEN HONGYAN , NG KAKA , LI YANBING
Published: June 2019

Aim: To investigate the correlation between Fibroscan® data controlled attenuation parameter (CAP), liver stiffness measurement (LSM) and metabolic syndrome (MetS) components.

Methods: A total of 817 subjects in this year’s staffs physical checkup screening for nonalcoholic fatty liver disease (NAFLD) were recruited. Questionnaires were filled, anthropometries including neck and waist circumferences, body mass index were collected. Fasting glucose, lipid profiles, serum insulin and plasma adiponectin were measured. Controlled attenuation parameter and LSM were recorded using FibroScan®. The subjects were divided into MetS and control groups. Clinical characteristics were compared. Independent predictors for MetS were analyzed.

Results: The CAP (277 ± 48 vs. 237 ± 44 dB/m, P<0.001), LSM (4.9 ± 2.2 vs. 4. 1 ± 1.0kpa, P<0.001), neck circumference (37.1 ± 3.3 vs. 34.1 ± 3.0, P<0.001) and fasting insulin (9.3 ± 4.7 vs. 5. 7 ± 2.9μU/mL, P<0.001) were significantly elevated in the MetS group, whereas adiponectin (10.6 ± 8.8 vs. 18.7 ± 14.9 ng/mL, P<0.001) were lower. With the accumulation of MetS components, thus increased CAP and LSM. When CAP and LSM were divided into quartiles, the number of MetS components increased with increasing quartiles, and CAP showed a stronger correlation with MetS than LSM. Binary Logistic regression analysis showed that CAP, age, neck circumference, adiponectin and fasting insulin were independent predictors for MetS. Even with no MetS components, subjects with CAP≥248dB/m had elevated BMI, neck and waist circumference, waist to hip ratio, increased fasting insulin, triglyceride, uric acid and reduced adiponectin.

Conclusion: CAP showed a close relationship with MetS. Increased CAP was associated with increased body weight and dyslipidemia, reduced adiponectin even before the occurrence of MetS.

Disclosure

Z. Huang: None. W. Deng: None. H. Chen: None. K. Ng: None. Y. Li: None.
2438-PUB: Adherence to Hypoglycemic Agents among Type 2 Diabetes Patients with Claims Database in Japan
Authors: HORII TAKESHI , MOMO KENJI , YASU TAKEO , KABEYA YUSUKE , ATSUDA KOICHIRO
Published: June 2019

Several studies have been conducted to understand adherence and to identify the determinants associated with it showing that medication adherence is influenced by numerous factors that may be related to patients and medication. There are no data of large-scale medication adherence originating in Japan. In this study, we examined non-adherence and predictive factors of T2DM patients in Japan. This was a retrospective cohort study using a Japanese claims database of patients with type 2 diabetes. Adherence to therapy was measured using the proportion of days covered (PDC) method over a fixed period of 3 years. If PDC <80%, patients were considered non-adherent, a commonly used standard. To assess the odds ratio (OR) of non-adherence, we performed a logistic regression analysis, having adjusted for patient characteristics. The final sample contained 885 patients. The mean PDC was 79.6%, with 50.2% of patients classified as non-adherence. The mean number of medicines was 2.4, with 11.1% of patients classified as polypharmacy. According to the inflection point of the ROC curve, the cut-off value of the number of outpatient visits associated with adherence was 17 times. In the multivariate logistic regression analysis, polypharmacy (OR:0.18), the older age (60y∼ OR:0.37, 50y∼OR:0.39) showed lower odds ratio. Men (OR:2.20), 17 or less times of outpatient visits in 3 years (OR:27.1) showed higher odds ratio. In this study, we investigated medication non-adherence in 3 years and showed adherence adequacy a little lower to that reported previously, which is one year observation period. Also, medication adherence tended to be lower in younger ages and cases with fewer drugs. Maintaining good medication adherence and achieving the targeted HbA1c in these cases are important for suppressing the onset of diabetic complications. We think that it is necessary to consider methods of intervention aimed at maintaining good medication adherence, such as by utilizing on-line medical treatment.

Disclosure

T. Horii: None. K. Momo: None. T. Yasu: None. Y. Kabeya: None. K. Atsuda: None.

Funding

Japan Association for Diabetes Education and Care
2447-PUB: The Effects of Acute Hyperglycemia on Driving Performance in People with T2DM
Authors: NGUYEN TIFFANY , DAO VIVIAN V. , TIMBERMAN JEFF , DAVIS SARAH , DOROUDGAR SHADI , SHUBROOK JAY H.
Published: June 2019

Objective: Hyperglycemia has been shown to induce cognitive changes in processing speed, executive function, attention, and working memory in several laboratory based mental tasks. It has also been identified as the main culprit in diabetes related cognitive decline. Driving is a complex task that requires intricate coordination between cognitive and motor skills and provides information on how acute hyperglycemia may affect people with type 2 diabetes in the real world. This study aims to identify associations between acute hyperglycemia in subjects with normally well controlled type 2 diabetes and measures of driving ability.

Methods: This randomized experimental crossover study selected actively driving subjects with well controlled type 2 diabetes between the ages of 25-45. Subjects were asked to operate a driving simulator (STISIM Drive M100) in two glycemic states: euglycemia and acute hyperglycemia. Subjects were randomized and cross-covered with each session separated by one week to account for any learning effects. Hyperglycemia was induced by asking subjects to withhold their usual diabetes related medications the day before the study.

Results: A total of 12 subjects have completed this study. No significant associations were found in several parameters examining adherence to speed limits, ability to maintain lane position, number of collisions, or ability to follow a lead car. When comparing euglycemic driving to acute hyperglycemic, subjects had a mean speed of 45.1 ± 6.81 vs. 43.4 ± 1.86 (p=0.42), time above speed limit 12.8 ± 15.0 vs. 13.9 ± 7.83 (p= 0.78), standard deviation in lateral position 1.63 ± 0.36 vs. 1.58 ± 0.35 (p=0.79), centerline crossings 3.08 ± 6.01 vs. 2.50 ± 2.11 (p=0.77), modulus car following 0.60 ± 0.31 vs. 0.52 ± 0.32 (p=0.30), and number of collisions 0.50 ± 0.67 vs. 0.17 ± 0.39 (p=0.17).

Conclusion: The current data is inconclusive given the small sample size and merits further exploration with a larger study.

Disclosure

T. Nguyen: None. V.V. Dao: None. J. Timberman: None. S. Davis: None. S. Doroudgar: None. J.H. Shubrook: Advisory Panel; Self; Intarcia Therapeutics, Inc. Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc.

Funding

Touro University California
2450-PUB: Association between Intake of Magnesium and Obesity in Japanese Patients with Type 2 Diabetes Mellitus
Authors: NEDACHI RINA , FUJIHARA KAZUYA , HATTA MARIKO , MATSUBAYASHI YASUHIRO , TAKEDA YASUNAGA , ISHII DAI , HORIKAWA CHIKA , KATO MITSUTOSHI , MAEGAWA HIROSHI , SONE HIROHITO
Published: June 2019

Obesity is known to increase the risks of cardiovascular events and mortality in patients with diabetes. Low serum magnesium (Mg) levels are reportedly associated with obesity and incident diabetes mellitus among nondiabetic individuals. Since only a few studies have addressed the relationship between intake of Mg and obesity, we analyzed our nationwide registry of diabetic patients to determine if there was an association between intake of Mg and obesity in Japanese patients with T2DM. We analyzed data on 1891 Japanese patients with T2DM (mean age, 62 y; men, 62%) who completed a food frequency questionnaire. Obesity was defined as BMI ≥25. Associations between obesity and intake of Mg were determined by multivariate regression and quintile analyses. After adjusting for confounders including energy intake, the odds ratio (OR) for obesity was 0.93 (0.91,0.96) per 10 mg increase in Mg intake. Quintile analysis revealed a stepwise significant decrease in ORs for obesity from Q1 (lowest, ref.) to Q5 (highest) (Table). Food groups potently related to Mg intake in our patients were beans (correlation coefficients, 0.64), vegetables (0.62), and fish (0.57). These results imply that intake of Mg might be closely associated with obesity in patients with T2DM, which should have clinical relevance in nutrition therapy.

Disclosure

R. Nedachi: None. K. Fujihara: None. M. Hatta: None. Y. Matsubayashi: None. Y. Takeda: None. D. Ishii: None. C. Horikawa: None. M. Kato: None. H. Maegawa: Research Support; Self; Antares Pharma, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.
2455-PUB: Number of Insulin Users May Explosively Increase with the Aging Population in Japan
Authors: KOKITA AYAKA , ARAKI MAKOTO
Published: June 2019

Background: The impact of recent advances of oral antidiabetic agent on insulin users is unclear.

Methods: A retrospective observational and comparative study using medical records of patients who were prescribed insulin at our facility between 2009 and 2017 for various parameters, excluding dialysis patients.

Results: The number of insulin users was almost negligible (309-311 people). The age of the subjects was shifted to the old side on the frequency distribution polygon. The number of subjects who used ≥1 oral antidiabetic agents concurrently increased from 17.0% to 80.0%, especially among those aged >80 years (about 8 times). HbA1c value remained negligible from 8.1% to 8.1%.

Conclusion: Our findings suggest an increasing number of patients with insulin secretory dysfunction masked using of oral antidiabetic agents.

Disclosure

A. Kokita: None. M. Araki: None.
2459-PUB: Clinical Characteristics and Management of Patients with Type 1 Diabetes—A National Population-Based Spanish Study (SED1)
Authors: GOMEZ-PERALTA FERNANDO , MENÉNDEZ-TORRE EDELMIRO , BARREIRO SANTIAGO CONDE , CONGET IGNACIO , NOVIALS ANNA
Published: June 2019

Introduction: Little is known about the clinical characteristics and management of type 1 diabetes (T1D) in Spain from a national perspective. To sort this lack of information out the Spanish Diabetes Society (SED) promoted a national population-based audit study. (SED1 Study).

Material and Methods: Observational, cross-sectional study of a nationally representative sample of patients with DM1 in 78 Spanish sites, including children and adults.

Results: A total of 647 participants were included: Aged 36.5+14.4 years (7.6% < 14), 55,3% female, 97.2% Caucasian, time since diagnosis 17.9±12.0 years and a BMI of 24.7±4.4 kg/m2 (40.2% > 25; 12.1% ≥30). 75.0% of the population had secondary or university studies. 20.2% of patients were active smokers and 48.7% had any type of comorbidity, mainly dyslipidemia (25.8%). Any kind of retinopathy and nephropathy was present in 19.3 and 5.9% of patients. Regarding disease management, 75.9% used basal-bolus insulin therapy, 20.4% pump therapy, half of patients used insulin/carbohydrate ratio (ICR), performed 3.0±0.9 blood glucose measurements/day (BG) and 24.9% used continuous-glucose monitoring. Mean last-year HbA1c was 7.6±1.2% (< 7%, 30.6%). The univariate logistic regression indicated that, HbA1c value was determined negatively by BG measurements (-0.045, p=0.03) and frequency of use of ICR (-0.236, p=0.008) and positively by disease duration (0.011, p=0.002) and lack of adherence to diet counseling (0.788, p=0.0001).

Conclusion: The management and type of treatment of T1D in Spain is similar to other western countries. There is still a substantial proportion of patients not reaching the recognized A1c target and with either overweight or obesity. Some factors related to T1D management prevent a greater effectiveness of treatment.

Disclosure

F. Gomez-Peralta: Advisory Panel; Self; Abbott, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Abbott, AstraZeneca, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S. E. Menéndez-Torre: None. S. Conde Barreiro: Other Relationship; Self; Lilly Diabetes, Sanofi. I. Conget: None. A. Novials: None.

Funding

Sanofi
2460-PUB: Metabolic Control in Three-Year Follow-Up in Guangdong Patients with Type 1 Diabetes Mellitus
Authors: ZHOU YONGWEN , YAN JINHUA , YANG DAIZHI , LUO SIHUI , ZHENG XUEYING , LING PING , WU ZEKAI , HUANG QIANWEN , XIAN YINGXIN , WANG CHAOFAN , LIN QIONGYAN , LIU HONGXIA , YAO BIN , WENG JIANPING
Published: June 2019

Previous data showed that poor metabolic control existed in Guangdong type 1 diabetes mellitus(T1DM) patients. Thus, scheduled follow-ups were initiated in our diabetic clinic. This study aimed to assess the effect of scheduled management and explore related factors. From June 2011 to November 2018, 342 patients with T1DM registered in our diabetic clinic. Clinical data was obtained, HbA1c and plasma lipids were measured at enrollment and then once a year. Patients who had been followed-up for three years were included. A total of 201 patients (59.7% female) were analyzed, with median age of 26.9(18.1,35.5) years and diabetic duration of 5.6(0.4,8.8) years. HbA1c levels fell from 8.0±2.0% at enrollment to 7.3±1.2% in the third year progressively (P<0.001) and the rate of age-specific target achievement raised from 38.0% to 47.2% (P=0.031).Serious hypoglycemia frequency decreased from 0.6(0,0.2) to 0.3(0,0) per month (P=0.046). Of adult patients(n=147) at enrollment, 71.3% of patients achieved the target level of blood pressure. Triglyceride (TG), low-and high-density lipoprotein cholesterol (LDL-C and HDL-C) were 1.0(0.6,1.2), 1.6(1.3,1.8) and 2.8(2.1,3.2) mmol/l, with 88.4%, 85.4% and 43.8% achieving targets, respectively. After follow-up, the rate of target achievement in HDL-C increased to 92.9% (P=0.039). LDL-C level increased to 2.9(2.3,4.3) mmol/l (P=0.008), with body mass index (BMI) (20.3±2.3 to 21.2±2.2kg/m2, P<0.001) and insulin dosage (36.2(29,42) to 28.5(29.1,47.1)) units/day, P=0.01) increasing. Compared with the insufficient group, those achieving targets of HbA1c, lipids and blood pressure (20.1%) had more frequent self-monitored blood glucose (P=0.002) and lower BMI(P=0.025). The benefits of scheduled follow-up in glycemic control were sustained but not sufficient enough in the management of lipids in T1DM patients. Comprehensive management was needed to improve metabolic control.

Disclosure

Y. Zhou: None. J. Yan: None. D. Yang: None. S. Luo: None. X. Zheng: None. P. Ling: None. Z. Wu: None. Q. Huang: None. Y. Xian: None. C. Wang: None. Q. Lin: None. H. Liu: None. B. Yao: None. J. Weng: None.

Funding

Natural Science Foundation of Guangdong Province (2018A030313251); Science and Technology Planning Project of Guangzhou (201709010037)
2465-PUB: Successful Management of Severe Diabetic Ketoacidosis in a Type 2 Diabetes Patient with Insulin Allergy
Authors: NGUYEN ANH D. , LUONG CHINH Q. , CHU HIEU C. , NGUYEN VAN K. , NGUYEN CHI V. , NGUYEN TUAN A. , NGUYEN QUAN H. , MAI TON D. , NGUYEN DINH V. , NGUYEN BAY Q. , TRAN THONG H. , NGUYEN NGUYET N. , DO SON N.
Published: June 2019

Objective: To report an episode of severe diabetic ketoacidosis (DKA) in a type 2 diabetes mellitus (DM) patient with insulin allergy treated by continuous intravenous (IV) regular insulin infusion.

Methods: We describe the clinical features, laboratory data, and management of severe DKA in a type 2 DM patient with insulin allergy.

Results: A 58-year-old man with type 2 DM initiated subcutaneous insulin administration (SIA) after failure of oral antidiabetic therapies. Symptoms of an allergic reaction then developed, especially distinct at the injection site. Pruritic wheals appeared within 10 minutes of injection and lasted over 24 hours. Both skin prick and intradermal tests were positive with different types of insulin. Two days before admission, he stopped SIA because of allergic symptoms, and then experienced weakness and upper abdominal pain. On admission, his heart rate was 130 beats/min, temperature 37°C, blood pressure 150/90 mmHg, and respiratory rate 28 breaths/min. Blood glucose level was 374.6 mg/dL, pH 6.984, bicarbonate 2.5 mmol/L, lactate 1.5 mmol/L, BUN 24.1 mg/dL, creatinine 1.46 mg/dL, and urinary ketone was 66.48 mg/dL. Over 24 hours, the metabolic acidosis was refractory to IV fluids, bicarbonate and potassium replacement, as well as hemodialysis. Ultimately, he received continuous IV regular insulin infusion at an initial rate of 0.1 units/kg/hour, no further allergic reactions were observed. On the day 5, ketonemia and metabolic acidosis completely resolved. He had transition from IV insulin infusion to SIA on day 14. He was discharged on the day 21 with the treatment of SIA. Three months later, he had a good glycemic control, but has still appeared allergic symptoms at the injection sites of insulin.

Conclusion: In this patient, SIA caused an allergic reaction in contrast to continuous IV insulin infusion, for which allergic symptoms did not appear. Thus, identical insulin molecules could behave in markedly different ways depending on the route of injection.

Disclosure

A.D. Nguyen: None. C.Q. Luong: None. H.C. Chu: None. V.K. Nguyen: None. C.V. Nguyen: None. T.A. Nguyen: None. Q.H. Nguyen: None. T.D. Mai: None. D.V. Nguyen: None. B.Q. Nguyen: None. T.H. Tran: None. N.N. Nguyen: None. S.N. Do: None.
2469-PUB: Exploring the Mechanisms of Berberine against Type 2 Diabetes Mellitus and Its Complications by Network Pharmacology
Authors: DI SHA , HAN LIN , ZHAO LINHUA , TONG XIAOLIN
Published: June 2019

Berberine (BBR), an extracted isoquinoline alkaloid from medicinal plants, is widely used to treat gastrointestinal infections, hypertension, hypercholesterolemia, diabetes, as well as diabetic complications (DC). In this study, network pharmacology was employed to exhibit the potential pharmacological mechanisms of BBR treating type 2 diabetes mellitus (T2DM) and DC, which need further research. Thirty-one overlapped targets were obtained from 313 potential targets of BBR and 178 related targets of T2DM retrieved and screened from databases, such as STITCH, PharmMapper, TTD, PharmGKB. It is worth noting that UCP2, AHR, GLUT4, PPARA, PTGS1/S2, LPL, HMGR, and NR1H4 have been reported which related to both BBR and T2DM. Visualized networks of function-target-pathway, revealed the underlying mechanisms of drug function, showed the core targets such as CYP3A4, CYP2C9 were mainly involved in xenobiotics/retinol/drug metabolism, as well as PPARA, INSR in PPAR/adipocytokine/insulin signaling pathway. Of which, several targets have relationship with DC, such as CYP2C9/PPARA related to blood vessel, RXRA related to retina reported. Taken together, this study revealed that BBR has efficacy effect on T2DM and DC mediated by vital targets using network pharmacology, which also provided a time-saving efficient approach in drug research including medicine function mechanism, and new drug development.

Disclosure

S. Di: None. L. Han: None. L. Zhao: None. X. Tong: None.

Funding

National Natural Science Foundation of China (81704067, 81430097)
248-LB: Deficiency of APPL1 in Macrophages Triggers Adipose Tissue Inflammation and Insulin Resistance by Potentiating NLRP3 Inflammasome Activation
Authors: WU KELVIN K.L. , XU AIMIN , CHENG KENNETH K.
Published: June 2019

Adipose tissue inflammation participates in the pathogenesis of type 2 diabetes in obesity. While the activation of the multiprotein complex known as NLRP3 inflammasome and subsequent release of IL-1β contribute to the development of adipose tissue inflammation and insulin resistance, the mechanisms of its regulation remain unclear. Here we revealed that APPL1, an adaptor protein essential for adiponectin and insulin signaling, is upregulated in the stromal vascular fraction of visceral fat of db/db diabetic mice. Also, lack of APPL1 in bone marrow-derived macrophages specifically enhanced inflammatory response mediated by NLRP3 inflammasome. Mice with hematopoietic cells-specific APPL1 deficiency (APPL1-BMT-KO) were then generated using bone marrow transplantation approach and subjected to high-fat diet (HFD) feeding. After 36 weeks of HFD feeding, APPL1-BMT-KO mice exhibited increased insulin resistance and glucose intolerance, accompanied with elevated IL-1β in serum, liver and epididymal adipose tissue and impaired Akt phosphorylation in the subcutaneous adipose tissue and liver. In vitro experiments suggest that ablation of APPL1 in bone marrow-derived macrophages promotes IL-1β secretion by enhancing ROS generation, which is an important intracellular signal for NLRP3 inflammasome activation. Pharmacological inhibition of intracellular and mitochondrial ROS successfully abrogated the upregulation of IL-1β secretion in APPL1 deficient macrophages. In this study, we demonstrated the novel role of APPL1 in alleviating macrophage-mediated adipose tissue inflammation and insulin resistance. Lack of APPL1 in macrophages promotes ROS generation and NLRP3 inflammasome activation, which causes enhanced IL-1β secretion in adipose tissue and the development of insulin resistance.

Disclosure

K.K.L. Wu: None. A. Xu: None. K.K. Cheng: None.

Funding

Research Grants Council of Hong Kong (171018/15M)
2483-PUB: Glycemic Control with Pramlintide and Insulin Coformulations: Preclinical Evaluation of a Novel Single Injection, Room Temperature Stable Formulation
Authors: THOHAN SANJEEV , HU WENDY T. , DONOVAN MARTIN J. , PRESTRELSKI STEVEN J. , CHOI MONICA S. , HESTER DENNIS M.
Published: June 2019

Mealtime pramlintide (PRAM) and insulin (INS) reduce postprandial glucose excursions, mimics natural pancreas physiology and improves glycemic control. Due to differences in physico-chemical characteristics of PRAM and INS, mixing these two products can cause precipitation. Xeris has developed novel room temperature stable co-formulations to overcome precipitation, simplify dose administration and reduce injection burden.

Streptozotocin (65 mg/kg) treated SD rats were given co-formulations of PRAM and Regular Insulin (RI) or Lispro Insulin (LISPRO) as a single injection and compared with dual injection of commercial Symlin, Humulin, or Humalog. Blood samples were evaluated for plasma glucose and PK.

A sparse sampling PK scheme resulted in ∼30% CV for glucose values. Mean glucose profiles with reductions in glucose AUC by treatment (efficacy).

PRAM-INS single injection co-formulations showed comparable efficacy and PK profiles to two injection commercial products. Consistent with PRAM's known pharmacological action, there was no glucose lowering with PRAM alone. These results support clinical development of room temperature stable PRAM-INS co-formulations.

Disclosure

S. Thohan: None. W.T. Hu: None. M.J. Donovan: None. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc. M.S. Choi: None. D.M. Hester: None.
2484-PUB: Association of Gastrin Levels and Parameters of Glucoregulation in Type 2 Diabetes Patients
Authors: BERKOVIC MAJA CIGROVSKI , MAHECIC DAVORKA HERMAN , BILIC-CURCIC INES
Published: June 2019

Background and Aims: Recent data suggest that co-administration of gastrin and GLP-1 improves glucose homeostasis and increase β-cell mass in a rodent model of diabetes, we hypothesized that higher baseline levels of endogenous gastrin prior treatment could be a predictor of beta cell function and glucoregulation in newly diagnosed DMT2 patients.

Patients and Methods: In this cross-sectional study 317 patients (116 males and 201 females) with new onset DMT2 were included. Patients treated with IPPs were excluded. Fasting plasma glucose (FPG), postprandial PG (PPG), HbA1c, fasting insulin, pancreatic B cell function (HOMA-B), insulin resistance index (HOMA-IR), c-peptide, CgA and gastrin levels were measured at the time of diagnosis, and after 6 months of follow-up.

Results: Baseline Hba1c was 7,49±2,09%, average age of patients was 62.53 ±11.33 years. 65.7% of patients were overweight and obese. Parameters of glucoregulation were not significantly correlated with gastrin (all p> 0.05), while there was moderate negative correlation with HOMA-B (HbA1c r=-.58, p<0.01, FPG r=-.62, p<0.01 and PPG r=-.33, p<0.01) and positive correlation with HOMA-IR (HbA1c r=.22, p<0.01, FPG r=.42, p<0.01 and PPG r=.25, p<0.01). After 6 months follow-up there was a significant reduction of HbA1c, FPG and PPG (all p<0.01), a significant decrease in fasting insulin level (p=0.006), while CgA and gastrin level increased (p=0.003 and p<0.001 respectively). In the stepwise regression analysis, only two independent predictors of gastrin and CgA levels emerged PPG (p=0.009) and BMI (p=0.016).

Conclusion: At the time of DMT2 onset there was no association between baseline gastrin levels and parameters of glucoregulation however after 6 months of follow-up increase in gastrin and CgA levels was observed along with the improvement of glycemic control indicating a possible relationship of gastrin levels and amelioration of beta cell function followed by metformin initiation as well as life style changes.

Disclosure

M. Cigrovski Berkovic: None. D. Herman Mahecic: None. I. Bilic-Curcic: None.
2496-PUB: Effect of Body Mass Index on HbA1c, Blood Pressure, and Cholesterol (ABC) Control in Patients with Type 2 Diabetes from Tibet in China
Authors: CHENGHUI ZHANG , MINGXIA LI , SUYUAN WANG , YUNHONG WU
Published: June 2019

Aim: To investigate the effect of body mass index (BMI) on the current control of HbA1c (A), blood pressure (B) and cholesterol(C) in patients with type 2 diabetes (T2D) from Tibet based on electronic medical records.

Methods: Patients aged 18-79 years with T2D documented from 2014 to 2018 were enrolled in this study. Control criteria were defined base on the 2017 Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes: HbA1c < 7.0%, blood pressure < 130/80mmHg and low-density lipoprotein-Cholesterol (LDL-C) < 1.8 mmol/L with coronary heart disease (CHD) and 2.6 mmol/L without CHD. Patients were divided into three groups according to BMI. One-way ANOVA and Chi-square tests were used to compare differences among groups.

Results: A total of 1999 patients were included in the study. The mean (SD) age was 55.2 (10.5) years. The median diabetic duration was 7.0 (range: 0.1-32) years and 879 (43.9%) patients were female. Among the three groups, patients with obesity had the worst metabolic profile with the highest systolic blood pressure, diastolic blood pressure and LDL-C. The achievement of ABC control has worsened in parallel with increasing BMI (Table).

Conclusions: Higher BMI was associated with lower ABC control of diabetes. More intensive weight management is warranted in this population.

Disclosure

Z. Chenghui: None. L. Mingxia: None. W. Suyuan: None. W. Yunhong: None.
25-LB: SGLT2 Inhibitors Are Renoprotective via Mitigation of Tubular Hypoxia and Protein O-GlcNAcylation
Authors: BALOGH DORA B. , HODREA JUDIT , LENART LILLA , HOSSZU ADAM , MEZEI CSENGE , WAGNER LASZLO , SZABO ATTILA J. , FEKETE ANDREA
Published: June 2019

Tubular hypoxia has a major pathogenic role in diabetic kidney disease (DKD). Hypoxia is in strong association with elevated glucose reabsorption and increased protein O-GlcNAcylation which could contribute to renal fibrosis. We recently showed that SGLT2 inhibitors (SGLT2i) are renoprotective in experimental type 1 diabetes. Considering emerging evidence of proximal tubular involvement in DKD and the major role of SGLT2 in glucose metabolism, here we investigated the direct effects of SGLT2i on hypoxia and O-GlcNAcylation.

Diabetes (D) was induced by streptozotocin in adult, male Wistar rats. Rats were treated for six weeks with dapagliflozin (D+DAPA, 1 mg/bwkg/day). Renal function and fibrosis were evaluated. The effect of hyperglycaemia was tested in human proximal tubular epithelial cells (HK-2) kept under normal glucose (5.5 mM), high glucose (35 mM) or high mannitol (osmotic control, 35 mM) conditions. HG cells were treated with 10 µM DAPA. O-GlcNAc, O GlcNAc transferase (OGT) and O GlcNAcase (OGA) were measured. To test the effect of hypoxia cells were treated with 10 µM DAPA and were placed in a hypoxic chamber for 2 hours. HIF1-α, EPO, VEGFA and PAI-1 were measured. Immunocytochemistry (ICC) of HIF1-α was performed.

DAPA improved renal function (creatinine clearance: D: 3.8±0.4 vs. D+DAPA: 8.9±1.0 mL/min; p<0.01) and decreased fibrosis. DAPA minimized hyperglycemia-induced total protein O-GlcNAcylation and OGT, while OGA was elevated in HK-2 cells. Hypoxia-induced HIF-1α elevation was suspended by DAPA treatment. Abolishment of HIF-1α upregulation by DAPA was confirmed by ICC staining. EPO, VEGFA and PAI-1 levels were also increased in hypoxia and DAPA prevented EPO and PAI-1 elevation.

Here we identified a novel mechanism of SGLT2i by which the direct reduction of tubular hypoxia and inhibition of OGT by DAPA results in decreased O-GlcNAcylation in proximal tubular cells. These processes contribute to improved renal function and alleviated kidney fibrosis.

Disclosure

D.B. Balogh: None. J. Hodrea: None. L. Lenart: None. A. Hosszu: None. C. Mezei: None. L. Wagner: None. A.J. Szabo: None. A. Fekete: None.

Funding

Hungarian Academy of Sciences (LP008/2017, OTKA-K112629-FK124491-NN-114607, VKE-2017-00006); Semmelweis University; New National Excellence Program of the Hungarian Ministry of Human Capacities (?NKP-18-3)
253-OR: Microvascular Complications in Latent Autoimmune Diabetes of Adults: Results from the UKPDS
Authors: MADDALONI ERNESTO , COLEMAN RUTH L. , HOLMAN RURY R.
Published: June 2019

Background: Latent Autoimmune Diabetes of Adults (LADA) is a mild form of autoimmune diabetes which can be identified in 3-12% of adults who have a clinical diagnosis of T2D. LADA differs in genetic and clinical features with T2D, but whether this translates into a different risk for complications remains controversial.

Aim: We examined the long-term risk of microvascular complications in the large population with a clinical diagnosis of new-onset T2D enrolled into the United Kingdom Prospective Diabetes Study (UKPDS), according to their LADA status.

Methods: Islet-cell cytoplasm, glutamic acid decarboxylase and islet antigen-2 autoantibodies (AAb) were measured in 5028 UKPDS participants at, or soon after, T2D diagnosis. Those with ≥1 detectable AAb were defined as LADA and their incidence of a composite microvascular outcome (first occurrence of renal failure, renal death or diabetic retinopathy [blindness, vitreous haemorrhage or photocoagulation]), was compared with T2D participants.

Results: There were 564 (11.2%) of participants with LADA. Compared with T2D, they were younger, with higher mean HbA1c and HDL-cholesterol, but lower body mass index (BMI), total cholesterol and systolic blood pressure (SBP) (all p<0.01). The microvascular outcome occurred in 1041 (51.3%) of UKPDS participants during median 17.3 (range: 0.1-29.9) years follow-up. A time-varying cox-model showed a lower risk of microvascular events in LADA participants during the first nine years of follow-up (HR 0.52, 95% CI 0.35-0.78, p<0.01), but a higher risk beyond nine years (HR 1.47, 95% CI 1.20-1.81, p<0.01). These HRs were unchanged after adjustment for age, HbA1c, lipids, SBP, BMI, estimated glomerular filtration rate, smoking and UKPDS treatment arm.

Conclusions: The risk of microvascular complications in LADA patients differs over time, being lower in the earlier years after diagnosis but higher in later years compared with T2D, potentially impacting on their diabetic management.

Disclosure

E. Maddaloni: Speaker's Bureau; Self; Merck & Co., Inc., Pikdare. R.L. Coleman: None. R.R. Holman: Advisory Panel; Self; Bayer AG, Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. Other Relationship; Self; AstraZeneca, Bayer AG, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.

Funding

European Foundation for the Study of Diabetes
254-LB: Induced Pluripotent Stem Cells for Type 1 Diabetes In Vitro Modeling and Immunoprotection of Beta Cells
Authors: LEITE NAYARA
Published: June 2019

Our understanding of the causes and possible treatments for type 1 diabetes (T1D) has been profoundly limited by a lack of in vitro models that recapitulate human T1D disease progression. As the foundation for such a model, we have successfully differentiated human induced pluripotent stem cells into functional β cells (hiPSC-β cells) that can reverse diabetes in mice. Herein, we propose that an in vitro platform can model human T1D using hiPSC-β cells and hypothesize that the complex immune features of human T1D can be reproduced in vitro using the hiPSC-β cells and donor-matched immune cells. In our experiments, a cell-type specific, donor-matched response against the hiPSC-β cells but not the hiPSC-α cells was achieved in vitro. Specifically, co-culturing donor-matched hiPSC-β cells and PBMCs resulted in activation of the effector cells, as assayed through cytokine secretion, induction of activation surface markers in T cells and specific killing of the hiPSC-β cells. Most importantly, we sought to determine whether the β cell killing was mediated by specific T cell receptor (TCR) engagement. We performed two experiments to test the requirement for direct TCR recognition of hiPSC-β cells in stimulating T cell activation. First, we incubated the targets β cells with an HLA-class I blocking antibody to prevent binding of T cells with the target cells and second, we used a transwell co-culture system that eliminated direct contact between the immune cells and hiPSC-β cells. Both experiments approach prevented T cell activation, thereby confirming the TCR engagement hypothesis.The developed T1D in vitro platform to measure immune responses will be used in future experiments aimed to test the ability to protect hiPSC-β cells from autoimmune attack. Collectively these data suggest that we developed a novel tool for patient-specific testing of immunoprotection strategies of the hiPSC-βcells in vitro before autologous transplantation.

Disclosure

N. Leite: None.

Funding

American Diabetes Association (1-19-PMF-024)
254-OR: Novel Biomarkers Predicting Renal Dysfunction in People with Dysglycemia in the ORIGIN Trial
Authors: GERSTEIN HERTZEL , PARE GUILLAUME , MCQUEEN MATTHEW J. , LEE SHUN FU , KANNT AIMO , HESS SIBYLLE
Published: June 2019

Diabetes is the most common cause of renal failure accounting for more than 50% of cases. Whereas HbA1c, age and albuminuria are independent risk factors for renal decline, adding novel serum biomarkers to routine clinical risk factors may help identify patients at high risk for renal decline. One ml of stored serum from 7,482 ORIGIN participants with a recorded eGFR at baseline and either the 2 year and/or final visit was assayed for 237 biomarkers using Myriad RBM’s customized human discovery multi-analyte profile 250+ panel, and hs troponin and anti-GAD biomarkers were measured locally. During a median follow-up of 6.2 years, 1,646 (22%) developed the renal outcome comprising renal failure, albuminuria regression or doubling of some creatinine. A linear mixed model using a forward selection approach was used to identify the subset of biomarkers that independently predicted a decline in eGFR after accounting for 9 clinical risk factors for renal decline including age, sex, smoking, body mass index, mean arterial pressure, log (albumin:creatinine), cholesterol, baseline eGFR and HbA1c. A Bonferroni-corrected P value for inclusion in the model of less than 0.00021 (i.e., 0.05/239) identified 13 significant and independent biomarkers that included: alpha 1 microglobulin (beta = -0.157); NT-pro BNP (beta = -0.081); IGF binding protein 4 (beta = -0.110); growth differentiation factor 15 (beta = -0.091); RAGE (beta = -0.052); myoglobin (beta = -0.073); growth regulated alpha protein (beta = 0.058); fibulin-1C (beta = -0.048); apolipoprotein A-4 (beta = -0.057); apolipoprotein A-2 (beta = 0.065); fas ligand (beta = -0.099); eotaxin E (beta = -0.052); and beta amyloid 1-40 (beta = -0.057). The addition of these selected biomarkers to the clinical variables improved the variance of the eGFR from 0.053 to 0.155 (difference in log likelihood = 849, P < 0.001). These novel biomarkers are potential therapeutic targets. They can also help identify dysglycemic people at risk for renal decline. (NCT00069784)

Disclosure

H. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Sanofi. G. Pare: Consultant; Self; Amgen Inc., Bristol-Myers Squibb Company, Lexicomp, Sanofi. Research Support; Self; Canada Research Chair in Genetic and Molecular Epidemiology, CISCO Professorship in Integrated Health Biosystems, Sanofi. M.J. McQueen: None. S. Lee: None. A. Kannt: Employee; Self; Sanofi. S. Hess: None.

Funding

Sanofi; Innovative Medicines Initiative (115974); European Union; European Federation of Pharmaceutical Industries; JDRF
255-OR: Temporal Trend in the Prevalence and Incidence of Depression and Antidepressant Usages in Incident Type 2 Diabetes from U.S. and UK
Authors: DIBATO JOHN , KOYE DIGSU , POLONSKY WILLIAM , MONTVIDA OLGA , PAUL SANJOY KETAN
Published: June 2019

Aim: Temporal trend in the prevalence and incidence of depression (DP), any mental illness (AMI) and use of anti-depressants (ADM) in incident T2DM pts is not well known. We evaluate these trends and the risk of developing DP in young pts in real world settings from U.S. and UK.

Method: Adults with diagnosis (Dx) of T2DM from 2000 from Centricity Electronic Medical Records of U.S. and The Health Improvement Network (THIN) database of UK were examined.

Results: In U.S. (n= 1,395,572)/UK (n= 343,714) cohorts, the age at T2DM Dx was 59/58 years, 2/8% had Dx of DP but were not on ADM, 16/10% were on ADM without DP or AMI Dx, 9/15% were using ADM with Dx of DP. The prevalence of DP, AMI and ADM use increased exponentially in UK since 2000 (Figure B), while an increasing prevalence in AMI and ADM use was seen in U.S. (Figure A). Between 2000-2016, the use of ADM without Dx of DP or AMI increased from 16-26%/5-41% in U.S./UK cohort. Incidence rates of DP and ADM use were significantly higher in the U.S. cohort compared to UK (Figures C and D).

Among pts without a co-morbid condition at T2DM Dx, younger U.S./UK pts (≤ 50 years) had 28%/18% significantly higher risks of developing DP compared to older pts (≥ 60 years); among pts with existing co-morbidity, the risks were higher by 46%/33%.

Conclusion: In incident T2DM pts in UK and U.S., a striking rise in the prevalence of DP and the ADP use without Dx of AMI is seen, with younger pts having higher risk of developing DP.

Disclosure

J. Dibato: None. D. Koye: None. W. Polonsky: Consultant; Self; Abbott, Bigfoot Biomedical, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Johnson & Johnson Diabetes Institute, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. O. Montvida: None. S.K. Paul: Consultant; Self; AstraZeneca, Roche Pharma. Research Support; Self; Roche Pharma.