bluuebunny/crossref_metadata_2025 huggingface dataset:
1665-P: Fracture Risk in Patients Using Sodium-Glucose Cotransporter 2 Inhibitors: A Real-World Study
Authors: ABRAHAMI DEVIN , DOUROS ANTONIOS , YIN HUI , YUN YU ORIANA HOI , AZOULAY LAURENT
Published: June 2019

There are concerns that sodium-glucose co-transporter 2 inhibitors (SGLT2Is) may increase the risk of fractures in patients with type 2 diabetes. To date, large cardiovascular outcome trials have generated conflicting findings, and few real-world studies have been conducted to assess this association. As fracture risk in this vulnerable population is associated with increased mortality, there is an urgent need to address this safety issue using real-world data. Thus, the objective of this population-based cohort study is to determine if use of SGLT2Is is associated with an increased fracture risk in patients with type 2 diabetes. Using the UK Clinical Practice Research Datalink, a large primary care database, we identified a cohort of patients newly treated with antihyperglycemic drugs between January 2013 and December 2017. Use of SGLT2Is was modeled as a time-varying exposure and compared with use of dipeptidyl peptidase-4 inhibitors (DPP-4Is). Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs of incident fractures associated with use of SGLT2Is overall and according to specific SGLT2Is (dapagliflozin, empagliflozin, canagliflozin). We conducted several sensitivity analyses to address potential sources of bias. The cohort included 73,178 patients, which generated 153,179 person-years of observation. During follow-up, 1,973 patients were newly diagnosed with fractures (incidence rate: 12.9/1000 per year). Compared with DPP-4Is, SGLT2Is were not associated with an increased risk of fracture (HR: 0.97, 95% CI: 0.79-1.19). Similar findings were observed when stratifying on specific SGLT2Is, with HRs ranging between 0.67 and 1.42, with all CIs including the null value. The sensitivity analyses yielded highly consistent findings. The results of this large population-based study suggest that use of SGLT2Is is not associated with fracture incidence. This finding should provide reassurance on the safety of this class of drugs.

Disclosure

D. Abrahami: None. A. Douros: None. H. Yin: None. O. Yu: None. L. Azoulay: None.

Funding

Canadian Institutes of Health Research
167-LB: Cost Optimization of Dorzagliatin Using Artificial Intelligence-Powered Population Modeling
Authors: BENNETT BRITTANY , ALLEN SYDNEY , EILERMAN BRADLEY , TESTA LEONARD J.
Published: June 2019

Introduction: Consideration of the role of new therapeutic agents has taken new dimensions in light of emerging cardiovascular and renal data in addition to consideration of total cost of care. Simulated decision made through Artificial Intelligence systems such as GlucosePATH can be used to determine the fit of new compounds to treating type 2 diabetes. Glucokinase activators are not available as therapeutic agents in the U.S.A. Phase 3 data of dorzagliatin was used to model projected retail cost in the current environment.

Methods: A data set of 366 patients with HbA1c > 7 was drawn from a distribution of patients from the GlucosePATH database. Total monthly cost of care was computed based on the mean retail cost drawn from the GoodRX API. Using scores drawn from GlucosePATH, drugs were redistributed to find the lowest total cost at which the population's score was > 70 out of 100. Total retail cost of care averaged $371.39 per month per patient for the 366 patients. Redistributed medication at this price generated a mean composite score of 80.36 at a projected mean HbA1c of 7.5.

Two price points were established for dorzagliatin. The "maximal price" (MP) is the highest price at which use of the agent in the population does not exceed the control group’s retail cost of care and the composite score threshold is met. (That is, introducing the new agent does not increase cost or worsen results for the population.) The "maximal revenue" (MR) is the price at which the agent’s manufacturer maximizes their gross revenue for the agent in the population.

Results: Price optimization for dorzagliatin showed a MP of approximately $145. At its MP, dorzagliatin would be prescribed to approximately 5% of the population with mean composite score of 80.17 and mean HbA1c 7.5. At dorzagliatin’s MR of approximately $75 per month, it would be prescribed to approximately 23% of the population and generate a mean composite score of 80.54 with a mean HbA1c of 7.5.

Disclosure

B. Bennett: None. S. Allen: None. B. Eilerman: Advisory Panel; Self; Dexcom, Inc., Medtronic. Speaker’s Bureau; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Corcept Therapeutics, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Stock/Shareholder; Self; PATH Decision Support Software LLC. L.J. Testa: Stock/Shareholder; Self; PATH Decision Support Software LLC.
1677-P: Ethnic Differences in the Peri-diagnostic Period of Type 1 Diabetes (T1D)
Authors: TOSUR MUSTAFA , CLEVES MARIO A. , SOSENKO JAY , LIBMAN INGRID , BAIDAL DAVID , REDONDO MARIA JOSE
Published: June 2019

We have previously shown that Hispanic ethnicity influences progression to T1D with interaction by obesity in children < 12 years of age. In this study, we aimed to compare ethnicities for characteristics in the peri-diagnostic period of T1D. We studied participants in TrialNet New Onset Intervention Trials (n=501, 9.4% Hispanics, 86.4% non-Hispanic whites [NHW], 4.2% non-Hispanic other) followed prospectively. We analyzed clinical, immunological and metabolic characteristics in the peri-diagnostic period of T1D. Mixed meal tolerance tests (MMTT) were performed within 6 months (median: 2 months, range: 4 days - 6 months) following diagnosis and then every 5-6 months in the first 3 years after diagnosis. Race and ethnicity categories were based on self-report and on standard NIH classifications. Unless otherwise indicated, all analyses were adjusted for age, age and sex-adjusted BMI Z-score, sex, as well as days from diagnosis to MMTT. Median ages (IQR) at enrollment were 14.1(6) years in Hispanics and 14.3(7.5) years in NHW. 44.7% of Hispanics and 41.8% of NHW were female. At T1D clinical diagnosis, Hispanics, compared with NHW, had a higher frequency of diabetic ketoacidosis [DKA] (42.9% vs. 22.8%, OR=2.45, p=0.008), lower fasting glucose (97.5 vs. 108.5 mg/dL, p=0.011), higher frequency of ZnT8 autoantibody positivity (n=201, 94.1% vs. 63.5%, p=0.039), and a trend for higher fasting C-peptide (0.39 vs. 0.32 ng/mL, p=0.093). When analyzing C-peptide trajectories by ethnicity in eligible participants (n=310), there were no significant differences during 3-year follow-up after adjusting for BMI-Z score and age (mean C-peptide AUC, p=0.74).

In conclusion, despite ethnic differences in the frequency of DKA, and metabolic and immunological characteristics at clinical diagnosis of T1D, C-peptide trajectories did not differ in the first 3 years following diagnosis between Hispanics and NHW. These findings may inform the design of observational studies and intervention trials in the peri-diagnostic period of T1D.

Disclosure

M. Tosur: None. M.A. Cleves: None. J. Sosenko: None. I. Libman: Consultant; Self; Novo Nordisk Inc. D. Baidal: None. M.J. Redondo: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
1684-P: Using Index60 to Detect Heterogeneity and Identify Subpopulations with Characteristic Type 1 Diabetes (T1D) Profiles among Individuals with Normal Two-Hour Glucose Levels
Authors: NATHAN BRANDON M. , GEYER SUSAN , BOCCHINO LAURA E. , PALMER JERRY P. , JACOBSEN LAURA M. , REDONDO MARIA JOSE , SIMS EMILY K. , SKYLER JAY S. , SOSENKO JAY M.
Published: June 2019

We assessed whether Index60 could identify subpopulations with heterogeneous T1D features among autoantibody positive (Ab+) individuals with a normal 2-hour glucose. Index60 is a composite measure of fasting C-peptide, 60-minute C-peptide, and 60-minute glucose that has potential utility as a prediabetes endpoint when values are ≥1.00. Baseline 2-hour OGTTs of Ab+ TrialNet Pathway to Prevention participants in the normal 2-hour glucose (<140 mg/dl) range and low Index60 range (<1.00) were studied. The top 2-hour glucose <140 mg/dl quartile was compared with the top Index60 <1.00 quartile for characteristic T1D features (groups mutually exclusive).

Those in the top Index60 quartile (Group B) or in both top quartiles (Group C) had profiles more typical of T1D than those in the top 2-hour glucose quartile (Group A), who had higher C-peptide levels, lower Ab+ frequencies, and were older (Table).

Also, as indicated by within group odds ratios, Group A had less association of DR3-DQ2/DR4-DQ8 with the top quartile (Group A: 1.19, ns; Group B: 1.49, p<0.01; Group C: 1.63, p<0.01).

In summary, Index60 can detect heterogeneity among those with normal 2-hour glucose levels, and identify subpopulations with appreciably more characteristic T1D features. The atypia of Group A demonstrates the importance of this Index60 utility.

Disclosure

B.M. Nathan: None. S. Geyer: None. L.E. Bocchino: None. J.P. Palmer: None. L.M. Jacobsen: None. M.J. Redondo: None. E.K. Sims: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Applied Therapeutics, Dance Biopharm Holdings Inc., Orgenesis Ltd., Tolerion, Inc., Viacyte, Inc. Board Member; Self; Dexcom, Inc., Intarcia Therapeutics, Inc., Moerae Matrix, Inc. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dalcor, Dialogics, Elcelyx Therapeutics, Inc., Esperion, GeNeuro Innovation, Ideal Life, Immunomolecular Therapeutics, Intrexon, Kamada, Nestlé, Sanofi, Valeritas, Inc., Zafgen, Inc. Stock/Shareholder; Self; Dexcom, Inc., Ideal Life, Intarcia Therapeutics, Inc., Intrexon, Moerae Matrix, Inc. J.M. Sosenko: None.

Funding

National Institutes of Health; JDRF
1685-P: Type 1 Diabetes Mellitus and Incident Bladder Cancer: A Systematic Review and Meta-analysis
Authors: OSKOUI HELENA B. , BOGUMIL DAVID D. , KYSH LYNN , BARRETT MALCOLM , SIEGMUND KIMBERLY , CORTESSIS VICTORIA K.
Published: June 2019

Background: A credible body of epidemiologic evidence documents elevated bladder cancer risk among patients with type 2 diabetes, but risk among those with type 1 diabetes (T1DM) has received less attention. We sought to identify and quantitatively synthesize epidemiologic data on the association between T1DM and incident bladder cancer.

Methods: We searched Medline, Embase, Cochrane, and Web of Science through June 5, 2018, to identify non-redundant English language reports of original human data estimating the association between T1DM and incident bladder cancer addressing age as potential confounder. Additional citations were identified through hand searching efforts including a Google Scholar search, contacting authors, and retrieving citations in selected studies. Candidate reports were critically appraised by two independent reviewers, with conflicts resolved by consensus. Harmonized estimates of the T1DM-bladder cancer association were extracted from qualifying reports and synthesized by random effects meta-analysis.

Findings: Among 7,673 reports identified in the search, 59 warranted critical full text review, and 4 described 7 non-redundant studies satisfying inclusion criteria (N=362 T1DM patients). Estimate of the overall summary odds ratio association was 1.07 (95% CI: 0.87-1.32; I2: 69.1%, p heterogeneity= 0.001; 7 studies). Gender-specific summary estimates were 1.40 (95% CI: 0.95-2.05; I2: 73.9%, p heterogeneity= 0.002; 6 studies) for females, and 0.95 (95% CI: 0.71-1.26; I2: 61.4%, p heterogeneity= 0.024; 6 studies) for males.

Interpretation: Available data reveal a modest positive association between incident bladder cancer and T1DM that does not achieve statistical significance. Etiologic interpretation is precluded by indicators of heterogeneity and design limitations of contributing studies, primarily confounding by smoking and error in measurement of diabetes in referent groups.

Disclosure

H.B. Oskoui: None. D.D. Bogumil: None. L. Kysh: None. M. Barrett: None. K. Siegmund: None. V.K. Cortessis: None.
1686-P: Lifetime Exposure to Diabetic Ketoacidosis Is Associated with Impaired Executive Function among Older Adults with Type 1 Diabetes: The Study of Longevity in Diabetes
Authors: LEIGH MARY E.LACY. , GILSANZ PAOLA , BEERI MICHAL S. , KARTER ANDREW J. , QUESENBERRY CHARLES , WHITMER RACHEL A.
Published: June 2019

Background: Diabetic ketoacidosis (DKA) is a life-threatening complication common in type 1 diabetes (T1D). DKA is associated with short-term cognitive impairment in children and adolescents with T1D, but it is unknown if a lifetime history of DKA is associated with poorer cognition in older adults.

Methods: We examined the association between self-reported frequency of lifetime DKA hospitalizations and cognition in 720 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Cognitive tests assessed 4 cognitive domains identified via factor analysis (language, executive function, episodic memory, attention). We examined: 1) the association between DKA and cognitive domains using adjusted linear regression; and 2) frequency of cognitive impairment (1.5 SD below mean) by DKA exposure.

Results: Overall, 28% of participants reported DKA resulting in hospitalization in their lifetime (18% had 1 hospitalization; 10% had 2+ hospitalizations). Compared to those with no DKA hospitalizations, those with 2+ had lower executive function scores and were more likely to have impaired executive function. Language, episodic memory and simple attention did not differ by DKA.

Conclusions: In older adults with T1D, lifetime exposure to DKA is associated with long-term impairment in cognition, specifically through executive function.

Disclosure

M.E.L. Leigh: None. P. Gilsanz: None. M.S. Beeri: None. A.J. Karter: None. C. Quesenberry: None. R.A. Whitmer: None.

Funding

National Institutes of Health (R01AG047500, T32AG049663, R01DK103721, R01DK081796, P30DK092924); Patient-Centered Outcomes Research Institute (PPRN-1306-04709)
1691-P: A Variant in the Melanocortin-4 Receptor (MC4R) Locus Is Associated with Glycemic Control and Insulin Resistance (IR) in Type 1 Diabetes (T1D)
Authors: MILLER RACHEL G. , COSTACOU TINA , ONENGUT-GUMUSCU SUNA , CHEN WEI-MIN , RICH STEPHEN S. , ORCHARD TREVOR J.
Published: June 2019

The MC4R gene (18q21.32) plays a role in regulating appetite and energy homeostasis and is consistently linked with obesity. A variant near MC4R (rs12970134) has also been associated with IR and type 2 diabetes, independent of BMI. We examined the association of rs12970134 with HbA1c, IR, and BMI in the Pittsburgh Epidemiology of Diabetes Complications study, a prospective T1D cohort (mean age 27, T1D duration 18 years at baseline, 1986-88). In 422 EDC participants of European ancestry with available DNA, we assessed associations between 16 published IR SNPs, including rs12970134, and longitudinal measures of HbA1c, estimated glucose disposal rate (eGDR, an inverse measure of IR), and BMI over 18 years of follow-up (1986-88 to 2004-06). General additive mixed models were adjusted for sex, T1D duration, and principal components of ancestry. The rs12970134 SNP was associated with longitudinal HbA1c (β=0.33, p=5x10-5, see Figure) and eGDR (β=-0.31, p=0.008) trajectories, but not BMI (β=0.21, p=0.38). The associations remained significant after adjusting for BMI and insulin dose. There was no evidence for a SNP x time interaction (p>0.25 for both); all groups showed a similar fall in HbA1c after publication of the DCCT results. Thus, the rs12970134 SNP near MC4R is associated with glycemic control and insulin resistance, despite no association with BMI, in this T1D cohort.

Disclosure

R.G. Miller: None. T. Costacou: None. S. Onengut-Gumuscu: None. W. Chen: None. S.S. Rich: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH.

Funding

National Institutes of Health; Rossi Memorial Fund; JDRF
1694-P: A New Developmental Model of Type 1 Diabetes—An Association between Autoimmunity, the Dynamics of Gut Amyloid-Producing E. Coli, and Their Phages
Authors: TETZ GEORGE
Published: June 2019

Background: The increase in incidence of type 1 diabetes (T1D) is not solely a result of genetics and environmental factors, but also that of gut microbiota, which play a crucial role in disease onset.

Methods: We performed a longitudinal microbiome analysis (Illumina Hiseq2500) in children (0-3 years) with HLA-susceptibility to T1D, using an algorithm focusing on amyloid producing bacteria. This analysis revealed an overlooked association between autoimmunity and the dynamics of gut amyloid-producing E. coli.

Results: Our analysis revealed a statistically significant association between the development of autoantibodies in T1D HLA-susceptible children and (i) significantly (p<0.05) high initial (0-12 months of age) abundance of gut amyloid-producing E. coli, (ii) depletion of E. coli prior to seroconversion due to prophage induction, and (iii) triggering of islet autoimmunity and T1D development. Notably, alterations in E. coli abundance were identified only in children who further developed seroconversion and T1D. E. coli depletion was found before the appearance of antibodies, suggesting a role of E. coli in disease onset. Further, our in vitro study revealed a highly immunogenic complex (amyloid curli-DNA composites) released from E. coli biofilms upon prophage induction, which triggered the production of type I IFN through the TLR2/9 stimulation of β-cells and DCs, and autoimmune cascade through the TLR-2-MyD88-NF-kB pathway.

Conclusions: Our study suggests that E. coli biofilm-derived highly immunogenic amyloid curly-DNA complexes might be involved in the activation of a pro-diabetic pathway in children who are at a risk of T1D. Besides, amyloid protein producing E. coli and their phages are the factors associated with T1D development that were previously overlooked.

Disclosure

G. Tetz: None.
170-OR: Tamoxifen Treatment Causes Insulin Resistance in Obese Mice
Authors: SCALZO REBECCA L. , HULL SARA E. , REUSCH JANE E.B. , MACLEAN PAUL , WELLBERG ELIZABETH
Published: June 2019

Breast cancer survivors treated with the selective estrogen receptor modulator tamoxifen have an elevated risk for developing type 2 diabetes (T2D) compared with cancer-free individuals, especially in the context of obesity. Half of T2D diagnoses in breast cancer survivors are attributable to the cancer therapy itself. The underlying mechanisms of tamoxifen-induced T2D are unknown. We hypothesized that the detrimental impact of tamoxifen on insulin sensitivity was mediated by changes in the liver and skeletal muscle, and was exacerbated by high fat diet (HFD). Ovariectomized female mice supplemented with estradiol were randomized to low fat diet (LFD), LFD + tamoxifen, HFD, or HFD + tamoxifen. In general, our preclinical model recapitulated the observations from epidemiological studies on breast cancer survivors. HFD + tamoxifen mice had greater body fat percentage and fasting glucose (P < 0.02 for the HFD-Tamoxifen interaction). The HFD + tamoxifen mice developed insulin resistance determined by HOMA-IR (P < 0.01) and tended towards impaired glucose tolerance measured by glucose AUC from a glucose tolerance test (P = 0.1). In the liver of HFD-fed mice, tamoxifen resulted in greater accumulation of triacylglycerol (P = 0.01) which correlated positively with HOMA-IR (R2= 0.4; P < 0.001). Gastrocnemius citrate synthase activity was elevated with tamoxifen treatment independent of diet, as was phosphorylation of AMP-activated kinase (P < 0.05). HFD + tamoxifen mice had lower content of muscle mitochondrial complex II (P = 0.05) and complex V (P = 0.1). These data suggest that the potential mechanisms underlying tamoxifen-induced T2D is ectopic hepatic fat accumulation and lowered skeletal muscle mitochondrial content. Importantly, this study reveals a difference in response to tamoxifen between lean and obese females. Future studies will explore interventions that can be combined with tamoxifen to prevent hepatosteatosis and protect skeletal muscle mitochondria with the goal of reducing T2D in breast cancer survivors.

Disclosure

R.L. Scalzo: None. S.E. Hull: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck & Co., Inc. P. MacLean: Advisory Panel; Self; Habit LLC. E. Wellberg: None.

Funding

Susan G. Komen Foundation; National Institutes of Health
1700-P: Association between Genetic Variation and Age of Onset of HNF1A MODY from the Expression Genetic Standpoint
Authors: SEWERYN MICHAL , LUDWIG-SLOMCZYNSKA AGNIESZKA , KIEC-WILK BEATA M. , KAPUSTA PRZEMYSłAW , SKUPIEN JAN , MALECKI MACIEJ , WOLKOW PAWEL P. , KLUPA TOMASZ ,   NEMO COLLABORATORS
Published: June 2019

HNF1A MODY is characterized by wide variability of the age of clinical manifestation. The aim of this study was to identify genes which expression would correlate with age of HNF1A-MODY onset in the skeletal muscle, adipose tissue, liver, pancreas, pituitary gland, colon and small intestine. 837 patients were used for GWAS on age of HNF1A-MODY onset. Data were imputed on MIS. All modeling and statistics was done in R and python. The 'PrediXcan' and related datasets were downloaded from the GitHub repository. Co-expression matrices, Spearman's correlation matrices, were estimated via the function 'cor' in R. We have imputed the genetic component of expression using the PrediXcan software. Two genes were associated with age of onset - RP11-535M15.2 in visceral adipose and C2CD4C in colon. Variants in RP11-535M15.2 were associated in the Roslin Gene Atlas PheWAS with metabolic traits and in C2CD4C with T2DM and the development of the pancreas in multiple studies. Using the inferred expression values we also build co-expression matrices (Spearman's correlation) and inferred that in early onset MODY3 (as compared to late onset) HNF1A targets are more tightly co-expressed. Examples of most significantly deregulated pairs of genes are: SUOX (sulfite oxidase) and MNAT1 (CDK-activating kinase assembly factor 1) in small intestine, HIVEP1 (transcription factor) and KCNH6 (potassium channel) in pituitary gland. All four genes have been previously reported to be associated with diabetes (either in genetic or expression studies).

In conclusion, the use of expression genetics may enhance the agnostic analysis of GWAS result and add biological likelihood to the results of association studies.

Disclosure

M. Seweryn: None. A. Ludwig-Slomczynska: None. B.M. Kiec-Wilk: None. P. Kapusta: None. J. Skupien: None. M. Malecki: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Bioton, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi-Aventis. Speaker’s Bureau; Self; Merck & Co., Inc. P.P. Wolkow: None. T. Klupa: Advisory Panel; Self; Abbott, AstraZeneca, Bioton, Lilly Diabetes, Novo Nordisk A/S. Employee; Spouse/Partner; Ascensia Diabetes Care. Other Relationship; Self; Ascensia Diabetes Care, Boehringer Ingelheim Pharmaceuticals, Inc., Medtronic MiniMed, Inc.

Funding

European Foundation for the Study of Diabetes
1703-P: Altered DNA-Methylation Modulates Adipose Tissue Gene Expression and Is Associated with Insulin Resistance in African Americans
Authors: SHARMA NEERAJ K. , COMEAU MARY E. , LANGEFELD CARL D. , DAS SWAPAN K.
Published: June 2019

Altered DNA-methylation has a well-documented mechanistic role in modulating gene expression. However, its contribution in modulating adipose tissue gene expression and insulin sensitivity (SI) in African Americans (AAs) is unknown. To understand the role of differential DNA methylation in determining SI we selected 12 insulin resistant (IR) and 12 insulin sensitive (IS) individuals from a cohort 253 nondiabetic AAs. IR and IS individuals were selected from the extremes of the distribution of SI (1.49±0.69 vs. 8.23±4.48), and expression levels of insulin resistance-associated transcripts in AAGMEx cohort. Reduced representation bisulfite sequencing (RRBS; >30M read) was used to quantify epigenome-wide DNA methylation levels in adipose DNA samples. To determine differentially methylated sites (DMS) linear regressions adjusting for age and sex were used to test for DMS at 774,095 CpG sites (≥ 10X coverage) passing quality control. We identified 8387 hypermethylated and 2532 hypomethylated autosomal DMS in IR individuals (mean methylation difference ≥5% and genomic control corrected-p ≤0.05). Among these DMS, 6414 were annotated to exon, intron or promoter regions of 3923 genes. Highest number of DMS (22, including 20 hypermethylated (5.5-30.2%) DMS) were annotated to PRDM16, a transcription co-factor critical for the development of brown adipocytes. We merged the DMS 3923 genes with 663 differentially expressed transcripts (GC-p≤0.05 and fold change ≥1.2) and identified 123 IR-associated genes with DMS. Genes containing hypermethylated CpG sites and downregulated expression in IR were enriched for long-chain fatty-acyl-CoA biosynthetic process (B-H p=0.0013, includes ELOVL6, ACSF2, ACOT2, FASN, and TECR), and mitochondrion (B-H p=0.0016, 14 genes).

In summary, differential DNA-methylation of a subset of genes in adipose tissue modulate expression of transcripts in key biological pathways and may determine insulin sensitivity.

Disclosure

N.K. Sharma: None. M.E. Comeau: None. C.D. Langefeld: None. S.K. Das: None.

Funding

American Diabetes Association (1-18-ICTS-113 to S.K.D.); National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases
1719-P: Plasma Glucose Response to Oral Dexamethasone Predicts Incident Prediabetes in Normoglycemic Offspring of Parents with Type 2 Diabetes
Authors: NYENWE EBENEZER , UMEKWE NKIRU A. , JAMES DEIRDRE J. , ARIGANJOYE FOLABI , WAN JIM Y. , DAGOGO-JACK SAMUEL
Published: June 2019

Background: Dexamethasone (dex) challenge was used historically to diagnose chemical diabetes. Here we determined its utility in predicting prediabetes in a biracial cohort.

Methods: We studied 190 euglycemic subjects with parental type 2 diabetes. After a baseline 75-gram OGTT, subjects ingested 2 mg dex at 10 PM and returned at 8AM for measurement of plasma cortisol and glucose. Subjects were followed quarterly for incident prediabetes for 5 years. Serial assessments included OGTT, insulin secretion (IVGTT), and insulin sensitivity (euglycemic clamp).

Results: Table 1 shows baseline characteristics and response to dex. Progressors to prediabetes had a higher glycemic response to dex than nonprogressors (<0.0001). In a regression model, post-dex fasting glucose level remained a significant predictor of Incident prediabetes after controlling for age, weight, waist, and baseline glucose (P<0.001). From ROC analysis, fasting plasma glucose ≥110 mg/dL after dex predicted incident prediabetes with 80% sensitivity and 60% specificity.

Conclusion: Glycemic response to 2mg dex predicts incident prediabetes and could be useful for stratification and selection of high-risk subjects for lifestyle intervention.

Table 1: Baseline demographic and glucoregulatory characteristics of subjects who developed prediabetes compared to those who remained normoglycemic.

Disclosure

E. Nyenwe: None. N.A. Umekwe: None. D.J. James: None. F. Ariganjoye: None. J.Y. Wan: None. S. Dagogo-Jack: Board Member; Self; Jana Care Inc. Consultant; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Stock/Shareholder; Self; Dance Biopharm Holdings Inc.

Funding

American Diabetes Association (7-07-MN-13 to S.D-J.); National Institutes of Health
172-LB: Phone-Based Management by a PharmD May Improve Glycemic Control More Than Endocrinology Care Alone
Authors: RUBIN DANIEL J. , WU JINGWEI , PATEL DEVANSHI , HAJARI UNNATI , BARROS MICHAEL
Published: June 2019

Clinical inertia is a widespread reason for suboptimal control of patients with diabetes (DM). One approach to addressing clinical inertia is to include non-physician providers in DM management. Evidence suggests that intervention by pharmacists improves glycemic control more than usual care. There is little data, however, on the effect of pharmacist care delivered by phone as an adjunct to DM care provided by an Endocrinologist. We conducted a retrospective analysis to assess the effect of phone-based DM management by a Doctor of Pharmacy (PharmD) on glycemic control among patients seen by an Endocrinologist.

Between 02/2018-12/2018, 65 adult DM patients were referred by their Endocrinologists to a PharmD for phone intervention at an urban academic medical center. The intervention included medication reconciliation, education on medication self-administration, coordination with pharmacies to dispense medications, and adjustment of DM medications. A total of 41 patients (INT) received 1+ intervention phone call (median [iQR] 3 [2-5] calls), and 24 patients (NoINT) were referred but could not be contacted (n=20) or required no intervention (n=4). At baseline, all INT patients and 96% of NoINT patients were on insulin, 41% and 21% were on a GLP-1RA, and 56% and 46% were on oral medication(s). In the INT group, mean A1C decreased significantly 1.9 ± 2.2% from 10.2 ± 2.4% before the first call to 8.3 ± 1.7% (p<0.0001) after the first call (mean 90.5 ± 50.8 days). In the NoINT group, mean A1C decreased nonsignificantly 0.7 ± 2.1% from 9.2 ± 2.4% to 8.5 ± 2.3% (p=0.123) after the first call attempt (mean 82.3 ± 42.7 days). The INT group had a significantly greater reduction in A1C than the NoINT group (1.2%, p=0.031, 2-sample t-test).

Phone-based DM management of Endocrinology patients by a PharmD may lead to better glycemic control than management by an Endocrinologist alone. These data should encourage the conduct of an RCT to test this promising strategy for addressing clinical inertia in DM patients.

Disclosure

D.J. Rubin: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. J. Wu: None. D. Patel: None. U. Hajari: None. M. Barros: None.
1723-P: Genetic Risk Scores Predict Glycemic Traits and Response to Glipizide Treatment in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)
Authors: LI JOSEPHINE H. , SZCZERBINSKI LUKASZ , KAUR VARINDERPAL , TODD JENNIFER , FLOREZ JOSE C.
Published: June 2019

Whether genetics can help predict response to type 2 diabetes (T2D) drugs is unknown. We set out to examine whether genetic risk scores (GRSs) composed of single nucleotide polymorphisms (SNPs) known to be associated with glycemic traits and T2D are associated with glycemic traits and the acute response to metformin and glipizide in SUGAR-MGH. We measured plasma glucose, insulin, glucagon, proinsulin, c-peptide, GLP-1, and GIP levels in 1,000 participants naïve to antidiabetes medications at 0, 30, 60, 90, 120, 180, and 240 minutes following administration of 5 mg glipizide (Visit 1, day 1), and during a 75-g oral glucose tolerance test following a short metformin course (Visit 2, day 8). We constructed a T2D, fasting glucose (FG), and fasting insulin (FI) GRS (with 65, 43 and 13 SNPs respectively) by summing the number of risk alleles carried by each person based on known genome-wide significant associations. Linear regression tested for associations between GRSs and glycemic traits as well as pharmacodynamic endpoints, adjusting for age, sex, race, and BMI. The FG GRS predicted FG in our cohort (β=0.46 increase in FG in mg/dL*allele, P<0.001). The FI GRS predicted fasting insulin (β=0.02 increase in ln FI in µU/mL*allele, P=0.04). A higher T2D GRS was associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough (P<0.05) after glipizide administration, indicating a stronger response. When we set a more stringent P-value of 0.008 to correct for multiple comparisons, the FG GRS remained associated with FG and the T2D GRS remained associated with the insulin-based endpoint. We conclude that established genetic determinants of glycemic traits predict FG and FI in our cohort of individuals free of overt diabetes; moreover, T2D risk alleles may predispose individuals to a greater insulin response to glipizide treatment.

Disclosure

J.H. Li: None. L. Szczerbinski: None. V. Kaur: None. J. Todd: None. J.C. Florez: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK-088214, R03DK-077675, P30-DK-036836); Joslin Clinical Research Center; Harvard Catalyst; National Center for Research Resources/National Center for Advancing Translational Sciences (M01-RR-01066, 1UL1-RR-025758-04, 88UL1-TR-000170-05; Harvard University
1725-P: Hsa-circ-000094 in Peripheral Blood Can Be Used as a Biomarker for the Diagnosis of Type 2 Diabetes
Authors: ZHU CHAOYU , WEI LI , XIAO YUANYUAN
Published: June 2019

Objective: To investigate the differential expression of circRNAs in human blood, as a diagnostic marker for type 2 diabetes mellitus (T2DM) and to explore the mechanism of action of circRNA on miRNA and its target genes.

Methods: Circular RNA microarrays were performed to identify T2DM-related circRNAs. qPCR assays were performed to detect circRNA expression pattern in clinical samples. TargetScan and miRBase program was used to predict circRNA/miRNA interaction. Dual luciferase reporter gene assay to detect the mechanism of action of circRNA on miRNA.A total of 1,439 up-regulated expressed circRNAs were found in microarray analysis. Nine of the carcRNAs were selected by qPCR in pre-research.Blood collected from normal people(NC, N=20), prediabetes(pre-DM, n=20) and T2DM(DM, N=20) for qPCR test.

Results: The results showed that the difference expression of hsa-circ-000094 among the nine circRNAs were the most obvious in the three groups, the area under the maximum curve was found by ROC curve analysis, Spre-DM =0.8025 (95% CI, 0.6655-0.9395, p=0.001); ST2DM=0.77(95% CI,0.624-0.916, p=0.003). In order to verify the clinical diagnostic ability of hsa-circ-000094, the sample were expanded to 60 in each three groups. The results showed that the expression of hsa-circ-000094 in the three groups were different, the difference and ROC curve analysis were statistically significant, Spre-DM =0.6733 (95% CI, 0.5757-0.7710, P<0.001);ST2DM=0.7231 (95% CI,0.6327-0.8134, P<0.001). The results of Dual luciferase reporter gene assay showed that the fluorescence activity was reduced by about 40% after transfection of hsa-circ-000094 WT and hsa-miR-370-5p mimic into cells. It suggests that hsa-circ-000094 acted as miR-370 sponge to inhabit miR-370 activity.

Conclusions: CircRNAs are involved in T2DM pathogenesis, and thus serve as a potential biomarkers of T2DM diagnosis.

Disclosure

C. Zhu: None. L. Wei: None. Y. Xiao: None.

Funding

National Natural Science Foundation of China (81500615)
1726-P: MDA5, a Janus-Faced dsRNA Sensor in Coxsackievirus-Accelerated Autoimmune Diabetes
Authors: BLUM SAMUEL I. , CHEN YI-GUANG , TSE HUBERT M.
Published: June 2019

While microbial infections can trigger type 1 diabetes (T1D), innate immune activation and the synthesis of free radicals, proinflammatory cytokines, and type 1 interferons contribute to pancreatic β-cell destruction. We previously demonstrated that Coxsackievirus B3 (CB3) infection of Non-Obese Diabetic (NOD) mice can accelerate T1D, partly due to the induction of antiviral signaling pathways including melanoma differentiation-associated protein 5 (MDA5). Single-nucleotide polymorphisms within Ifih1, the gene encoding for MDA5, is associated with multiple autoimmune diseases including T1D, but the molecular mechanism contributing to innate immune dysregulation is not known. Since T1D is a chronic proinflammatory autoimmune disease involving MDA5, we hypothesized that attenuated MDA5 expression and signaling can delay diabetogenic viral-accelerated T1D. We generated NOD mice mutated in Ifih1 that exhibited a delay in spontaneous T1D due to the loss of MDA5 expression (NOD.Ifih1-m1) or an in-frame deletion in the helicase domain that decreased MDA5 synthesis (NOD.Ifih1-m4). Interestingly, CB3-infected NOD and NOD.Ifih1-m1 mice displayed virus-accelerated T1D, but NOD.Ifih1-m4 (n=9 per group) mice were significantly (p < 0.001) delayed. CB3-infected NOD.Ifih1-m4 mice exhibited a 5-fold decrease in IFN-β synthesis in the pancreas, the reduction in inflammation may be a driving factor to prevent the induction of autoimmunity. The Ifih1-m4 mutation did not compromise pancreatic viral clearance, and this was complemented by a ∼34% and ∼32% reduction in pancreas-infiltrating CD8 T cells and activated macrophages (F4/80+, I-Ag7+), respectively, in comparison to CB3-infected NOD mice. The protective Ifih1-m4 mutation may establish an acute level of type 1 interferons and islet-infiltrating lymphocytes to sufficiently inhibit CB3 replication without mediating bystander activation of autoreactive T cells, preventing virus-accelerated autoimmune diabetes.

Disclosure

S.I. Blum: None. Y. Chen: None. H.M. Tse: None.

Funding

American Diabetes Association (7-12-CD-11 to H.M.T.)
1728-P: Inhibition of PKC-Theta in Prediabetic NOD Mice Prevents Diabetes Onset and Increases Regulatory CD4 T Cells in a Subset of Animals
Authors: DILISIO JAMES E. , MISHKIN NOAH , PODELL BRENDAN
Published: June 2019

The novel PKC isoform, PKC-theta, is particularly enriched in T lymphocyte populations, serving a critical role in signal transduction after CD3/CD28 T cell receptor stimulation. PKC-theta is known to be involved in promoting T cell mediated immunity and has been implicated in other autoimmune diseases. We hypothesized that inhibition of this isoform would increase regulatory T cell phenotypes, promote an anti-inflammatory environment, and lead to delayed onset of type 1 diabetes in the NOD mouse model. A cell permeable pseudosubstrate peptide inhibitor was identified with potent suppression of IL-2 secretion at concentrations ≤15 μg in T cell enriched populations stimulated in vitro with CD3 and CD28 antibodies and a significant reduction in stimulated IL-2 secretion after 7 days of intraperitoneal treatment with 50 μg of pseudosubstrate inhibitor. Five-week-old prediabetic NOD mice were either treated daily with 50 μg of inhibitor or mock treated with saline for 4 weeks, then allowed to progress until 17 weeks of age. An 80% conversion to diabetes, based on IP glucose tolerance tests, was observed in saline mice compared to 30% conversion in inhibitor-treated mice, which correlated with a greater frequency of inflammation-free islets and islets with periinsulitis only in inhibitor-treated mice. Inhibitor-treated mice had increased frequencies of IL-10 secreting cells by ELISPOT, and increased Tregs in spleen at 17 weeks of age while reduced frequencies of IL-17+ CD4+ T cells. This study was repeated with a scrambled peptide control and later endpoint to determine if T1D would be prevented entirely. At 25 weeks of age a 66% conversion to diabetes was observed in scrambled peptide treated mice, while only 33% converted in the peptide treated. Our data demonstrate that PKC theta activation contributes to the progression of beta cell destruction in NOD mice, where inhibition of this isoform may confer an increase in protective regulatory T cell populations.

Disclosure

J.E. DiLisio: None. N. Mishkin: None. B. Podell: None.

Funding

National Institutes of Health (5K01OD016997 to B.P.); National Center for Advancing Translational Sciences (UL1TR001082 to B.P.)
174-OR: Dorsal Vagal Complex Is a Site for Brain Lipid Sensing to Regulate Lipid Homeostasis
Authors: BATCHULUUN BATTSETSEG , ZAVED WAISE T. M. , YUE JESSICA T. , LAM TONY K.
Published: June 2019

Obesity and diabetes are characterized by dyslipidemia due partly to an overproduction of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The hypothalamus regulates whole-body lipid homeostasis in rodents but whether extra-hypothalamic brain regions can impact lipid homeostasis remain unclear. We here assessed whether the dorsal vagal complex (DVC), a region in the brainstem which contains a circumventricular organ termed the area postrema, as well as the nucleus of the solitary tract and the dorsal motor nucleus of the vagus, senses oleic acids to regulate whole-body lipid homeostasis. We first surgically implanted a guide cannula into the DVC of male 280-300g rats for vehicle (3% cyclodextrin in saline) or oleic acid (1 mM dissolved in vehicle) infusion, followed by catheter placements (7 days after) in the left carotid artery and right jugular vein for sampling and infusion. After an additional 5 days of recovery, 10h-fasted rats received either vehicle or oleic acid pre-infusion to the DVC for 10 min, and DVC infusion was maintained for an additional 150 min after an i.v. injection of poloxamer (600 mg/kg; a lipoprotein lipase inhibitor), while plasma samples were collected every 15 min for TG measurement. The rate of plasma TG appearance as a function of time (slope) reflects the rate of VLDL-TG secretion in the current experimental context. DVC oleic acid vs. vehicle infusion (0.33 ul/h) lowered VLDL-TG secretion (mM/min) in healthy rats (0.032±0.003, n=7 vs. 0.049±0.006, n=5; p<0.001), but interestingly failed to do so in high-fat fed rats. Taken together, our findings indicate that: (i) the DVC is a novel site of fatty acid sensing that impacts whole-body lipid homeostasis by regulating hepatic VLDL-TG secretion, and (ii) a disruption in DVC fatty acid sensing may contribute to the overproduction of hepatic VLDL-TG and a disruption in lipid homeostasis in obesity and diabetes.

Disclosure

B. Batchuluun: None. T. Waise: None. J.T. Yue: None. T.K. Lam: None.

Funding

Canadian Institutes of Health Research
1744-P: DBI-500 Significantly Increases Adipose Tissue Expression of PPAR-gamma and Adiponectin in DIO Mice and Significantly Decreases Markers of Fibrosis in Two Murine NASH Models
Authors: LEIGHTON ANTON
Published: June 2019

Introduction and Aims: The aims of these studies were to explore the scope of activity of oral DBI-500, an atypical glycolipid, in a murine model of prediabetic type 2 diabetes and obesity, and in two models of NASH.

Methods: Part 1. Male C57BL/6 mice (14 weeks old) that received a high fat diet were divided into 3 groups (8 - 9 per group) and were either dosed with up to 144 mg/kg, 72 mg/kg or matching placebo via once daily oral gavage for 7 days. Fasting glucose, body weight and gene expression analyses were performed. Part 2. NASH was induced in male C57BL/6 mice using a standard methionine/choline deficient diet. Concomitant with initiation of diet, 4 groups of 8 mice received either placebo, 80 or 40 mg/kg DBI-500 or 40 mg/kg + metformin every other day for 4 weeks per gavage. Part 3. NASH was induced by diet in apolipoprotein-E-deficient mice using western diet (WD). Dose groups of 5 dose groups of 8 mice were dose with DBI-500 (100, 50 or 25mg/kg, or 25mg+metformin).

Results: Part 1. Gene expression analysis of epidymal fat samples showed significant increases in PPAR-gamma and adiponectin expression with concomitant significant reduction in CD8+ expression. Blood glucose and body weight were reduced. Plasma levels of PAI-1 and CD40L were also significantly reduced. Part 2. MCD mice showed significant and dose dependent reduction in hepatic collagen. Part 3. In ApoE deficient mice, DBI-500 significantly reduced expression of hepatic alpha-SMA and TGF-beta1, and significantly increased PPAR-delta. BDI-500 also significantly increased HNF4-alpha.

Conclusions: DBI-500 is a potential once daily novel therapy for type two diabetes and NASH that also significantly reduces markers of cardiovascular risk. DBI-500’s capacity to increase expression of HNF4-alpha strongly indicates potential as combination treatment with FXR agonists.

Disclosure

A. Leighton: Stock/Shareholder; Self; Dale Biotech, Inc.
1745-P: Inhibition of Soluble Epoxide Hydrolase 1 (sEH1) Improves Glucose Tolerance and Decreases Diabetes Incidence
Authors: WHITE TAYLEUR , RAMANADHAM SASANKA , HAMMOCK BRUCE
Published: June 2019

Type 1 diabetes (T1D) is the result of autoimmune-mediated destruction of pancreatic islet β-cells by activated autoreactive inflammatory cells, effecting insulin production from β-cells. The Ca2+-independent phospholipase A2β(iPLA2β), a member of PLA2 family, hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid, which can be metabolized to bioactive lipids. Our work has revealed that iPLA2βactivation shifts macrophage polarization towards an inflammatory phenotype and that inhibition of iPLA2βreduces the development of T1D. We have now identified that iPLA2βactivation induces generation of select pro-inflammatory lipids in the non-obese diabetic (NOD) mice, including prostaglandins (PGs) and DHETs that accompany T1D development. To assess the role of these lipids in T1D development, NOD mice were administered (ip) polyethylene glycol 400 (vehicle), TPPU (sEH inhibitor, 3mg/ml), or PTUPB (dual antagonist of COX2/sEH, 9mg/ml) for up to 30 weeks. Measurement of blood concentrations of TPPU and PTUPB confirmed availability of the inhibitors between dosages. As expected, over the study-period glucose tolerance was impaired in the PEG group. Whereas glucose tolerance was not improved by PTUPB, it was significantly ameliorated by TPPU. These findings suggest that sEH1 inhibition, and thus the production of DHETs, can have beneficial effects in mitigating T1D development. Because different PGs can have pro- or anti-inflammatory effects, they further suggest that inhibition of COX2 may not be as effective as it may also lead to reductions in anti-inflammatory PGs. Overall, our findings support a role for select iPLA2β-derived lipids (iDLs) in T1D development and suggest developing strategies to target iPLA2βor the generation of select iDLs to prevent onset/progression of T1D.

Disclosure

T. White: None. S. Ramanadham: None. B. Hammock: None.

Funding

University of Alabama at Birmingham, Iacocca Family Foundation; U.S. Department of Veterans Affairs (BX001792, 13F-RCS-002); National Institutes of Health (R01DK69455, R01DK110292 to S.R.), (R01HL125353), (U01HD087198), (RR031535), (R01AI139072)
1748-P: Brucine Topical Administration Promotes Wound Healing through Downregulation of Proinflammatory Markers and Chemokine Expressions in Alloxan-Induced Diabetic Mice
Authors: MADKHALI HASSAN , GANAIE MAJID , ANSARI MOHD N.
Published: June 2019

Diabetes mellitus is a complex metabolic disease and delayed wound healing constitutes one of the most serious diabetes-associated complications. Diabetes can impede the wound healing process by inducing inflammation which can lead to delayed maturation of granulation tissues and reduced wound parallel tension. Brucine, one of the major constituents in Strychnos nux-vomica has antioxidant and anti-inflammatory properties. In this study, we investigated the effects of topical administration of brucine on the key mediators of wound healing, namely T cell subsets, glucocorticoid-induced tumor necrosis factor receptor expressing cells, CD4+CD25+Foxp3+ regulatory T (Treg) cells, Th17 cells, Th1 cytokines, and inflammatory mediator mRNA expression.In current study, 5 groups of mice were used (10/group): group 1, the nondiabetic normal control; group 2, wound in nondiabetic mice; group 3, wound in diabetic mice; group 4, brucine 20mg/kg treated wounds in diabetic mice. Wound size was recorded on every third day and after 14 days of treatment, the heparinized whole blood and the wound tissue of all the groups was collected and tested. Brucine administration showed a significant reduction in wound size, the levels of GITR-expressing cells, and Th1 cytokines as well as substantial down regulation of mRNA expression of the inflammatory mediators compared with the diabetic mice. Brucine also significantly up regulated the number of Tregs or also induced Th17/Treg balance and modulated various pro-inflammatory and anti-inflammatory cytokines and the mRNA expression of their mediators. Furthermore, histopathological examination showed complete re-epithelization, decreased inflammatory cells and presence of granulation tissue in the brucine treated mice. Therefore, our results suggest the beneficial effect of brucine in enhanced wound healing and rebalancing the wound environment in diabetes.

Disclosure

H. Madkhali: None. M. Ganaie: None. M.N. Ansari: None.