bluuebunny/crossref_metadata_2025 huggingface dataset:
1673-P: The Neighborhood Deprivation Index and Provider Geocoding Identify Critical Catchment Areas for Diabetes Outreach Programs
Authors: WALKER ASHBY F. , HU HUI , CUTTRISS NICOLAS , HALLER MICHAEL J. , WANG C. JASON , ANEZ-ZABALA CLAUDIA , YABUT KATARINA , GURKA MATTHEW J. , MAAHS DAVID M.
Published: June 2019

Extension for Community Health Outcomes (ECHO) programs have successfully empowered primary care providers (PCPs) to deliver advanced care to patients lacking access to subspecialists. In designing an ECHO type 1 diabetes (T1D) program in Florida and California, the Neighborhood Deprivation Index (NDI) was used in conjunction with geocoding of primary care providers (PCPs) and endocrinologists in each state to concurrently identify areas with low endocrinology provider density and high health risk/poverty areas. The NDI measures many aspects of poverty proven to be critical indicators of community health outcomes such as cardiometabolic risk, adverse birth outcome, and substance use. Data from the 2013-2017 American Community Survey (ACS) 5-year estimates were used to create census tract- and block group-level NDI maps for California and Florida. In addition, geocoding and 30-minute drive-time buffers were performed using publicly available provider directories for PCPs and endocrinologists in both states by Google Geocoding API and TravelTime Search Application Programming Interface (API). Based on these findings, we defined high need catchment areas as census tracts or census block groups with: 1) more than a 30-minute drive to the nearest endocrinologist, but within a 30-minute drive to the nearest PCP; 2) an NDI in the highest quartile; and 3) a population above the median (5,199 for census tracts, and 1,394 for census block groups). Out of the 12,181 census tracts and 34,490 census block groups in California and Florida, we identified 57 tracts and 215 block groups meeting these criteria as high need catchment area. Geospatial analysis provides an important precursory methodologic step to effectively focus outreach efforts in diabetes program development. The integration of the NDI with geocoded provider directories enables more cost-effective and targeted interventions to reach the most vulnerable populations living with T1D.

Disclosure

A.F. Walker: None. H. Hu: None. N. Cuttriss: None. M.J. Haller: Advisory Panel; Self; Pancreum, SAB Biotherapeutics. C. Wang: None. C. Anez-Zabala: None. K. Yabut: None. M.J. Gurka: None. D.M. Maahs: Advisory Panel; Self; Novo Nordisk Inc. Consultant; Self; Abbott, Sanofi. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
1680-P: Impact of Diabetic Environment on Sclerostin Levels in Adult Patients with Type 1 Diabetes Mellitus
Authors: BARMPA ELEFTHERIA , BARGIOTA ALEXANDRA
Published: June 2019

Introduction: The aim of this study is to examine sclerostin levels in uncomplicated patients T1DM and its correlation with bone metabolism.

Methods/Design: We studied 118 (M/F:53/65) uncomplicated T1DM patients (Group-D) aged >20 and <50 years, diabetes duration>5 years and 50 healthy controls matched for age, sex and body mass index (BMI)(Group-C). In both groups Sclerostin, β-crosslaps, TP1NP and HbA1c were measured and the mean HbA1c of the last 5 years was calculated (HbA1c-5). BMD at lumbar spine (LS), femoral neck (FN) and total hip (HIP) by dual energy X-ray absorptiometry (DXA) was measured.

Results: In Group-D, mean age was 35.4±10.3years, age of diagnosis was 19.2±9.8years, disease duration was 16.6±9.5years, mean HbA1c and HbA1c-5 were 7.8±1.4%, 7.4±1.1, respectively. Z-scores were lower in the Group-D compared to controls in all the 3 regions [(LS: p=0.009), (FN: p=0.000), (HIP: p=0,000)]. Lower sclerostin levels, but not statistically significant, were observed in group-D compared to group-C (D: 19.0±11.6 vs. C: 23.3±13.6, p=0.059). No difference was found between sexes. Β-CrossLaps was significantly lower in the D-group (D: 198.9±19.6 vs. C: 262.5±53.6, p=0.001), but no significant difference was observed in TP1NP (D: 50.34±30.98 vs. C: 58.47±30.74, p=0.256) between the two groups. Regression analysis showed: a negative correlation between sclerostin and bone markers (βCrosslaps: r=-0.0288, p=0.003, TP1NP: r=-0.0255, p=0.009). No correlation was observed between sclerostin and glycemic control. A positive correlation was found between sclerostin and patients’ age (r=0.490, p=0.000) and between sclerostin and BMD in both LS and FN (LS: r=0.311, p=0.001, FN: r=0.183, p=0.049).

Conclusion: Sclerostin levels were lower, but not statistically significant, in T1DM patients compared to controls. Sclerostin was positively correlated with BMD and negative correlation was found with both bone turnover markers. No correlation was found with the metabolic control.

Disclosure

E. Barmpa: None. A. Bargiota: None.
1682-P: A Rule-Based Discovery of Gene-Environment Interactions on Risk of Islet Autoimmunity: TEDDY Study
Authors: LYNCH KRISTIAN F. , FENG TIANSHU , QIAN XIAONING , HAGOPIAN WILLIAM , LERNMARK ÅKE , ZIEGLER ANETTE , TOPPARI JORMA , REWERS MARIAN , SHE JIN-XIONG , SCHATZ DESMOND , AKOLKAR BEENA , KRISCHER JEFFREY , HUANG SHUAI , VEHIK KENDRA
Published: June 2019

Type 1 diabetes (T1D) associated genetic factors affect risk of islet autoantibodies (IA), but non-genetic factors show conflicting associations. Mechanistic interactions may play a role. Under a sufficient-component causal framework, we used a rule-based discovery method to investigate if genetic factors, early environment and first appearing IA (IAA or GADA) act synergistically to mark different disease mechanisms.

TEDDY children (n=7512) were followed until age 6 years for IA development (n=518). Rules differentiating IAA-first (n=258) from GADA-first (n=243) were identified by a rule discovery algorithm (RuleFit) and examined in logistic regression models. Rule components were assessed for additive interaction on IAA-first and GADA-first separately using Relative Excess Risk due to Interaction (RERI) calculated from Cox regression models.

Here we show 2 of the 5 top rules, the first involving the child having CTLA4-AA (rs231775) and mother with a gestational respiratory but no skin infection (rule1, OR=5.6, 95% CI=2.6-12.0, p<0.0001); the second involving child having BACH2-T (rs3757247) and sufficient weight gain by age 3 months (rule2, OR=0.47, 95% CI=0.30-0.72, p<0.0001). Each differentiated IAA from GADA, and rule components showed interaction on absolute risk of IAA-first or GADA-first.

Figure 1. Gene-environmental interaction with first appearing IA may mark different mechanisms.

Disclosure

K.F. Lynch: None. T. Feng: None. X. Qian: None. W. Hagopian: Research Support; Self; Novo Nordisk A/S. Å. Lernmark: None. A. Ziegler: None. J. Toppari: None. M. Rewers: None. J. She: None. D. Schatz: None. B. Akolkar: None. J. Krischer: None. S. Huang: None. K. Vehik: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Centers for Disease Control and Prevention; JDRF; University of Florida (UL1TR000064); University of Colorado (UL1TR001082)
1693-P: Rapamycin Reduces Maternal Diabetes-Induced Neural Tube Defects by Suppressing Premature Senescence
Authors: XU CHENG , YANG PEIXIN
Published: June 2019

Maternal diabetes significantly increases the risk of structural birth defects. Senescence occurs after neural tube closure. We aimed to determine whether maternal diabetes induces premature senescence in the developing neuroepithelium. Maternal diabetes induced robust senescence associated β-galactosidase (SAβG) activity in the apical side of the developing neuroepithelium at embryonic day 8.5 (E8.5). The major senescence mediator p21 was induced preceding the SAβG signal at the same region. p21 gene deleted embryos of diabetic dams had a significantly lower neural tube defects (NTDs) incidence (3.6%) compared to wild type litter mates (25.9%). The transcriptional factor Forkhead transcription factor 3a (FoxO3a) is activated in diabetic embryopathy, and Foxo3a knockout reduces maternal diabetes-induced NTDs. Our data showed Foxo3a deletion diminished the signals of SAβG, and abrogated diabetes-increased abundance of p21 and DNA damage response proteins. MicroRNAs have been identified as novel inducers of cellular senescence. Two FoxO3a binding sites were found in the promote region of miR-200c. In vitro study confirmed both FoxO3a and high glucose stimulated miR-200 promoter activity. miR-200c null embryos had a lower NTD rate (4.3%) compared with that of WT embryos (29.2%) from diabetic dams. miR-200c repressed the expression of ZEB1 and ZEB2, which are transcription repressors for p21. In addition to the revelation of the gene regulation pathway in maternal diabetes-induced premature senescence, we found intraperitoneal injection of the senescence inhibitor Rapamycin in diabetic dams during E5.5-E9.5 diminished SAβG signal, and reduced the NTD rate from 24.0% to 4.5%) in diabetic pregnancy. Thus, our study revealed a novel FoxO3a-miR-200c-p21-mediated premature senescence pathway, and provided the mechanistic basis for targeting premature senescence in preventing diabetes-induced NTDs.

Disclosure

C. Xu: None. P. Yang: None.

Funding

American Diabetes Association (1-13-BS-220 to P.Y.); National Institutes of Health
1699-P: Identification of HNF1A Target Gene SNPs Associated with the Age of Onset of HNF1A MODY
Authors: LUDWIG-SLOMCZYNSKA AGNIESZKA , SEWERYN MICHAL , KAPUSTA PRZEMYSłAW , SKUPIEN JAN , KIEC-WILK BEATA M. , MACHLOWSKA JULITA , MALECKI MACIEJ , WOLKOW PAWEL P. , KLUPA TOMASZ ,   NEMO COLLABORATORS
Published: June 2019

HNF1A MODY is characterized by impaired insulin secretion but wide variability exists in the severity of hyperglycemia and in the age at which it becomes clinically manifest. Here we focus on molecular targets of the transcription factor HNF1A and variants in these genes to identify variants associated with HNF1A-MODY age of onset. GWAS on age of onset in 837 HNF1AMODY patients was done and data were used for further analysis. Imputation was done on the Michigan Imputation Server. All modeling and statistics was done in R and python. Genetic association and relatedness structure estimation was done in package 'GENESIS.' The list of HNF1A target genes was based on the TRANSFAC database. For this analysis the HNF1A causal variants were binned according to the domain: DNA-binding, trans-acting, and dimerization. For each of the target gene, variants in the intergenic regions (500kb up- and down-stream) were selected for the analysis. Several common variants: rs12510870 in AFP, rs12441817 in CYP1A2, rs10841644 in SLCO1B3, rs12647527 in MTTP, rs12094103 in CRP and rs7525711 in CSRP1 were identified to be robustly associated with age of onset of MODY3. Moreover, the effect size (beta) of these SNPs were found to be dependent on the HNF1A functional variant. rs12441817 was found to be a significant eQTL for multiple genes in the locus across various tissues, rs10841644 was found to affect SLCO1B3 in the basal ganglia, and rs7525711 was found to be associated with the non-coding RNA in the CSRP1 locus (all in the GTEx eQTL analysis).

In conclusion, common variants in HNF1A target genes are associated with age of onset of MODY3 with the strength of association being dependent on the functional variant in HNF1A.

Disclosure

A. Ludwig-Slomczynska: None. M. Seweryn: None. P. Kapusta: None. J. Skupien: None. B.M. Kiec-Wilk: None. J. Machlowska: 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
170-LB: Efficacy and Safety of Technology in Type 1 Diabetes: A Systematic Review and Network Meta-analysis
Authors: PEASE ANTHONY J. , LO CLEMENT , EARNEST ARUL , KIRIAKOVA VELISLAVA , LIEW DANNY , ZOUNGAS SOPHIA
Published: June 2019

Background: Comparisons of new technologies for type 1 diabetes through synthesis of randomized controlled trial (RCT) evidence are critical to guiding device selection. We thus conducted a systematic review and network meta-analysis to compare and rank the efficacy and safety of technologies for the treatment of type 1 diabetes.

Methods: We searched MEDLINE, MEDLINE In-Process and other non-indexed citations, EMBASE, PubMed, All Evidenced Based Medicine Reviews, Web of Science, PsycINFO, CINAHL and PROSPERO. We included RCTs ≥6 weeks duration comparing technologies among non-pregnant adults (≥18 years of age). We assessed risk of bias using a validated tool and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were HbA1c, rates of severe and non-severe hypoglycemia, and quality of life.

Findings: We identified 15,691 publications of which 50 eligible studies compared 12 technologies, with 3,885 participants. Integrated insulin pump and continuous glucose monitoring (CGM) systems resulted in HbA1c levels 0·95% (95% predictive interval 0·02-1·87) and 0·86% (0·10-1·61) lower than multiple daily injections (MDI) with either flash glucose monitoring or capillary glucose testing, respectively. Integrated systems also had the best overall ranking for HbA1c reduction. MDI with flash glucose monitoring was ranked as the best treatment for prevention of non-severe hypoglycemia with event rates significantly lower than any other intervention. The best treatment rankings for severe hypoglycemia and quality of life were MDI with flash glucose monitoring and CGM, respectively. The overall risk of bias rating was moderate-high for all outcomes. The certainty of evidence was very low.

Interpretation: Integrated insulin pump and CGM systems appeared superior for lowering HbA1c while glucose sensing devices appeared superior for preventing hypoglycaemia and improving quality of life.

Disclosure

A.J. Pease: None. C. Lo: None. A. Earnest: None. V. Kiriakova: None. D. Liew: Advisory Panel; Self; AstraZeneca, Bayer AG. Research Support; Self; AbbVie Inc., AstraZeneca, Bristol-Myers Squibb Company, CSL Behring, Pfizer Inc. S. Zoungas: None.
1713-P: ASB4 Regulates Glucose Homeostasis and Body Adiposity during Aging
Authors: VAGENA EIRINI , HE LI , ENGSTRÖM PAULINE , YULYANINGSIH ERNIE , OLSON DAVID , XU ALLISON
Published: June 2019

Age is a major risk factor for the development of obesity and type 2 diabetes. However, how this process is regulated is poorly understood. Hypothalamic agouti-related peptide (AgRP) or the proopiomelanocortin (POMC), are important regulators of energy balance and glucose homeostasis. Notably, AgRP-deficient mice exhibit normal body weight as young adults but develop a lean phenotype as they age. We showed that AgRP neuronal innervation increases markedly with age onto specific neurons within the hypothalamus, and that this increased innervation exerts tonic inhibition onto these cells. Together these findings suggest that the age-associated increase in AgRP innervation is responsible for the increase in adiposity. However, the downstream components of this circuit are not well defined.

In a microarray screen, we identified ankyrin repeat and SOCS box-containing 4 (ASB4) as a potential downstream target of AgRP. We found that ASB4 protein is specifically expressed in brain areas innervated by AgRP. ASB4 expression in arcuate nucleus of the hypothalamus increases with age and ASB4 neurons are the prime targets of AgRP neuronal innervation that increases with age. As GWAS studies link ASB4 locus with human obesity we generated mice with germline deletion of ASB4. In direct contrast to the age-dependent leanness of AgRP-deficient mice, ASB4 knockout mice develop obesity with age. The loss of ASB4 also resulted in impaired glucose tolerance with age, independently of body adiposity. This weight-independent glucose intolerance phenotype was recapitulated when ASB4 was specifically removed from POMC neurons.

Together, we identified ASB4 as a key regulator of body weight and glucose homeostasis during aging. As ASB4 is known to be stimulated by leptin, our results suggest that the age-dependent increase of AgRP innervation onto ASB4 neurons may progressively inhibit ASB4 neuronal function with age, thereby attenuating the metabolic effects of anorexigenic hormones such as leptin whose levels increase with age.

Disclosure

E. Vagena: None. L. He: None. P. Engström: None. E. Yulyaningsih: None. D. Olson: Research Support; Self; MedImmune, Novo Nordisk A/S. A. Xu: None.

Funding

American Diabetes Association (1-18-PDF-023 to E.V.); Larry L. Hillblom Foundation
1718-P: Type 2 Diabetes Is Associated with Higher Serum Levels of Circulating Adenylyl Cyclase 8: A Novel Biomarker of the Disease
Authors: MADHOUN ASHRAF AL , AL-MULLA FAHD
Published: June 2019

Aim: A prospective study to evaluate the functional relevance of circulating adenylyl cyclase’s (ADCY), specifically ADCY1, 3 and 8 in patients with type 2 diabetes (T2D) vs. controls.

Method: A total of 188 individuals, 92 T2D and 96 nondiabetic (ND) were recruited. Specific enzyme-linked immunosorbent assay kits were used to quantify the levels of circulating plasma ADCY and its end product cyclic AMP (cAMP) in our study population.

Results: Plasma levels of ADCY1, 3 and 8 were measured. We observed significantly increased measures of plasma levels of ADCY8 in T2D compared to ND (mean ± SEM: 12.645 ± 0.179 vs. 12.056 ± 0.167 ng/mL, p= 0.017). Increased ADCY-8 levels exhibited a positive correlation with the prevailing Hb1Ac levels (r = 0.188, p= 0.012). T2D patients who are obese (12.941 ± 0.207) showed increased levels of ADCY8 relative to non-obese (12.142 ± 0.317, p= 0.039). No significant differences were observed between the plasma concentrations of ADCY -1 or -3 relative to T2D or obesity. The functional relevance of this increased circulating ADCY levels were investigated. Hence, significantly higher levels of plasma cAMP were observed in T2D compared to ND (p< 0.001); irrespective of their obesity status. Higher levels of cAMP positively correlated with fasting plasma glucose levels (r= 0.266, p= 0.026).

Conclusion: Heightened state of ADCY8 and cAMP possibly reflects its potential as a biomarker for disease progression and development of complications in T2D.

Disclosure

A. Al Madhoun: None. F. Al-Mulla: None.

Funding

Kuwait Foundation for the Advancement of Science; Dasman Diabetes Institute
1724-P: Interaction between Genetic Variants and Hemoglobin A1c Level on the Risk of Sight-Threatening Diabetic Retinopathy in Patients with Type 2 Diabetes
Authors: KI NG KELVIN KA , LEE CHI HO , WOO YU CHO , FONG HO YI , WONG RACHEL , LAM KAREN S. , YAN CHEUNG CHLOE YU
Published: June 2019

Objectives: While hemoglobin A1c (HbA1c) is a well-established risk factor of diabetic retinopathy (DR), it only accounts for limited variation in DR risk. Recent genome-wide association studies (GWAS) have identified some susceptibility single nucleotide polymorphisms (SNPs) for DR. This study aimed to evaluate the possible SNPxHbA1c interaction for the risk of sight-threatening DR (STDR) among patients with type 2 diabetes (T2DM).

Methods: Sixty-nine SNPs that showed top association signals (P<5x10-4; r2<0.9) in previous GWAS of DR were genotyped in 1106 STDR cases and 2069 non-DR controls. The associations between the SNPs and STDR were examined by multiple logistic regression analyses with adjustment for the traditional risk factors. HbA1c level was dichotomized according to a cut-off of 7% as suggested for an optimal glycemic control of diabetes. Interaction with HbA1c was examined by implementing an interaction term of SNP x dichotomized HbA1c in the logistic regression model.

Results: COL5A1 rs59126004 (P=0.016;OR=0.82), IGSF21-KLHDC7A rs3007729 (P=0.022;OR=0.86), LOC728275-LOC728316 rs227455 (P=0.031;OR=0.88), C6orf170 rs17083119 (P=0.035;OR=0.82) and SLC25A32 rs3098241 (P=0.046;OR=0.88) showed significant associations with STDR. Among these, COL5A1 rs59126004 also showed a significant interaction with HbA1c for the risk of STDR (Pinteraction=0.002). Stratified analysis showed that the minor allele of this SNP was associated with a reduced risk of STDR only in the patients with HbA1c <7% (P=1.79x10-4; OR=0.58), but not in patients with HbA1c ≥7%.

Conclusions: We have demonstrated a potential interaction between the COL5A1 rs59126004 and HbA1c for the susceptibility to STDR. Further studies to validate our findings are warranted.

Disclosure

K. Ng: None. C. Lee: None. Y. Woo: None. H. Fong: None. R. Wong: None. K.S. Lam: None. C.Y. Cheung: None.

Funding

Hong Kong Health and Medical Research Fund; Hong Kong Special Administrative Region
173-OR: Effects of Mild Acute Hypertriglyceridemia on Fasting and Post-Load Glucose Homeostasis
Authors: TRICO DOMENICO , MENGOZZI ALESSANDRO , SEGHIERI MARTA , MARI ANDREA , NATALI ANDREA
Published: June 2019

Background: Mild hypertriglyceridemia is associated with reduced glucose tolerance and increased risk of type 2 diabetes, independent of obesity and insulin sensitivity, in cross-sectional and prospective studies. To what extent these effects are directly produced by triglycerides and which are the major glucose homeostatic mechanisms involved is unclear.

Methods: We examined the effects of acute triglyceride elevation on tracer-derived glucose metabolic fluxes, model-derived β-cell function, insulin sensitivity, and insulin clearance during two 3-h oral glucose tolerance tests with infusion of either normal saline or 20% Intralipid (25 ml/min/m2, without heparin) in 8 healthy lean volunteers.

Results: A 2-h Intralipid infusion increased plasma TG by 2.7-fold (from 52±7 to 192±29 mg/dl; p=0.0003) without affecting plasma FFA, glucose, or insulin levels. After glucose ingestion, the lipid infusion elicited a marked increase in plasma glucose (iAUC +60%, p=0.01) and insulin (iAUC +52%, p=0.02) levels, while FFA were similarly suppressed. The deterioration in glucose tolerance was associated with reduced insulin sensitivity (Matsuda index -22%, p=0.04) and glucose clearance (-16%, p<0.05), and occurred despite a mild inhibition of the endogenous glucose production (-17%, p<0.05). Hyperinsulinemia was produced by reduced insulin clearance (-15%, p=0.04) and enhanced insulin secretion (assessed by C-peptide deconvolution; +29%, p=0.02) due to higher glucose levels and increased β-cell potentiation (+53%; p=0.04).

Conclusions: Mild acute hypertriglyceridemia, independent of FFA, impairs glucose tolerance in healthy subjects by reducing insulin sensitivity and glucose clearance. The magnitude of these effects on glucose tolerance exceeds that of hyperinsulinemia resulting from enhanced β-cell potentiation and reduced insulin clearance.

Disclosure

D. Trico: None. A. Mengozzi: None. M. Seghieri: None. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. A. Natali: None.

Funding

Italian Society of Diabetology; European Foundation for the Study of Diabetes
1738-P: Immune Checkpoint Inhibitor Therapy Precipitates the Rapid Development of Type 1 Diabetes
Authors: AKTURK HALIS K. , KAHRAMANGIL DOGA , SARWAL ASHWIN , MURAD M. HASSAN , MICHELS AARON
Published: June 2019

Immune checkpoint inhibitors (ICI) that target programmed cell death protein-1 (PD-1) and its ligand (PD-L1) are beneficial cancer immunotherapies but infrequently cause type 1 diabetes (T1D), which can present with life-threatening diabetic ketoacidosis (DKA). We conducted a systematic review and meta-analysis to understand the timing and factors associated with ICI-induced T1D. We searched MEDLINE, EMBASE, SCOPUS and Cochrane databases (August 2000-2018) for studies of any design on ICI and identified 71 cases in 55 publications. Comparisons were made using Fisher’s exact and Student t-tests. Mean age at T1D presentation was 61.7±12.2 years, 55% were male, and melanoma (53.5%) was the most frequent cancer. Mean duration to T1D onset was only 83.5±88.5 days with DKA in 76% of cases. Average HbA1c was 7.84±1.0% at presentation. All cases had insulin deficiency and required permanent insulin treatment. The majority of patients developed T1D within just 3-months of initial ICI exposure (Figure). Half of the cases reported T1D associated antibodies at diabetes presentation, and those with antibodies had a more rapid onset (p=0.005) and higher incidence of DKA (p=0.02) compared to patients without antibodies. This study provides a framework for prospective clinical studies to screen patients receiving these state-of-the-art therapies for risk factors associated with T1D onset to prevent life-threatening DKA.

Disclosure

H.K. Akturk: Advisory Panel; Self; Sanofi. Research Support; Self; Eli Lilly and Company, MannKind Corporation, REMD Biotherapeutics. Speaker's Bureau; Self; MannKind Corporation. D. Kahramangil: None. A. sarwal: None. M. Murad: None. A. Michels: Stock/Shareholder; Self; IM Therapeutics.

Funding

National Institutes of Health (DK108868, DK110845, DK032083)
1739-P: Checking the Checkpoints: A Case of Type 1 Diabetes following PD-1 Inhibition in a Patient with HIV
Authors: HUGHES MICHAEL S. , BEDROSE SARA , VASUDEVAN MADHURI , MARCELLI MARCO
Published: June 2019

Introduction: Type 1 diabetes mellitus (T1DM) is a known immune related adverse event (irAE) following treatment with Programmed Death 1 (PD-1) immune checkpoint inhibitors with reported 0.9% incidence. Little is known about such irAEs in individuals with HIV treated with PD-1 inhibitors.

Case: A 48-year-old man with HIV on HAART, diagnosed with Hodgkin’s lymphoma, initiated PD-1 inhibitor nivolumab. After 6 months, he reported polydipsia and polyuria. Labs revealed glucose 764 mg/dl and A1c 7.1%. Low C-peptide and elevated GAD-65 antibody levels confirmed T1DM, and he started insulin therapy. Nivolumab continued for 12 more months. Despite discontinuation of nivolumab, he remains on insulin therapy.

Discussion: While A1c may reflect average glycemia, it alone cannot distinguish T2DM from T1DM progression. C-peptide and autoantibodies for T1DM must be included when screening patients on PD-1 inhibitors.

Patients with HIV have higher autoantibody titers in active disease states or following HAART initiation, as seen in immune reconstitution. Moreover, in vitro PD-1 inhibition elevates HIV cell proliferation and immune hyperactivity. The challenge in patients with HIV on HAART and PD-1 inhibitors is unraveling whether autoantibody generation resulting in T1DM is potentiated by pre-existing HIV on HAART and/or provoked by immune response to PD-1 inhibition.

Conclusion: Clinicians treating patients with immune checkpoint inhibitors should maintain a high index of suspicion for development of autoimmune disorders. Literature on the use of PD-1 inhibitors in HIV patients is limited and warrants further investigation. To our knowledge, this is the first reported case of T1DM following PD-1 inhibition in a patient with HIV on HAART therapy. Such patients are predisposed to immune reconstitution, and response to PD-1 inhibition may potentiate risk for autoimmune complications. Therefore, higher clinical suspicion for irAEs is merited in patients with HIV on PD-1 inhibitors.

Disclosure

M.S. Hughes: None. S. Bedrose: None. M. Vasudevan: None. M. Marcelli: None.
1747-P: 3D Imaging and Quantification of Pancreatic Immune Cell Infiltration during Emergence and Progression of Spontaneous Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice
Authors: BOLAND BRANDON B. , MANRESA-ARRAUT ALBA , GRÔNLUND RIKKE V. , ROOSTALU URMAS , HECKSHER-SØRENSEN JACOB , VRANG NIELS , JELSING JACOB , FINK LISBETH N.
Published: June 2019

The non-obese diabetic (NOD) mouse develops diabetes as the result of spontaneous autoimmune insulitis and is widely used as a translational polygenic model of type 1 diabetes. Disease progression in the NOD mouse model is slow, involving a long prodromal phase of pancreatic islet infiltration before autoimmune β-cell destruction and manifestation of diabetic hyperglycemia, making the NOD mouse ideal for probing the effectiveness of potential disease prevention therapies. Improved understanding of the spatial dynamics of immune cell infiltration of the pancreas during the emergence and natural progression of autoimmune diabetes would permit further resolution of drug treatment effects in this model. The present study therefore aimed to image the spontaneous development and progression of autoimmune diabetes dynamically and at 3-dimensional cellular resolution in the NOD mouse. Female NOD mice were terminated before diabetes onset, at 14 and 18 weeks of age, and pancreata were isolated and divided into two alternating samples consisting of either the head and tail. One half was stained for insulin and CD45 using iDISCO whole-mount immunohistochemistry and subsequently scanned using a light sheet microscope. Islet infiltration was quantified using an in-house developed algorithm. The other half of each pancreas was simultaneously evaluated by flow cytometry to discriminate and quantify immune cells of lymphoid and myeloid lineage. Infiltrating CD45-positive leukocytes progressively increased in abundance over time, however, with highly variable distribution in the pancreas. Flow cytometry confirmed extensive leukocyte infiltration and revealed predominant changes in T-cell profiles.

In conclusion, 3D imaging allows for visualization and unbiased quantitative analysis of the unsynchronized spreading of insulitis into different parts of the pancreas in NOD mice.

Disclosure

B.B. Boland: Employee; Self; Gubra, MedImmune. A. Manresa-Arraut: None. R.V. Grônlund: None. U. Roostalu: Employee; Self; Gubra. J. Hecksher-Sørensen: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Jelsing: Stock/Shareholder; Self; Gubra. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S.
1751-P: Human Islet Response to Selected Type 1 Diabetes Associated Bacteria
Authors: ABDELLATIF AHMED M. , SARVETNICK NORA E.
Published: June 2019

Type 1 diabetes (T1D) is a chronic autoimmune disease that results from destruction of pancreatic β-cells. A role of gut bacteria in T1D has been suggested. However, the nature of that role remains largely unknown. Bacterial blooms are reported to be increased in gut prior to incidence of autoimmunity. One hypothesis is that these bacteria might elicit a response from human islets associated with immune cells recruitment. We have tested this hypothesis using 3 bacteria, namely Bacteroides dorei (BD), Ruminococcus gnavus (RG), both increased before T1D and Escherichia coli (EC), ubiquitous bacteria. Briefly, human islets were exposed to one of these bacteria for 6 and 24h. After that, RNA-Seq analysis was performed. The three bacteria altered expression of a number of genes at 6 and 24h. Additionally, each bacteria displayed a unique set of differentially expressed genes (DEG). Ingenuity pathway analysis of DEG revealed that top activated pathways and diseases included Th17 activation and inflammatory response respectively. A common set of DEG was also noted among different treatments at both 6 and 24h. The commonly upregulated genes were mostly cytokines (42.5%) including members of C-C and C-X-C motif chemokines followed by enzymes (13%) e.g., PTGS2 and SOD2, suggesting a selective effect of gut bacteria on islet immune and biosynthetic pathways. Immunoblotting for NAMPT, SOD2 and TRAF3IP2 revealed similar trends to those observed in RNA-Seq. From the list of tested cytokines, only CXCL8 was significantly increased, with its release being highest in EC. When injected into the pancreas through the bile ducts of normal mice, each bacteria elicited a unique pattern of islet inflammation. However, diabetes doesn’t not result from these injections, indicating other missing factors e.g., genetics or environment. Our data reveal several details about islet response to T1D associated bacteria. Understanding the changes induced by host-microbiome interaction could help for diabetes prevention by their reversal.

Disclosure

A.M. Abdellatif: None. N.E. Sarvetnick: None.

Funding

National Institute of Allergy and Infectious Diseases; The Leona M. and Harry B. Helmsley Charitable Trust; JDRF; J.W. Kieckhefer Foundation
1756-P: ß-Cell Glucose Sensitivity and Intrapancreatic Adipose Tissue as Predictors of Diabetes Onset
Authors: CINTI FRANCESCA , MEZZA TERESA , ASSUNTA CEFALO CHIARA MARIA , SORICE GIAN PIO , MOFFA SIMONA , SEVERI ILENIA , CINTI SAVERIO , GIACCARI ANDREA
Published: June 2019

Several evidences suggest that the functional β cell defects anticipate the onset of hyperglycemia and the reduction of mass. To assess whether the β-cell deterioration corresponds to a loss of β-cell mass, we performed glucose oral tolerance test (OGTT) and hyperglycemic clamp (HC) followed by arginine stimulation, in 16 nondiabetic patients who underwent pancreatoduodenectomy (PD), pre and post-surgery. Based on the post-operative OGTT, the subjects were divided into 3 glucose tolerance groups: normal (NGT, n = 5), altered (IGT, n = 4) or diabetes (DM, n = 7) (8F/8M, 51 ± 15 years). To evaluate β cell function, βcell glucose sensitivity (GS) was calculated during HC, as a ratio between insulin secretion and glucose increase. On surgical pancreas samples, the% of intraparenchymal white adipose tissue (WATi score) was measured. Before surgery, insulin secretion after arginine (AIS) was similar between groups, while GS was lower in IGT and DM compared to NGT subjects (62.9 ± 23.1 and 45.5 ± 11.2 vs. 90.6 ± 18.7 pmol • min-1 • m-2, respectively). After 50% PD, the GS decreased in all patients (p <0.01 for all groups), but the reduction was greater in DM than in patients with IGT and NGT (ΔGS: NGT -0.20 ± 0, 19 vs. IGT -0.27 ± 0.11 vs. DM 0.37 ± 0.08, p <0.003). A similar reduction was observed in ΔAIS (NGT -0.38 ± 0.13 vs. IGT -0.76 ± 0.06 vs. DM -0.90 ± 0.04; p <0.01) and in the second phase of insulin secretion. WAT score was significantly higher in IGT and DM than in NGT (WATi score IGT 37.75 ± 11.07%, DM 44.46 ± 31.83%, NGT 5.8 ± 2.35%, p <0.01 and p <0.05 respectively). The loss of GS is the most sensitive predictive parameter of diabetes onset after a 50% reduction in mass. The accumulation of WATi could in turn predict the loss of GS and represent a new potential target for the preservation of the function.

Disclosure

F. Cinti: None. T. Mezza: None. C. Cefalo: None. G. Sorice: None. S. Moffa: None. I. Severi: None. S. Cinti: None. A. Giaccari: Advisory Panel; Self; Sanofi. Board Member; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Merck Sharp & Dohme Corp., Sanofi.
1758-P: Alterations in Human Visceral Adipose Tissue Type 2 Innate Lymphoid Cells (ILC2s) with Aging: A Determinant of Insulin Resistance
Authors: BRADLEY DAVID , BLASZCZAK ALECIA M. , LIU JOEY Z. , JALILVAND ANAHITA D. , WRIGHT VALERIE P. , NORIA SABRENA , JOSEPH JOSHUA , HSUEH WILLA
Published: June 2019

Background: The obese adipose tissue (AT) immune cell microenvironment contributes to low-grade inflammation increasing the risk of multiple metabolic complications. Type 2 innate lymphoid cells (ILC2s) were recently discovered in mice to regulate metabolic health, but the clinical relevance of ILC2s in human AT is unknown.

Rationale: Our goals were to characterize changes human AT ILC2s in obesity, insulin resistance, and aging. We further examined changes in AT ILC2s with aging, high fat diet (HFD), and weight loss in mice.

Methods: We collected visceral AT (VAT) biopsies from 50 obese and 9 lean patients during elective surgery, isolated the adipocytes from the stromal vascular fraction, and performed flow cytometry.

Results: Human VAT %ILC2s were not different between lean and obese subjects (p=0.896), but were negatively associated with insulin sensitivity (r=-0.449, p=0.005), beta-cell function (r=-0.364, p=0.024), and increasing age (r=-0.337, p=0.012). ILC2s were also positively associated with T helper type 2 cells (Th2s). All of these relationships were independent of BMI and gender, suggesting that ILC2s play a weight-independent role in human glucose homeostasis and age-related insulin resistance, possibly through an interaction with Th2s. When placed on HFD for 6 and 12 weeks, mice demonstrated a depletion in VAT ILC2s, and 12- vs. 3-month old mice had decreased VAT ILC2s, which did not recover after 12 weeks of weight loss despite normalization of body weight.

Conclusions: In humans and mice, VAT ILC2s decrease with HFD and age. In humans ILC2s may be a weight-independent determinant of hyperinsulinemia and insulin resistance, provide a potential link to reduced insulin sensitivity in aging, and offer a novel therapeutic target in insulin resistance and T2D.

Disclosure

D. Bradley: None. A.M. Blaszczak: None. J.Z. Liu: None. A.D. Jalilvand: None. V.P. Wright: None. S. Noria: None. J. Joseph: None. W. Hsueh: None.

Funding

American Diabetes Association (1-16-ICTS-049 to W.H.); National Institutes of Health (KL2TR001068, HL135622)
1781-P: Adipocyte GI Signaling Regulates Whole-Body Glucose Homeostasis and Insulin Sensitivity
Authors: WANG LEI , PYDI SAI PRASAD , ZHU LU , JAIN SHANU , CUI YINGHONG , GAVRILOVA OKSANA , WESS JÜRGEN
Published: June 2019

Adipocyte dysfunction links obesity to insulin resistance and type 2 diabetes (T2D). Receptor-mediated activation of heterotrimeric G proteins plays a pivotal role in regulating adipocyte function. Little is known about the potential in vivo metabolic roles of Gi-type G proteins expressed by adipocytes, primarily due to the lack of suitable animal models. To address this issue, we generated adipocre-ROSA 26PTXmice in which Gisignaling was selectively disrupted in adipocytes ('adipo-Gi KO mice'). Compared to control mice, adipo-Gi KO mice displayed increased lipolysis and decreased fat mass when maintained on regular chow or a high fat diet (HFD). Moreover, HFD adipo-Gi KO mice showed impaired glucose tolerance and reduced insulin sensitivity. In vitro studies with primary adipocytes prepared from adipo-Gi KO mice indicated that the lack of Gisignaling led to impaired insulin signaling and reduced insulin-stimulated glucose uptake. In parallel, we also used a chemo-genetic approach to generate a mouse line selectively expressing a CNO-sensitive, Gi-coupled DREADD (designer receptor exclusively activated by a designer drug) in adipocytes (adipo-GiD mice). CNO-induced activation of adipocyte Gi signaling in adipo-GiD mice significantly improved glucose tolerance and insulin sensitivity independent of the diet that the mice consumed (regular chow or HFD). In vivo 14C-2-deoxy-glucose uptake assays demonstrated that activation of adipocyte Gisignaling enhanced insulin-induced glucose uptake in adipose tissues. Stimulation of adipocyte Gisignaling activation also further enhanced insulin signaling in adipose tissues. Taken together, our data clearly demonstrate that adipocyte Gisignaling is a critical regulator of insulin signaling in adipocytes and is critical for the maintenance of glucose homeostasis. A better understanding of the mechanisms through which Gipromotes adipocyte insulin signaling should stimulate the development of novel antidiabetic drugs.

Disclosure

L. Wang: None. S. Pydi: None. L. Zhu: None. S. Jain: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None.

Funding

National Institutes of Health
1786-P: ACSL1 Contributes to Thermogenesis and Differentiation of Brown Adipose Tissue
Authors: REN GUANG , KIM JEONGA
Published: June 2019

Long chain acyl-CoA synthetases (ACSLs) convert fatty acids (FA) to fatty acyl-CoAs that are utilized for various cellular processes, including triglyceride synthesis, activation of transcription factors, signal transduction, and providing energy sources via oxidation. Among 5 isotypes (ACSL1, 3, 4, 5, and 6), ACSL1 is the predominant isotype in adipocytes, and it is known to play important roles in adipocyte physiology, including FA uptake, triglyceride (TG) synthesis, thermogenesis, and FA oxidation. However, the roles of ACSL1 in brown adipocyte differentiation is incompletely understood. During the in vitro differentiation of brown adipocytes from stromal vascular cells (SVC), mRNA expression of ACSL1 was drastically increased. Pharmacological inhibition of ACSLs by triacsin C suppressed the differentiation of brown adipocytes. Interestingly, triacsin C inhibited the expression of uncoupled protein 1 (UCP1), which plays the major role in thermogenesis in mitochondria. Thus, we hypothesize that ACSL1 regulates thermogenesis and energy utilization by regulation of brown adipocyte differentiation. To examine the role of ACSL1 in brown adipose tissue (BAT), we generated BAT specific ACSL1 knockout mice by breeding UCP1-Cre with ACSL1 flox/flox mice (ACSL1BATKO). ACSL1 deficiency in BAT reduced the weight gain and glucose intolerance in high fat diet (HFD)-fed mice. ACSL1BATKO mice were severely cold intolerant. Furthermore, ACSL1BATKO mice were resistant to beta 3-agonist (CL-316243)-stimulated weight loss. Fat mass in HFD-fed ACSL1BATKO was lower than HFD-fed wild type mice. These data suggest that ACSL1 in BAT contributes to BAT differentiation, which causes the impairment of FA utilization. However, the mechanisms by which deficiency of ACSL1 in BAT reduces HFD-induced weight gain need to be further investigated.

Disclosure

G. Ren: None. J. Kim: None.

Funding

National Institutes of Health (R01HL128695R03AG058078)
1791-P: A New Antidiabetic Monomers Composition against Insulin Resistance via Modulation of Bacteria-Cometabolism-Inflammation-Diabetes Axis
Authors: HAN LIN , ZHAO LINHUA , ZHANG MINGLIANG , DI SHA , GAO ZEZHENG , WANG XINMIAO , WU HAORAN , JIA WEIPING , TONG XIAOLIN
Published: June 2019

Intestinal flora disturbance can cause chronic inflammation, which leads to metabolic disorders such as obesity and insulin resistance. Insulin resistance is the main pathogenesis of T2DM. Recent studies indicated that changes of host-microbiome metabolic axis also play an important role in the pathogenic process. Based on previous experiments and literatures, Baicalin, Berberine, Puerarin, Paeoniflorin, Mangiferin, Ginsenoside Rb1 and other effective hypoglycemic compounds were combined to be a new antidiabetic monomers composition (AMC). C57BL/6J mice were used to establish T2DM models with high-fat diet (HFD). The mice in AMC group were observed with an effective weight loss, reduced blood glucose, lower insulin level and content of cholesterol and LDL, and increased metabolic rate and energy consumption compared with HFD group, and impaired glucose tolerance was also alleviated treated with AMC. Further studies showed that AMC improved the disordered of intestinal flora, especially the increase of beneficial bacteria such as Akkermansia, and the decrease of harmful bacteria such as Bacteroides and Collinsella. Afterwards, host-microbial metabolome, inducing inflammatory response, such as Ethylmethylacetic acid and Hydroxyphenyllactic acid reduced. As a result, the level of inflammation in the body decreased as well, and the suppressed signaling pathways related to insulin resistance alleviated.

In conclusion, we explored the potential mechanism of AMC against insulin resistance via modulation of bacteria-cometabolism-inflammation-diabetes axis.

Disclosure

L. Han: None. L. Zhao: None. M. Zhang: None. S. Di: None. Z. Gao: None. X. Wang: None. H. Wu: None. W. Jia: None. X. Tong: None.

Funding

National Natural Science Foundation of China (81704067, 81430097)
1794-P: Perineuronal Net Destabilization in Neural Network Dysfunction Common to Both T2D and Alzheimer’s Disease
Authors: ALONGE KIMBERLY M. , REED MAY J. , BENTSEN MARIE A. , KEENE C. DIRK , GUTTMAN MIKLOS , SCHWARTZ MICHAEL W.
Published: June 2019

The risk of Alzheimer’s disease (AD) and other forms of cognitive impairment is increased in patients with T2D. Both conditions are characterized by brain insulin resistance and regional brain hypometabolism, and the brain of T2D animal models also exhibit classical AD pathologies (e.g., P-tau, Aβ plaques). Here, we investigated whether pathological changes in brain ECM composition contribute to these shared defects. AD pathology in human hippocampus includes loss of perineuronal nets (PNNs), which are chondroitin sulfate (CS)-containing matrices that regulate key neurocircuit interactions critical to cognitive function. We report that as in humans, rat PNNs (identified by Wisteria floribunda agglutinin (WFA) labeling of CS) are comprised mainly of the CS-proteoglycan aggrecan (ACAN). Furthermore, we report a significant loss of stable WFA+/ACAN+ PNN structures in both the hypothalamus and hippocampus of ZDF rats, an established model of T2D that is also known to develop AD neuropathology, compared to aged-matched WT controls (Hypo: WFA 51.8±8.2% and ACAN 64.9±2.4% decrease; Hippo: WFA 43.9±5.2% and ACAN 25.9±3.8% decrease). PNN matrix stability is strongly influenced by CS composition, with an increase in 6S-CS promoting matrix destabilization. Using a novel mass spectrometry-based approach to characterize the CS composition isolated from brain tissue, we show that the sustained normalization of glycemia by fibroblast growth factor 1 (FGF-1) in T2D-ZDF rats is accompanied by both a reduction in hypothalamic 6S-CS abundance and restoration of normal WFA+/ACAN+ PNN structures (WFA: 2.0±0.2 and ACAN: 2.2±0.2-fold increase). Studies to determine if this is also true in hippocampus are ongoing. These results suggest that destabilized PNN structures cause neurocircuit dysfunction that affects glycemic control and impairs memory. FGF-1-induced normalization of PNNs underscores the potential for neurocircuit remodeling as a therapy for T2DM and AD.

Disclosure

K.M. Alonge: Research Support; Self; Novo Nordisk Inc. M.J. Reed: Stock/Shareholder; Spouse/Partner; Amgen Inc. M.A. Bentsen: None. C. Keene: None. M. Guttman: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.

Funding

National Institutes of Health; Novo Nordisk