bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 &lt; 0.02 for the HFD-Tamoxifen interaction). The HFD + tamoxifen mice developed insulin resistance determined by HOMA-IR (P &lt; 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 &lt; 0.001). Gastrocnemius citrate synthase activity was elevated with tamoxifen treatment independent of diet, as was phosphorylation of AMP-activated kinase (P &lt; 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; &gt;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 (&lt;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&lt;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&lt;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&lt;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&lt;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&lt;0.001);ST2DM=0.7231 (95% CI,0.6327-0.8134, P&lt;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 &lt; 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&lt;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