bluuebunny/crossref_metadata_2025 huggingface dataset:
1614-P: Relationship between Out-of-Pocket Costs, Life-Course Socioeconomic Status, and Acculturation in Immigrants with Diabetes
Authors: DAWSON APRILL Z. , WALKER REBEKAH J. , EGEDE LEONARD E.
Published: June 2019

Introduction: About 9.4% of the United States (U.S.) population has diabetes. Diabetes is a prevalent and expensive disease costing more than $320 billion annually. Immigrants, about 13% of the U.S. population, often lack health insurance and pay out of pocket for healthcare. Immigrants also have cultural and other barriers to accessing healthcare that affect their ability to care for chronic diseases like diabetes. The aim of this study was to examine the relationship between life-course socioeconomic status (SES), acculturation, and out of pocket (OOP) costs among immigrants with diabetes.

Methods: Data from the New Immigrant Survey, a multi-cohort study of U.S. immigrants, was analyzed. Linear regression with OOP costs as the outcome was used to investigate the relationship between acculturation and life-course SES. Additionally, a linear regression model with acculturation as an outcome was run to understand predictors including life-course SES in immigrants with diabetes.

Results: Three hundred seventeen individuals were included in the study. The mean age was 53 years, 56% were female, and 66% had less than high-school level of education. Unadjusted models found an association between acculturation and OOP costs (β: 664.4; p<0.001), which remained significant after adjustment for age, sex, race/ethnicity, marital status, education and income (β: 663.7; p=0.008). Life-course SES was significantly associated with acculturation (β: 0.061; p=0.041) after adjusting for demographics.

Conclusions: Acculturated immigrants with diabetes have higher OOP costs compared to those who are not acculturated. Life-course SES was identified as a significant predictor of acculturation in this sample. Our findings support the idea of acculturation increasing access to care for foreign-born individuals with diabetes. Future research will examine direct and indirect relationships between life-course SES, acculturation, and diabetes outcomes in United States immigrants.

Disclosure

A.Z. Dawson: None. R.J. Walker: None. L.E. Egede: Consultant; Self; Novo Nordisk Inc. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases.

Funding

National Institutes of Health
1617-P: Serum Fatty Acid Proportions Are Associated with Development of Abnormal Glucose Metabolism in Male Japanese: Tokushima Cohort Study
Authors: HATA AKIKO , AKI NANAKO , ICHIHARA TAKAKO , TAMURA AYAKO , MINAGAWA TAKAKO , KUWAMURA YUMI , FUNAKI MAKOTO
Published: June 2019

Few prospective cohort studies have examined the association between serum fatty acid (FA) proportions and type 2 diabetes (T2D). In addition, the involvement of serum FAs in the development of early stage abnormality of glucose homeostasis remains unclear. The present study investigated the association between serum FA proportions or FA ratios, which reflect desaturase activity, and the incidence of early stage abnormal glucose metabolism before the actual onset of T2D. We here report a prospective occupational-based cohort study, which has been conducted since 2008 in Japan. A total of 396 male workers without abnormal glucose metabolism aged 20 to 60 years were followed-up prospectively (mean follow-up period: 5.9 years). Abnormal glucose metabolism was defined as either: 1) fasting plasma glucose ≥ 110 mg/dl, 2) HbA1c ≥ 6.0% or 3) medication for hyperglycemia. We evaluated serum FA proportions and the activities of ⊿5desaturase, ⊿6desaturase and ⊿9desaturase, which reflect desaturation of FAs estimated from the FA product-to-precursor ratios. In multivariate analysis after adjusting for age, BMI, smoking habit, alcohol intake, regular exercise, HDL cholesterol, triglycerides, family history of diabetes, and hypertension, the HR of developing abnormal glucose metabolism was 4.42 [95% CI: 1.81 to 10.76, P=0.001] in the highest quartile of baseline serum dihomo-γ-linolenic acid proportion, compared with the lowest quartile. In addition, the age-adjusted incidence and multivariate-adjusted HR of abnormal glucose metabolism also increased with increasing quartile of ⊿6desaturase (P for trend for both <0.01). Our findings suggest that increased serum dihomo-γ-linolenic acid proportion and enhanced activity of ⊿6desaturase are predictive markers for the development of early stage abnormal glucose metabolism in male Japanese. These results imply that altered FA metabolism may associate with early stage disorders of glucose metabolism.

Disclosure

A. Hata: None. N. Aki: None. T. Ichihara: None. A. Tamura: None. T. Minagawa: None. Y. Kuwamura: None. M. Funaki: Consultant; Self; Happy, Inc. Research Support; Self; Otsuka Holdings Co., Ltd.

Funding

Japan Ministry of Education, Culture, Sports, Science and Technology
1619-P: Risk Factors for Sleep Apnea Syndrome in Nonobese Type 2 Diabetics
Authors: KAWASAKI SATSUKI , MISAWA HARUO , KONDO TETSURI , KONDO YOSHINOBU , TERAUCHI YASUO
Published: June 2019

Diabetics often have vascular diseases and other comorbidities. Sleep apnea syndrome (SAS) is a disorder characterized by repeated episodes of apnea and hypopnea during nocturnal sleep. Risk factors for SAS include obesity, male gender, and advanced age. It was reported that type 2 diabetes patients (T2DM) without obesity often have SAS. Among the 1,367 ambulant T2DM who were being treated at our institution, 245 (165 men, 80 women) with a BMI <25kg/m2 and who agreed to undergo a portable sleep polygraph test, were evaluated to identify risk factors for SAS, focusing on micro- and macroangiopathy and stable comorbidities. The rates of retinopathy, nephropathy, carotid artery stenosis, coronary artery disease, and peripheral arterial disease were 32.2%, 45.1%, 19.3%, 39.6%, and 15.2%, respectively. The rates of intracranial lesions, respiratory diseases, cardiovascular diseases, cancer, thyroid diseases, and mental illness were 25.7%, 9.4%, 42.4%, 19.2%, 8.6%, and 4.1%, respectively. The apnea-hypopnea index (AHI) was 11.3±9.7 (mean±standard deviation) (12.1±9.9 in men, 9.8±9.1 in women). The prevalence of SAS (AHI≥15) was 25.5% in men and 18.8% in women. Carotid artery stenosis and intracranial lesions were more common among patients with SAS than among those without SAS (p<0.05 each), while no such association was found for microangiopathy. Multivariate analysis adjusting for BMI, male gender, and age identified BMI (odds ratio, 1.23; 95% confidence interval, 1.04-1.47; p<0.05) and intracranial lesions (2.93; 1.51-5.71; p<0.005) as independent risk factors for SAS. The intracranial lesions identified were stable and diverse, ranging from infarction and hemorrhage to benign brain tumor and contusion. The association of intracranial lesions with hypoxia may be related to the respiratory centers, although the underlying mechanism is unknown. T2DM with stable intracranial lesions even without obesity, should be carefully monitored for nocturnal hypoxia, particularly during emergency hospitalization.

Disclosure

S. Kawasaki: None. H. Misawa: None. T. Kondo: None. Y. Kondo: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.
162-LB: Pharmacokinetics, Pharmacodynamics, and Tolerability of Single- and Multiple-Dose of Janagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, in Chinese Patients with Type 2 Diabetes Mellitus
Authors: DING YANHUA
Published: June 2019

Objectives: Janagliflozin (JGZ) is a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor in development for the treatment of type 2 diabetes mellitus (T2DM). This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of JGZ in Chinese patients with T2DM.

Methods: In this double-blind, parallel-controlled study, 36 patients with inadequately controlled T2DM were randomized into JGZ 25 mg, JGZ 50 mg, dapagliflozin 10 mg, or placebo cohort in a 1:1:1:1 ratio. Patients were treated with a single dose on Day 1, and then once daily from Day 4 to Day 17.

Results: JGZ was readily absorbed with Cmax observed at 2.00 hours (median). The half-life was estimated to be 21.2-23.3 hours at steady state. Plasma JGZ exposure increased in a dose-proportional manner and the accumulation rates were relatively low in Cmax (1.46-1.49) and AUC0-24 (1.67-1.81). Mean (SD) changes from baseline in 24 hour urinary glucose excretion (UGE) were 72.8 (26.2), 78.7 (17.3), 85.8 (25.2), and 2.20 (7.22) g after single dose, and were 92.4 (25.4), 94.2 (29.1), 87.6 (32.2), and 6.26 (24.3) g after multiple doses with JGZ 25 mg, JGZ 50 mg, dapagliflozin 10 mg, and placebo, respectively. Mean (SD) changes from baseline in fasting plasma glucose on Day 17 were 2.18 (1.62), 2.66 (2.01), 2.79 (1.44), and 1.70 (2.04) mmol/L for the four groups, respectively. Mean (SD) changes from baseline in A1C on Day 18 were 0.45% (0.29%), 0.33% (0.57%), 0.62% (0.35%), and 0.07% (0.80%) for the four groups, respectively. Adverse events were mostly mild or moderate with no hypoglycemia episode, serious adverse event, or discontinuation due to adverse event.

Conclusions: JGZ exhibited favorable pharmacokinetics profiles in Chinese patients with T2DM and was well tolerated. JGZ treatments resulted in increase in UGE and improvement in glycemic control. JGZ 25 mg and 50 mg are recommended for further clinical studies.

Disclosure

Y. Ding: None.

Funding

XuanZhu Pharma Co., Ltd.
1624-P: Changes in Childhood Adiposity and Adolescent Testosterone in the EPOCH (Exploring Perinatal Outcomes among Children) Study
Authors: KIM CATHERINE , HARRALL KYLIE K. , GLUECK DEBORAH H. , DABELEA DANA
Published: June 2019

Whether changes in visceral adipose tissue (VAT) in childhood predict adolescent androgens is not known. We examined the longitudinal relationship between MRI-assessed visceral adipose tissue (VAT) in childhood and future testosterone (T) among 418 EPOCH participants (209 girls and 209 boys) who were, on average 10.5 years at visit 1 and 16.7 years at visit 2. We used reverse Cox proportional hazards models in which hazard ratios less than 1 indicate greater risk for low (undetectable) sex hormones consistent with pre-puberty. Models explored the associations of baseline VAT, and change in VAT from visit 1 to visit 2, with risk of low sex hormone levels at visit 2, adjusted for covariates selected through backwards regression (race, self-reported Tanner stage, maternal income, insulin and leptin levels). All analyses were stratified by sex. In addition, due to different patterns of fat deposition in white and non-white adults, we tested for effect modification by race. In boys, the association between VAT at visit 1 and T at visit 2 differed by race; more VAT at visit 1 was associated with lower risk of low T at visit 2 among non-white boys (HR 1.02, 95% CI 1.007, 1.04) but not white boys (HR 1.00, 95% CI 0.98, 1.01). In contrast, greater fat accumulation between visits was associated with higher risk of low T at visit 2 (HR 0.90, 95% CI 0.83, 0.96), independent of race and other covariates. Among girls, neither baseline VAT levels, nor VAT accumulation between visits predicted risk of later low T concentrations. We conclude that greater VAT accumulation in childhood is associated with increased risk for low T levels, suggesting delayed puberty, in boys. These associations suggest that fat deposition may influence sex hormone profiles even in early childhood.

Disclosure

C. Kim: None. K.K. Harrall: None. D.H. Glueck: None. D. Dabelea: None.

Funding

National Institutes of Health
1632-P: Trends in Obesity and Medical Expenditure among Women with Diabetes, 2008-2016: Differences by Race/Ethnicity
Authors: WILLIAMS JONI S. , NAGAVALLY SNEHA , EGEDE LEONARD E.
Published: June 2019

Background: Obesity results in significant morbidity, preventable mortality, and increased medical expenditures among women with diabetes. The aim of this study was to examine racial/ethnic differences in obesity trends and medical expenditures among a nationally representative sample of women with diabetes.

Methods: Nine years of data (2008-2016) from the Medical Expenditure Panel Survey (MEPS) Full Year Consolidated File were used for the analyses. Cochran-Armitage tests were used to determine statistical significance of trends in obesity and mean expenditure for women with diabetes. Two-part statistical modeling with a combination of binomial and positive distributions was used to evaluate differences in medical expenditure. Data were clustered to 3 time points: 2008-2010, 2011-2013, 2014-2016. BMI levels were classified as underweight (<18.5), normal (≥18.5 - 24.9, overweight (≥25.0 - 29.9), and obese (≥30.0 - 134.7). Analyses were weighted for the U.S. population.

Results: Cochran-Armitage tests showed trends in obesity from 2008 to 2016 differed significantly between Hispanic and Non-Hispanic white (NHW) women with diabetes (p=0.01). Among obese women, trends in mean medical expenditures differed significantly between Hispanic (p<0.001), non-Hispanic black (NHB) (p<0.001), and other (p<0.001) women with diabetes compared to NHW women with diabetes. Two-part modeling showed obese Hispanic (-0.66 (-0.87, -0.42)) and NHB (-0.33 (-059, -0.01)) women with diabetes were significantly less likely to spend on healthcare compared to NHW women with diabetes; however, among those with expenditure, Hispanic women spent 30% less ($4520.81) and NHB women spent 17% less ($2555.72) compared to NHW women with diabetes.

Conclusions: These findings suggest further understanding of the factors associated with differences in trends for obesity between Hispanic and NHW women with diabetes and medical expenditures among obese minority and NHW women with diabetes.

Disclosure

J.S. Williams: None. S. Nagavally: None. L.E. Egede: Consultant; Self; Novo Nordisk Inc. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases.

Funding

National Institutes of Health
1646-P: The Impact of a Diabetes Codiagnosis on Hospitalisation and Mortality in Patients with Malignancy
Authors: KIBURG KATERINA V. , WARD GLENN , STEELE KATHLEEN M. , MULROONEY ELIZABETH M. , LOH MARGARET M. , MCLACHLAN SUE-ANNE , SUNDARARAJAN VIJAYA , MACISAAC RICHARD
Published: June 2019

Objective: To document the characteristics and outcomes for patients with malignancies with or without diabetes at a tertiary referral hospital.

Research Design and Methods: Emergency department and hospital discharge data between 1 Jan 2015 and 31 Dec 2017 were used to identify patients with a diagnosis of a malignancy and diabetes. Multivariate Cox-regression models were used to estimate the effect of diabetes on all-cause mortality. A truncated negative binomial regression model was used to assess the impact of diabetes on length of hospital inpatient stay. Prentice, Williams and Peterson Total Time (PWP-TT) models were used to assess the effect of diabetes on number of Emergency Department presentations and inpatient admissions. Results are presented as incidence-rate ratios (IRR) or hazard ratios (HR). These models were adjusted for age, gender, type of malignancy and Charlson comorbidities.

Results: For 7,058 patients identified with malignancies, 1,230(17.4%) were also diagnosed with diabetes. During the three-year study period a diagnosis of diabetes was associated with an increased number of inpatient admissions (adjusted Hazard Ratio (adjHR): 1.14, 95% CI: 1.04, 1.25), increased number of emergency department presentations (adjHR: 1.19, 95% CI: 1.11, 1.28) and length of stay for patients with diabetes (adjIRR: 1.16, 95% C.I: 1.06, 1.28). A co-diagnosis of diabetes was also associated with a 48% increased risk of all-cause mortality (adjHR 1.48, 95% CI: 1.23-1.77).

Conclusions: Patients with diabetes had significantly higher numbers of emergency department presentations, inpatient admissions, length of hospital stay and higher rates of all-cause mortality compared to cancer patients without diabetes. This adverse link between diabetes and health outcomes in patients with malignancies requires further exploration.

Disclosure

K.V. Kiburg: None. G. Ward: None. K.M. Steele: None. E.M. Mulrooney: None. M.M. Loh: None. S. McLachlan: None. V. Sundararajan: None. R. MacIsaac: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. Other Relationship; Self; AstraZeneca, Novo Nordisk Inc.

Funding

Australian Government Research Training Program (to K.V.K.)
165-LB: The SGLT2 Inhibitor Canagliflozin Prevents Increased Lipid Oxidation in the Heart following High-Fat Feeding
Authors: FLORES ITZEL , SHANNON CHRIS , FOURCAUDOT MARCEL , BAKEWELL TERRY , NORTON LUKE
Published: June 2019

Patients with type 2 diabetes (T2DM) are at increased risk for developing cardiovascular disease (CVD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are antidiabetic agents that significantly reduce the risk of acute myocardial infarction, stroke and CV death in patients with T2DM. However, the physiologic, metabolic and molecular mechanism of this cardioprotective effect are unclear. Given our preliminary and published findings, we hypothesized that SGLT2i may regulate mitochondrial function in the heart to improve cardiac function in the context of obesity and T2DM. We treated high-fat diet (HFD)-fed mice with canagliflozin (CANA; 10 mg/kg/day) for 1-week, and examined mitochondrial function in the heart, as well as in skeletal muscle, kidney and liver. Glucose tolerance tests were performed before and after treatment, and blood was collected at the end of the study to quantitate plasma lipids and ketones. Isolated mitochondria were provided with either pyruvate/malate (P/M) or palmitoylcarnitine/malate (PC/M) in the absence or presence of ADP to analyze basal and state III respiration. The CANA treatment prevented HFD-induced glucose intolerance independent of changes in body weight or free fatty acids (FFA), but significantly increased plasma ketones. The HFD markedly increased ATP-linked oxidation of PC/M in cardiac mitochondria, which was completely prevented by short-term CANA treatment. Canagliflozin did not affect pyruvate oxidation in the heart and had no effect on mitochondrial function in the other tissues tested. These data suggest that SGT2i may improve cardiovascular health through primary effects on mitochondrial metabolism. Further studies are needed to relate these metabolic effects of SGLT2i to improved cardiac function in vivo.

Disclosure

I. Flores: None. C. Shannon: None. M. Fourcaudot: None. T. Bakewell: None. L. Norton: None.
1671-P: Comorbid Autoimmune Disease in Participants at Risk for Type 1 Diabetes
Authors: SIMMONS KIMBER , GEYER SUSAN , WHERRETT DIANE K. , ISMAIL HEBA M. , LUNDGREN MARKUS , BOCCHINO LAURA E. , SOSENKO JAY M. , GREENBAUM CARLA , STECK ANDREA
Published: June 2019

People with type 1 diabetes (T1D) are at increased risk for comorbid autoimmune disease (CAID). The TrialNet Pathway to Prevention (PTP) Study screens relatives of people with T1D for islet autoantibodies (Ab) to determine T1D risk. PTP Ab+ participants self-reported (Y vs. N) whether or not they had CAIDs at the start of monitoring. Outside of celiac disease, CAID has not been examined in Ab+ participants. Of the 5,740 Ab+ participants, 586 (10.2%; 95% CI: 9.4 - 11.0%) reported having a CAID. Of those with a single confirmed Ab+, GADA+ participants had a higher prevalence of CAID (230/1709=13.5%) vs. those who were IA-2A+ (8/88=9.1%) or mIAA+ (40/592=6.8%; p<0.0001). Across all Ab+ participants, the number of Abs was inversely associated with prevalence of CAID at baseline, where a higher number of Abs corresponded to a lower likelihood of CAID (1 Ab+: 278/2393=11.6%; 2 Ab+: 165/1388=11.9%; 3 Ab+: 73/891=8.2%; 4 Ab+: 44/687=6.4%; 5 Ab+: 26/381=6.8%; p<0.0001). The most prevalent CAID reported was thyroid disease (5.7%) with celiac disease reported in 1.3%. The influence of HLA status on CAID prevalence was mixed; celiac disease was more prevalent in those with DR3 (OR=2.79, p<0.0001) while thyroid disease was less prevalent in those with DR4/DQ8 (OR=0.61, p<0.0001). Although being single confirmed Ab+ at screening was associated with a higher likelihood of having CAID in the univariate setting, it was significantly protective (OR=0.77; p=0.007) when adjusting for age, sex and HLA status. In multivariable logistic regression models, the prevalence of CAID at baseline was associated with older age, being female and HLA DR4/DQ8 negative.

In conclusion, the reported prevalence rates of CAID is high in Ab+ relatives of people with T1D, inversely correlated with the number of Ab present, and related to DR3 and DR4/DQ8 haplotypes. The change in the direction of association of CAID with Ab number after an adjustment for HLA status suggests that DR3 and DR4/DQ8 could contribute to both CAID and Ab development.

Disclosure

K. Simmons: None. S. Geyer: None. D.K. Wherrett: None. H.M. Ismail: None. M. Lundgren: None. L.E. Bocchino: None. J.M. Sosenko: None. C. Greenbaum: Research Support; Self; Janssen Research & Development. A. Steck: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK0855095, K12DK094712-08)
1674-P: Age of Onset Is Associated with Insulin Resistance in Patients with Type 1 Diabetes Mellitus
Authors: YANG DAIZHI , WEI XUEYING , WANG CHAOFAN , ZHENG XUEYING , LUO SIHUI , LIN QIONGYAN , YAN JINHUA , WENG JIANPING
Published: June 2019

Objective: Data are limited on insulin resistance (IR) status in patients with type 1 diabetes (T1D). This study aimed to assess the IR status and the effect of onset age on IR in patients with T1D.

Methods: Through the Guangdong T1D registry study, we identified adult patients (aged≥18 years) with a diabetes duration≥1 year. Clinical data were collected. A previously established model based on euglycemic-hyperinsulinemic clamp were used to calculate the estimated glucose disposal rate (eGDR) via clinical parameters. Participants were categorized into groups based on age of onset: childhood-onset group (cT1D, age of onset<12 years); adolescent-onset group (pT1D, age of onset 12-17 years); and adult-onset group (aT1D, age at onset ≥18 years). Spearman correlation was used to analyze the correlation between IR and age of onset. ANOVA and Chi square test were used for comparisons of IR status and clinical parameters among the three groups.

Results: This analysis included 872 adults with T1D (58.3% female). The mean (SD) eGDR was 8.98 (3.34) mg/kg/min. There was a negative correlation between the level of IR status and the onset age (r=-0.093, p=0.003). The IR status assessed by eGDR decreased alongside an increase in age of onset (p=0.018). Compared with participants with older age of onset, patients in cT1D group had a higher level of A1c, lower proportion of participants with A1c less than 7%, higher daily insulin dose and higher frequency of hypoglycemic events (all p<0.05).

Conclusions: Age of onset was significantly and negatively correlated with IR status. Childhood-onset patients with T1D are more likely to benefit from treatment of IR condition.

Disclosure

D. Yang: None. C. Wang: None. X. Zheng: None. S. Luo: None. Q. Lin: None. J. Yan: None. J. Weng: None.
1675-P: Does Intensification of Insulin Therapy Lead to Increased Body Fat among Youth and Young Adults with Type 1 Diabetes (T1D)?
Authors: MAYER-DAVIS ELIZABETH , REBOUSSIN BETH A. , PIHOKER CATHERINE , KAHKOSKA ANNA R. , DABELEA DANA , DOLAN LAWRENCE M. , JENSEN ELIZABETH T. , IGUDESMAN DARIA , LAWRENCE JEAN M. , SAYDAH SHARON , WADWA R. PAUL ,   FOR THE SEARCH FOR DIABETES IN YOUTH STUDY GROUP
Published: June 2019

Intensive insulin therapy may have the unintended consequence of increased adiposity, contributing to the high prevalence of overweight and obesity in people with T1D.

We examined the longitudinal association of insulin intensification with estimated body fat percentage (eBFP) among 746 individuals with T1D (age 10-21 years at initial visit) in the SEARCH for Diabetes in Youth study.

eBFP was calculated using validated, published sex and race/ethnic specific formulae incorporating age and anthropometrics. Insulin intensification was defined as more intense, less intense or no change, in which “more intense” was an increased number of injections or addition of long-acting insulin, or a change from injections to an insulin pump. Sex-specific, linear mixed effects models used continuous eBFP at each available visit (baseline, and 1-4 follow-up visits; median T1D duration at the last visit, 8 years). Interaction terms between time and insulin intensification relative to change in eBFP tested the study hypothesis.

Mean diagnosis age was 12.7 years ± 2.5, 47% were female, 80% non-Hispanic white. At baseline, mean BMIz score was 0.51 ± 0.93, with 32% overweight or with obesity. Although BMIz and weight status did not differ by sex, eBFP was significantly higher in females compared to males (32.4% ± 5.3 and 25.3% ± 5.9 respectively; p<0.0001). After adjustment for age at diagnosis, study site, and sociodemographic factors, there was a statistically significant increase in eBFP over time for females (4.8% over the median duration of 8 years) and a statistically significant decrease for males (1.6% over the median duration of 8 years). For females, this increase was 2.2% greater over the median duration of 8 years for more intense compared to less intense therapy (p=0.0009). Rates of change in eBFP did not depend on insulin intensification for males (p=0.09). Further work may determine metabolic and behavioral drivers of this unintended increase in eBFP, particularly among females with T1D.

Disclosure

E. Mayer-Davis: None. B.A. Reboussin: None. C. Pihoker: None. A.R. Kahkoska: None. D. Dabelea: None. L.M. Dolan: None. E.T. Jensen: None. D. Igudesman: None. J.M. Lawrence: None. S. Saydah: None. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Beta Bionics, MannKind Corporation, Novo Nordisk Inc., Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Other Relationship; Self; Dexcom, Inc.

Funding

Centers for Disease Control and Prevention; National Institutes of Health
1696-P: PBMC of Recent-Onset Patients with Type 1 Diabetes Present a Differential Gene Expression Profile
Authors: SANTOS ARITANIA , CHEVILLARD CHRISTOPHE , GONFINETTI NELSON , BERTONHA FERNANDA , MOREIRA-FILHO CARLOS , KALIL JORGE , CUNHA-NETO EDECIO , SILVA MARIA ELIZABETH
Published: June 2019

Introduction: Type 1 diabetes is characterized by the autoimmune destruction of insulin-secreting β-cells, mediated by T auto reactive infiltrating cells, inflammatory cytokines and immunological mechanisms. However, little is known about the expression of genes and pathways dysregulated in peripheral blood mononuclear cells of patients with T1D.

Objective: to investigate the gene expression profiles of circulating PBMC in recent-onset T1D patients (up to 6 months of diagnosis) in comparison with controls in the context of putative disease-related pathobiological processes and pathways.

Methods: expression of mRNA from PBMC of 20 T1D patients, 15.8±8.6 years and age-matched 20 healthy controls, 14.7±6.7 years, (p>0.05) was evaluated with the Whole Human Genome Microarray Agilent and analyzed by GeneSpring with a fold change cutoff of 1.5 and adjusted P value <0.05; pathways analysis was performed with the software IPA.

Results: 326 genes were differentially expressed between T1D patients and controls, being 204 (63%) upregulated, and 122 (37%) downregulated in T1D. Interactions between the differentially expressed genes evidenced expression patterns of 24 networks. The most significantly enriched canonical pathways were namely ErbB (erythroblastic leukemia viral oncogene) signaling, micropinocytosis signaling, savage pathways of pyrimidine ribonucleotides and hepathocyte growth factor in descending order of significance. The up-regulated protein targets within these signaling pathways were NEK2, PLK1, ATM, PRKCD, CCND1, NRG2 and those down regulated were AREG, CDC42 and CDADC1.

Conclusion: The majority of upregulated genes of patients with T1D was related to cell cycle control, mitotic progression, proliferation and DNA repair, probably related to changes in PBMC metabolism and function due to DNA damage associated with hyperglycemia. The lower expression of AREG and CDC42 can be related to reduce immunosuppressive activity of regulatory T cells and B cell functions.

Disclosure

A. Santos: None. C. Chevillard: None. N. Gonfinetti: None. F. Bertonha: None. C. Moreira-Filho: None. J. Kalil: None. E. Cunha-Neto: None. M. Silva: None.

Funding

European Foundation for the Study of Diabetes; São Paulo Research Foundation
1698-P: Integrative Genomics Analysis Reveals Tissue-Specific Pathways and Gene Networks for Type 1 Diabetes
Authors: BLENCOWE MONTGOMERY , SALEEM ZARA , YANG XIA
Published: June 2019

Type 1 diabetes (T1D) is a complex disease involving genetic predisposition that interacts with environmental triggers, leading to the loss of insulin producing beta cells. However, the molecular cascades underlying T1D are poorly understood. We hypothesize that genetic risk factors of T1D perturb tissue-specific biological pathways and gene networks, ultimately leading to the pathogenic end point in beta cells. We sought to identify the gene networks and key regulators for T1D by conducting a comprehensive, data-driven multi-omics analysis that integrates human genome-wide association studies (GWAS) of T1D, tissue-specific genetic regulation of gene expression in the form of expression quantitative trait loci (eQTLs), and tissue-specific gene network models using a computational pipeline Mergeomics. Our analysis revealed immune pathways such as adaptive immune system, cytokines and inflammatory response, primary immunodeficiency and immunoregulatory interactions between a Lymphoid and non-Lymphoid cell, across various tissues as well as tissue-specific signals such as regulation of complement cascade, class B/2 (Secretin family receptors) and neuroactive ligand-receptor interaction. Our integrative genomics approach offers comprehensive insights into the tissue-specific molecular networks and regulators underlying T1D.

Disclosure

M. Blencowe: None. Z. Saleem: None. X. Yang: None.

Funding

National Institutes of Health (R01DK104363)
17-LB: Prognostic Value of Gamma-Glutamyl Transferase Variability in Individuals with Diabetes: A Nationwide Population-Based Study
Authors: LEE DA YOUNG , YU JI HEE , HAN KYUNGDO , SEO JI A , KIM NAN HEE
Published: June 2019

Objective: We investigated whether gamma-glutamyltransferase (GGT) variability can predict the risk of stroke, myocardial infarction (MI), and all-cause mortality in individuals with diabetes.

Methods: The study subjects were Koreans with diabetes who had undergone health examinations provided by the Korean National Health Insurance Corporation more than once during 2009-2012 (baseline). After excluding subjects aged <40 years and those with histories of stroke, MI, chronic liver disease, or drinking ≥30g/day of alcohol, a total 698937 individuals were included. As a parameter of variability, we calculated the average successive variability (ASV) of GGT values measured during the five years before the baseline exam. We estimated the risk of stroke, MI, all-cause mortality according to GGT ASV quartiles using multivariate-adjusted Cox analyses, until December 31, 2016. Stroke and MI was defined using ICD-10 codes (I63-I64 and I21-I22) and admission record.

Results: During follow-up period, 26119 cases of stroke, 15103 cases of MI, and 39982 cases of death were identified. GGT ASV quartile showed significantly higher risk of stroke and all-cause mortality compared with quartile 1, even after adjustment for age, sex, renal function, obesity, drinking, smoking, exercise, presence of hypertension and dyslipidemia, hemoglobin, income status, glucose and GGT level, duration of diabetes, the number of histories of oral antidiabetic medication, prescription history of insulin, presence of diabetic retinopathy and peripheral artery disease. The fully adjusted HRs (95% CIs) of GGT ASV quartiles 4 were 1.06 (1.03-1.10) and 1.23 (1.20-1.27), respectively. This significance was maintained regardless of baseline GGT quartile in all-cause mortality.

Conclusions: GGT variability was associated with the risk of all-cause mortality and stroke. This tendency is most pronounced in all-cause mortality, regardless of baseline GGT levels.

Disclosure

D. Lee: None. J. Yu: None. K. Han: None. J. Seo: None. N. Kim: None.

Funding

National Research Foundation of Korea
17-OR: Efficacy and Safety of Chiglitazar, a Novel PPARα/γ/d Pan-Agonist, in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Superiority Trial (CMAP)
Authors: JI LINONG , SONG WEIHONG , FANG HUI , LI WEI , GENG JIANLIN , XU YAN CHENG , WANG YANGANG , GUO LIAN , CAI HANQING , YANG TAO , LI HONG-MEI , YANG GANGYI , LI QIFU , LIU KUANZHI , LI SHUYING , LIU YANJUN , SHI FUYAN , LI XIN SHENG , GAO XIN , JI QIUHE , TIAN HAOMING , SU QING , ZHOU ZHIGUANG , WANG WENBO , ZHOU ZUNHAI , LI XUEJUN , XU YAN CHENG , NING ZHIQIANG , LU XIANPING , JIA WEIPING
Published: June 2019

Chiglitazar showed favorable effect on glycemic control and lipid modulation with well tolerated safety profile in phase 2 trials. This trial aimed to further compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes inadequately controlled with lifestyle interventions (ClinicalTrials.gov NCT02121717). Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or placebo once daily. After 24-week treatment, patients in placebo group were randomly assigned to receive chiglitazar 32 mg or 48 mg, while others remained on the planned treatment till to 52 weeks. The primary endpoint was change in HbA1c at week 24 with superiority of each chiglitazar dose versus placebo. Analysis was done in all randomized patients who received at least one dose of study drug (n= 535). Chiglitazar was superior to placebo in HbA1c reduction at 24 weeks (LS mean difference -0.87% [95% CI -1.10 to -0.65] and -1.05% [95% CI -1.29 to -0.81] for 32 mg and 48 mg, respectively) and achieved sustainable effect till to 52 weeks. Overall adverse events were comparable across groups. The incidences of weight gain, edema, and hypoglycemia were relatively higher in chiglitazar groups. Chiglitazar showed superior and sustainable HbA1c lowering effect with well tolerated safety profile in patients with type 2 diabetes.

Disclosure

L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. W. Song: None. H. Fang: None. W. Li: None. J. Geng: None. Y. Xu: None. Y. Wang: None. L. Guo: None. H. Cai: None. T. Yang: None. H. Li: None. G. Yang: None. Q. Li: None. K. Liu: None. S. Li: None. Y. Liu: None. F. Shi: None. X. Li: None. X. Gao: None. Q. Ji: None. H. Tian: None. Q. Su: None. Z. Zhou: None. W. Wang: None. Z. Zhou: None. X. Li: None. Y. Xu: None. Z. Ning: None. X. Lu: None. W. Jia: None.

Funding

Ministry of Science and Technology of the People´s Republic of China (2013ZX09401301)
1702-P: Fine-Scale Haplotype Mapping of PPM1K Gene Reveals New Genetic Markers for the Study of Insulin Resistance at Clinical Scale
Authors: HAYDAR SARA , LAUTIER CORINNE , GRIGORESCU FLORIN
Published: June 2019

Branched chain amino acids (BCAA) plasma levels represent potential biomarkers for development of type 2 diabetes (T2D). Mendelian randomization and prospective studies indicated causal relationship between SNPs in PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) gene (Chr 4q22.1) and increased risk of incident T2D while other studies, including ours suggested the contribution of MUT (metylmalonyl-CoA mutase) gene (Chr 6p12.3) in insulin resistance (IR). To define genetic markers we performed fine-scale haplotype mapping of PPM1K in two populations (French and Romanians) with metabolic syndrome (n = 465). SNPs were genotyped with Affymetrix and enriched by imputation at 1000 genome density (BEAGLE 4.1). Haplotype association was performed by sliding window (4 SNPs windowing) and analyzed in HAPLOVIEW and PHASE 2.1. Previous leader SNPs in PPM1K (rs7678928 and rs1440581) were not associated with IR in our population but haplotype mapping revealed two major signals downstream (GGGC) and upstream (ACAG), centered by rs71609524 and rs4423843 with P < 3.76 x 10-3 (OR 1.59, 95% CI [1.13 - 2.23]) and < 4.72x10-3 (OR 1.50, 95% CI [1.12 - 2.01]), respectively. Values were weaker that those from MUT gene (P-value of the most significant haplotype, centered by rs2167284 was < 10-5). Total BCAA plasma levels were associated with PPM1K by several SNPs, including rs7656367 and rs4693955 with P < 5 x 10-3, OR of 0.41 and 3.22, respectively. Interestingly, correlation trend test with leucine, isoleucine and valine were better correlated with SNPs in the MUT gene: rs10948396 was associated with P < 7.91 x 10-5 (Bonferroni 6 x 10-2) and confirmed by correlation with total BCAA levels (P < 1.60 x 10-6, Bonferroni 1.22 x 10-3). These data suggest synergistic effects and indicate that new valuable genetic markers can be defined for clinical trials using fine-scale haplotype mapping, thus revealing complex relationship between genes in the determinism of IR and BCAA metabolism.

Disclosure

S. Haydar: None. C. Lautier: None. F. Grigorescu: None.

Funding

MEDIGENE (FP7-279171)
172-OR: Perfusion Controls Insulin-Stimulated Glucose Uptake in Skeletal Muscle by Altering the Rate of Glucose Dispersion In Vivo
Authors: MCCLATCHEY PENN MASON , WILLIAMS IAN M. , MIGNEMI NICHOLAS A. , HUGHEY CURTIS C. , MCGUINNESS OWEN P. , BECKMAN JOSHUA A. , WASSERMAN DAVID
Published: June 2019

Objective: It has been proposed that the microcirculation contributes to insulin-stimulated muscle glucose uptake (MGU) by recruiting capillaries and thus enhancing the dispersion of insulin from capillaries into interstitium. This theory contrasts with intravital microscopy (IVM) measurements showing near-complete capillary recruitment at baseline, and it does not address the possibility that dispersion of glucose, rather than insulin, could limit MGU. This study tests the hypotheses that perfusion effects on MGU are 1) capillary recruitment-independent and 2) critical more so for the interstitial dispersion of glucose, rather than insulin.

Methods: In one experiment, microvascular perfusion was measured using IVM before and after intravenous insulin injections. In a second experiment, mice were treated with vasoactive drugs. Microvascular perfusion, dispersion of fluorophores approximating insulin size (10 kDa dextran) and glucose (2-NBDG), and muscle accumulation of a radioactive glucose analogue (phospho-2[14C]DG) were measured.

Results: The first experiment showed ∼95% recruitment of capillaries before insulin with no recruitment following insulin. In the second experiment, perfusion-limited delivery indices (calculated from capillary blood flow and its distribution) and 2-NBDG dispersion, but not diffusion-limited delivery indices (calculated from perfused surface area and permeability) or 10 kDa dextran dispersion, predicted phospho-2[14C]DG accumulation.

Conclusions: These findings show that the role of perfusion in insulin-stimulated MGU is mediated by blood flow rather than capillary recruitment, and that the rate of glucose dispersion into the interstitium overrides insulin dispersion as a determinant of muscle insulin sensitivity in vivo.

Disclosure

P.M. McClatchey: None. I.M. Williams: None. N.A. Mignemi: None. C.C. Hughey: None. O.P. McGuinness: None. J.A. Beckman: Consultant; Self; AstraZeneca, Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; Bayer AG, Novartis AG. D. Wasserman: None.

Funding

National Institutes of Health (DK059637, DK054902, DK050277, T32DK101003, F32DK120104, P30DK020593); American Heart Association
1732-P: ERK1 and ERK2 Are Required for Lipopolysaccharide-Induced Production of Cytokines and Chemokines by Macrophages
Authors: CHANG PHOEBE F. , REYNA SARA M.
Published: June 2019

Low-grade chronic inflammation may be a factor in the development of insulin resistance. Studies suggest that chronic inflammation may be due in part to changes in composition and function of gut microflora, which provide an intestinal barrier preventing bacterial lipopolysaccharide (LPS) release. Animal and human studies demonstrate that obesity increases gut permeability leading to elevated plasma LPS levels resulting in inflammation and metabolic dysfunction. We hypothesized that insulin resistance could be produced by inflammatory factors secreted by macrophages when exposed to gut-released LPS. We examined the extracellular signal-regulated kinase (ERK) signaling pathway, which may be responsible for the macrophage inflammatory response. We examined whether inhibition of ERK activity blocked LPS-mediated responses in bone marrow derived macrophages (BMDM). To determine which ERK isoform is involved in the regulation of inflammatory factor production, we used siRNA to knockdown ERK1, ERK2, or both. BMDM were treated with LPS (100 ng/ml, 6hr). LPS induced TNF-α, RANTES, MCP-1, and IFN-β production of 106371±18250 pg/ml, 11827 ± 1168 pg/ml, 851 ± 73 pg/ml, and 454 ± 46 pg/ml, respectively. Knockdown of ERK1 decreased the release of TNF-α and RANTES to 26534 ± 1471 pg/ml and 5938 ± 806 pg/ml, respectively. Knockdown of ERK2 decreased the release of TNF-α and RANTES to 11600±3610 pg/ml and 7289 ± 265 pg/ml, respectively. Knockdown of either ERK1 or ERK2 did not decrease the release of MCP-1 and IFN-β. However, double knockdown of ERK1 and ERK2 had the greatest inhibition of TNF-α, RANTES, MCP-1, and IFN-β release (not detected, 1540 ± 240 pg/ml, 549 ± 32 pg/ml, and 31 ± 1 pg/ml, respectively).

In summary, knockdown of both ERK isoforms is necessary to completely abrogate the LPS effect in macrophages. We propose that ERK positively regulates LPS-mediated inflammatory responses and inhibition of ERK signaling may protect against development of insulin resistance.

Disclosure

P.F. Chang: None. S.M. Reyna: None.

Funding

National Institutes of Health; University of Texas Rio Grande Valley
1733-P: Cross Talk between Palmitate and LPS Leads to a Synergistic IL-6 Production in Human Monocytic Cells: Implications for Metabolic Inflammation
Authors: AHMAD RASHEED , KOSHY MERIN SERA , KOCHUMON SHIHAB PUTHIYAVEETTIL , THOMAS REEBY SARA , AL-MULLA FAHD
Published: June 2019

IL-6 concentrations are positively correlated with the level of obesity and associated proinflammatory state that promotes the development of insulin resistance. The metabolic stimuli that regulate IL-6 production has not been fully revealed. Since metabolic concentrations of plasma LPS and palmitate (free fatty acid) are increased in obesity and are considered as potent inducers of IL-6. Therefore, we have examined whether interaction of palmitate with LPS trigger the production of IL-6 in human monocytic cells. THP-1 and primary human monocytic cells incubated with palmitate and LPS together produced more biological active IL-6 compared to monocytes incubated with palmitate or LPS alone. Synergistic IL-6 induction was blocked either by silencing the expression of TLR4 or MyD88. However, IRF3 did not have impact on this synergism. Non-metabolizable analog as well as specific metabolic pathway inhibitors of palmitate showed that esterification of palmitate with coenzyme A (CoA) involved, in part, in this synergism. Furthermore, synergistic upregulation of IL-6 was suppressed by histone acetyltransferase inhibitor (anacardic acid). Histone deacetylase (HDAC) inhibitor (sodium butyrate) enhanced IL-6 production.

In conclusion, our results show that an interaction between palmitate and LPS depends on TLR4/MyD88, lipid metabolism and epigenetic signaling pathways, which leads to the elevation of IL-6, providing interesting pathophysiological connections among FFAs, LPS, and IL-6 in settings such as obesity or metabolic inflammation.

Disclosure

R. Ahmad: None. M.S. Koshy: None. S.P. Kochumon: None. R.S. Thomas: None. F. Al-Mulla: None.

Funding

Kuwait Foundation for the Advancement of Science
1734-P: A Considerable Mismatch of Measurements between Radioimmunoassay and Enzyme-Linked Immunosorbent Assay Tests for Anti-Glutamic Acid Decarboxylase Antibody
Authors: OIKAWA YOICHI , KONDO TAKUMA , SHIMADA AKIRA , SEINO YUTAKA , KITAOKA MASAFUMI
Published: June 2019

Most cases of type 1 diabetes mellitus are considered to be caused by pancreatic β-cell destruction through islet cell autoimmunity. Anti-glutamic acid decarboxylase antibody (GADA) is an important islet cell-associated autoantibody in the diagnosis of autoimmune type 1 diabetes mellitus. In Japan, the GADA assay kit was changed from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA) in 2015. Thereafter, a mismatch of measurements between the two tests became apparent in clinical situations. The aim of this study was to clarify the extent of the mismatch between the two tests on a larger scale. In this cross-sectional non-local/non-hospital-based study, we collected anonymized data on GADA levels of 598 randomly selected participants in whom GADA levels were simultaneously measured by GADA-RIA and GADA-ELISA tests. We found that 34% (= 162/477) of the GADA-RIA-positive participants showed negative results in the GADA-ELISA test; the mismatch was predominantly observed in participants with relatively low GADA-RIA levels. Concretely, when considering lower GADA-RIA levels alone (1.5-32 U/mL), GADA-ELISA-negative participants accounted for 44.8% (= 162/362) of the GADA-RIA-positive participants. These findings suggest that a single application of the GADA-ELISA test may affect the precise diagnosis of type 1 diabetes mellitus, and cause physicians’ confusion on the diagnosis. Therefore, the cause for the mismatch should be promptly identified.

Disclosure

Y. Oikawa: None. T. Kondo: None. A. Shimada: Advisory Panel; Self; Terumo Medical Corporation. Speaker's Bureau; Self; Abbott, Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Y. Seino: Research Support; Self; Arkray, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. M. Kitaoka: Research Support; Self; AstraZeneca, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd.