bluuebunny/crossref_metadata_2025_split huggingface dataset:
164-OR: Role of Small Extracellular Vesicles for the Metabolic Response to Exercising in Insulin Resistant Humans
Authors: MASTROTOTARO LUCIA , APOSTOLOPOULOU MARIA , HARTWIG SONJA , PESTA DOMINIK , STRASSBURGER KLAUS , DEFILIPPO ELISABETTA , KARUSHEVA YANISLAVA , GANCHEVA SOFIYA , MARKGRAF DANIEL F. , LEHR STEFAN , MUSSIG KARSTEN , AL-HASANI HADI , SZENDROEDI JULIA , RODEN MICHAEL 
Published: June 2020

Small extracellular vesicles (SEV) are secreted into circulation after acute exercise suggesting a new mode of tissue crosstalk. High intensity interval training (HIIT) leads to improved insulin sensitivity and oxidative capacity in patients with type 2 diabetes. As the impact of HIIT on SEV release is unknown, this study examined its effects on number and proteome of SEV in insulin sensitive (IS) and insulin resistant (IR) humans to identify biomarkers for the early prediction of individual responses of insulin sensitivity to exercising.
Eight T2D, 8 glucose tolerant IR and 6 IS humans with similar age and BMI (HbA1c in %: 7.4 ± 0.4, 5.3 ± 0.1, 5.5 ± 0.1; M-value in mg*kg-1*min-1: 1.8 ± 0.4, 4.1 ± 0.4, 7.2 ± 0.5) performed a 12-weeks HIIT cycling protocol for 3 days/week. Before the intervention (baseline) and 72 h after the last exercise bout, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps and serum samples were collected to isolate SEV by size exclusion chromatography. SEV size and number were measured by Nanoparticle Tracking Analysis and proteomic profiling was done by mass spectrometry using data independent acquisition. After 12 weeks of HIIT, T2D and IR improved their insulin sensitivity (M-value: T2D 3.5 ± 0.8, IR 6.2 ± 0.7; p&lt;0.01 vs. baseline) and increased the number of circulating SEV by 52 ± 19% and 58 ± 21% (p&lt;0.05 vs. baseline). Quantitative proteomic analysis of SEV revealed that HIIT regulated 258 proteins (118 in T2D, 125 in IR, 89 in IS) with an enrichment of proteins related to glycolysis in T2D, to antioxidative metabolism in IR and to lipid metabolism in IS.
In conclusion, HIIT increases SEV number, but differently affects SEV mass and proteome in IS and IR humans, suggesting that SEV cargo could contribute to the individual response of insulin sensitivity to HIIT. Detailed characterization of SEV cargo can help to better understand the mechanisms of tissue crosstalk in the adaptation to exercise training and to develop novel exercise mimetics.

Disclosure
L. Mastrototaro: None. M. Apostolopoulou: None. S. Hartwig: None. D. Pesta: None. K. Strassburger: None. E. DeFilippo: None. Y. Karusheva: None. S. Gancheva: None. D.F. Markgraf: None. S. Lehr: None. K. Mussig: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S.
1641-P: Changes in Adipocyte Function in Response to Weight Gain in Young, Lean European and South Asian Men
Authors: GAO XUAN , MCLAREN JAMES , FREEMAN DILYS J. , GILL JASON M.R. 
Published: June 2020

South Asians (SA) develop T2DM at younger age and lower BMI than Europeans (EU). We hypothesized that a low ability of pre-adipocytes to differentiate to adipocytes resulting in hypertrophy may explain the high risk of T2DM. Abdominal subcutaneous adipose tissue was obtained at baseline (BL) and after 6.3[SD1.3] % weight gain (WG) from 20 EU and 13 SA. Adipocytes and pre-adipocytes were isolated and adipocyte diameter measured. Gene expression was quantified relative to PPIA by rtPCR after pre-amplification and analysed using a mixed model. Diameter increased after WG in EU (BL 71[8] vs. WG 76[10] µm p=0.007, paired t test) but not in SA (85[12] vs. 86[11] µm p=0.40). SA had more large (L 90-145μm) and very large (VL &gt;145μm) adipocytes than EU at BL (L 37.3 vs. 16.7%, VL 1.92 vs. 0.25 % p&lt;0.001, χ2 test) and after WG (41.1 vs. 23.1 %, 1.85 vs. 0.17 % p&lt;0.001). Proportions of small (S &lt;45µm) and L (S 10.0 vs. 4.7 %, L 16.7 vs. 23.1 % p&lt;0.001) adipocytes were reduced and increased respectively in EU after WG. Smaller changes were seen in SA (S 6.2 vs. 4.1 %; L 37.3 vs. 41.0 % p=0.001). At BL and WG TNF expression was higher in SA (EU 0.04[0.04] vs. SA 0.12[0.15] % expression/PPIA p=0.004) while ADIPOQ (1069[372.1] vs. 874.1[271.8] % p=0.042) and ESR1 (6.7[3.0] vs. 4.2[2.8] % p&lt;0.001) were lower. SREBF1 and LEP expressin were higher in SA and increased after WG, while INSR, SIRT1, CIDEA, GHR and PLIN2 were lower in SA and reduced after WG. An interaction (p=0.06) was found between ethnicity and WG for APOE which decreased after WG to a greater extent in EU (EU 42.2 vs. SA 16.6 % change in expression p&lt;0.001). To conclude, SA store fat in larger adipocytes than EU that are minimally altered by WG. SA adipocytes express higher levels of inflammation and fat storage genes and lower levels of insulin sensitivity and adipogenesis genes which are further increased and decreased respectively by WG. The adverse impact of WG on SA adipocyte may underlie their higher risk of T2DM. Assessment of pre-adipocyte differentiation ability in response to WG is underway.

Disclosure
X. Gao: None. J. McLaren: None. D.J. Freeman: None. J.M.R. Gill: None.
1644-P: High Throughput Approach Enables Expanded Clustering of Type 2 Diabetes Genetic Loci Informed by Phenotypic Associations
Authors: KIM HYUNKYUNG , VON GROTTHUSS MARCIN , MERCADER JOSEP M. , CHIOU JOSHUA , GAULTON KYLE J. , MANNING ALISA , FLOREZ JOSE C. , UDLER MIRIAM 
Published: June 2020

Improved understanding of disease-causing pathways for type 2 diabetes (T2D) may lead to novel therapeutic targets and individualized treatment. Rapid expansion in the number of T2D genetic loci over the past few years can be leveraged to identify pathways via cluster analysis.
We developed an automated pipeline to enable clustering of T2D genetic loci starting with genome-wide association study (GWAS) summary statistics from 6 European T2D studies. The pipeline 1) extracts variants reaching genome-wide significance, 2) replaces multi-allelic, ambiguous (A/T, C/G), or low-trait count SNPs with appropriate proxies, and 3) filters for independent signals using r2=0. Traits in the T2D Knowledge Portal with summary GWAS data in European populations were included if they met a minimum Bonferroni p-value across the selected variants. This pipeline generated a matrix of associations for 259 independent T2D variants and 32 traits to which we applied Bayesian Non-negative Matrix Factorization (bNMF) clustering.
We identified 6 robust clusters of T2D loci, 5 of which overlapped with a previously published analysis of 94 loci. Three clusters indicated variant-trait associations related to insulin deficiency, while the other three clusters displayed insulin resistance-related features including: obesity, lipodystrophy, and liver-lipid metabolism. The new cluster identified in this analysis is related to beta cell function. Increased polygenic scores for clusters were associated with distinct clinical outcomes in GWAS, including coronary artery disease (UK BioBank CARDIoGRAM), ischemic stroke (MEGASTROKE), chronic kidney disease (CKDGen). Clusters also displayed tissue-specific epigenomic enrichment.
Our approach expands upon previous clustering work of T2D loci and allows for efficient updating as additional GWAS results become available. This method can also be readily applied to other diseases beyond T2D to identify key pathways.

Disclosure
H. Kim: None. M. von Grotthuss: None. J.M. Mercader: None. J. Chiou: None. K.J. Gaulton: Consultant; Self; Genentech, Inc. Employee; Spouse/Partner; Vertex Pharmaceuticals. A. Manning: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. M. Udler: None.

Funding
National Institutes of Health
165-LB: Increasing Heart-Healthy Behaviors in Youth with Type 1 Diabetes (T1D): A Feasibility Study
Authors: KAUSHAL TARA , CHARMANT CHARNICE O. , VOLKENING LISA K. , LAFFEL LORI M. , KATZ MICHELLE 
Published: June 2020

Background: Diabetes increases cardiovascular disease (CVD) risk, yet many youth with T1D are not effectively managed for hypertension (HTN) or hyperlipidemia (HPL). Lifestyle management remains 1st-line pediatric therapy, creating a need for effective clinical interventions. As digital health and financial incentives may help motivate behavior change, we sought to test feasibility of a scalable digital health intervention to motivate heart healthy behaviors in youth with T1D.
Methods: We recruited 44 teens (ages 14-19 years; T1D duration ≥6 months; and either HTN, HPL, overweight/obesity, or A1C ≥8%) into a 3-month pilot RCT. Teens were randomized 1:1 to intervention (INT) or control (C) groups. INT received educational/goal-setting modules and bi-weekly team challenges using a smartphone with participants earning points leading to financial rewards; C group received educational/goal-setting modules after 3 months. Primary outcome was the Adolescent Food Habits Checklist (AHFC), a 23-item questionnaire (higher score = healthier food habits), administered at baseline and after 3 months. Participants completed a satisfaction survey after the RCT.
Results: At entry, the sample was 30% male, 88% non-Hispanic white, aged 17±1.6 (X±SD) yrs with T1D duration 8.7±3.3 yrs; 82% were pump-treated, 63% used CGM, A1C was 9.3±1.6%; BMI %ile was 84±17, BP 106±9/66±6, LDL 99±33 mg/dL. Groups only differed in BMI %ile (INT 90 vs. C 77, p&lt;.03). Both groups increased their AHFC scores over time (INT +3.5, p&lt;.01; C +2.3, p&lt;.03); change in AHFC did not differ between groups (p=.33) when adjusting for baseline score. In INT group, 64% found materials/activities engaging and 79% were glad to participate.
Conclusions: An intervention with educational materials supplemented by a smartphone app using a point-based financial reward structure was feasible and acceptable for teens with T1D at increased CVD risk. Further research is needed to assess durability of the intervention and its impact on CVD risk factors.

Disclosure
T. Kaushal: None. C.O. Charmant: None. L.K. Volkening: None. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. M. Katz: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Funding
National Institutes of Health (5K12DK094721-09, P30DK036836, K23HL125976)
166-LB: Participants with KATP-Related Neonatal Diabetes (KATP-NDM) Experience More Sleep Disruption than Sibling Controls
Authors: TIAN PERSEPHONE , CHOPPARA SAMPATH , HARRIS ANASTASIA , LETOURNEAU-FREIBERG LISA R. , GREELEY SIRI ATMA W. 
Published: June 2020

Background: Neonatal diabetes is rare, but most commonly caused by activating heterozygous mutations in either of the KATP channel genes KCNJ11or ABCC8. While a large fraction of those with KATP-NDM exhibit a spectrum of neurodevelopmental difficulties, patients and families also describe difficulties with sleep that has not been well-characterized.
Methods: To assess sleep duration and quality, all participants wore an actigrapher (Actiwatch® 2) for at least 7 full days and completed sleep questionnaires based on age: parents of 0-11 years old participants completed the Children’s Sleep Habits Questionnaire (CSHQ), while participants 12+ years completed the Pittsburgh Sleep Quality Index (PSQI) themselves.
Results: 12 affected individuals and 5 sibling controls completed all components of the study: 0-11 yo: 7 affected, 3 controls; 12+ yo: 5 affected, 2 controls. Affected participants had significantly less total sleep time of 433.4 minutes/night, compared to 506.2 minutes/night in controls (p = 0.003). All affected 0-11 yo individuals exhibited sleep disturbance on CSHQ (qualified as a score greater than 41). In contrast, affected 12+ yo individuals did not report significantly greater global sleep scores on the PSQI compared to controls; however, those with R201H/C mutations reported a sleep disturbance score that trended towards being significantly greater than those with V59M/A mutations (55 vs. 46; p = 0.0525).
Conclusion: Objective total sleep time was reduced in KATP-NDM, with parents reporting greater sleep difficulties than self-reported measures by older affected individuals. Neurodevelopmental supports in individuals with KATP-NDM should include assessment of sleep, but more study is required to further characterize specific disruptions that may depend on age and/or specific mutations.

Disclosure
P. Tian: None. S. Choppara: None. A. Harris: None. L.R. Letourneau-Freiberg: None. S.W. Greeley: None.

Funding
American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)
1670-P: Enalapril Maleate, Angiotensin-Converting Enzyme Inhibitor, Suppresses the Expression of the MHC Molecules in Mucosal Cells of the Small Intestine Leading to the Delayed Onset of Autoimmune Type 1 Diabetes Mellitus in NOD Mice
Authors: HATTORI MASAKAZU , UEDA AIKO , KATOH RYUICHI , HIRAI MASATAKA , NODA AKIHIRO , MAYANAGI KAZUYA , FURUICHI YOSHITO , HATTORI KIMIE , LUND TORBEN , KOBAYASHI KENJI , NAKAMURA YASUYUKI 
Published: June 2020

Angiotensin-converting enzyme (ACE) exists in the kidney, lung and small intestine of the NOD mouse (autoimmune type 1 diabetes animal model). ACE changes Angiotensin I to Angiotensin II. ACE exists in the small intestinal epithelial cells and villi, and digests the protein antigen molecules in the small intestine. ACE plays an important role in the antigen presenting process in the mucosal immune system of the duodenum and jejunum. To examine if ACE has a role in the development of type 1 diabetes of the NOD mouse, ACE Inhibitors, enalapril maleate (EM) or captopril (CA) was dissolved in a drinking water at the concentration of 12.5μg/ml and given daily to 28-day-old NOD mice ad libitum (89 females and 70 males in CA, 72 and 52 in EM, 120 and 87 in water control group, respectively). The animals were screened for the development of diabetes twice a week for 7 months and subjected to the Life Table analysis. The incidence of diabetes in our NOD/Kmc colony is 83% in females and 40% in males at 210 days of age. The EM-treated NOD mice showed a significant delay of the onset of diabetes at 120 days of age in comparison with the controls (25% vs. 45% in females, P=0.002; 0% vs. 8% in males, P=0.037). The CA treatment was ineffective to delay the onset of diabetes. The histological examination of the pancreata showed that the EM-treated females had more islets without lymphocytic infiltration than the water-control females (mean number of undamaged islets±SD: 11.1±8.5 in EM vs. 1.9±2.5 in Control, P=0.009). The undamaged islets weighed 0.772±0.383 in EM and 0.441±0.386 in water-control (mg: mean±SE). The mRNA expression of MHC K and A genes was suppressed in the duodenum and jejunum of the NOD mice by EM- or CA-water for 14 days. Flow cytometric analysis showed suppression of the MHC K and I-A expression in the pancreatic lymphocytes of the EM- and CA-treated mice in comparison with the control mice.

Disclosure
M. Hattori: None. A. Ueda: None. R. Katoh: None. M. Hirai: None. A. Noda: None. K. Mayanagi: None. Y. Furuichi: None. K. Hattori: None. T. Lund: None. K. Kobayashi: None. Y. Nakamura: None.
1675-P: Adipocyte Adaptive Immune Cell Function and Exhaustion Contribute to the Drop in Adipose Tissue (AT) Regulatory T-Cells (Tregs) in Human Obesity
Authors: BRADLEY DAVID , BLASZCZAK ALECIA M. , SMITH ALAN , JALILVAND ANAHITA D. , WRIGHT VALERIE P. , WYNE KATHLEEN , NORIA SABRENA , JOSEPH JOSHUA , LIU JOEY Z. , HSUEH WILLA 
Published: June 2020

Background: AT Tregs are decreased in obese mice. We have previously shown that preventing this decline improves insulin sensitivity, despite persistent obesity, underscoring a key role for AT Tregs in systemic metabolism. Therefore, we sought to examine AT Treg changes in human subjects and elucidate potential mechanisms responsible for these changes.
Methods: We obtained visceral (VAT) and subcutaneous adipose tissue (SAT) at elective surgery in 54 obese and 18 lean subjects, and SAT via liposuction in 15 lean subjects before and after 2 weeks high fat diet (HFD).
Results: Obese individuals had 67% less Treg abundance in VAT (p&lt;0.001) and 79% in SAT (p&lt;0.001); Tregs as %CD4+ cells correlated with insulin sensitivity and inversely with BMI. Subjects ingesting a HFD experienced a 50% drop in SAT Tregs (p&lt;0.001), which correlated with decreased insulin sensitivity by clamp. To understand this drop, we next performed gene expression analyses on isolated adipocytes, AT T cells, and VAT Tregs. Obese adipocytes had profound increases in major histocompatibility class II (MHCII) genes, but decreases in fatty acid oxidation and mitochondrial genes, suggesting a functional switch from a primary metabolic to an adaptive immune cell. These changes were associated with decreased AT Treg abundance, and increased insulin resistance and BMI. T cells revealed increased Tbet, a proinflammatory CD4+ Th1 cell marker, and decreased FOXP3, a Treg marker, consistent with our demonstration that human adipocytes can present antigen to activate CD4+ Th1 cells. Obese vs. lean VAT Tregs also had a 3-fold (p&lt;0.05) increase in the T cell exhaustion marker, program cell death protein-1 (PD-1), and a 75% (p&lt;0.05) decrease in CD127, which is attenuated in exhausted T cells.
Discussion: Thus, human adipocyte immune cell activity, combined with Treg exhaustion, contributes to the drop in AT Tregs and strongly affects metabolism.

Disclosure
D. Bradley: None. A.M. Blaszczak: None. A. Smith: None. A.D. Jalilvand: None. V.P. Wright: None. K. Wyne: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Sanofi. S. Noria: None. J. Joseph: None. J.Z. Liu: None. W. Hsueh: None.

Funding
American Diabetes Association (1-16-ICTS-049 to W.H.); National Institutes of Health (KL2TR001068, R01HL135622)
1686-P: Brown Adipose Tissue as a Novel Site for Islet Transplantation
Authors: BARRA JESSIE , KEPPLE JESSICA , TSE HUBERT M. , HUNTER CHAD S. 
Published: June 2020

Type 1 diabetes (T1D) results in hyperglycemia, increased risk for secondary complications, and life-long dependence on exogenous insulin. Islet transplantation is a promising alternative to insulin therapy for T1D treatment. However, long-term function of islets transplanted into the FDA approved hepatic portal vein remains low, with much of the islet mass being lost early after transplantation due to immune responses and drug toxicity. These challenges have prompted a search for alternative transplantation sites that are readily accessible, immune-privileged, offer graft retrievability, and promote islet survival. A novel site that exhibits these traits is brown adipose tissue (BAT), which is highly vascularized, innervated, and contains immunomodulatory immune cells. BAT functions to maintain thermogenesis and can regulate metabolic homeostasis. We hypothesize that islet engraftment in BAT can restore euglycemia in diabetic mice, promote revascularization, and delay immune rejection. Syngeneic transplantation of 250 NOD.scid islets into the BAT of streptozotocin (STZ)-treated diabetic NOD.scid mice restored euglycemia for over two months, similar to islets transplanted under the pre-clinical kidney capsule transplant site. Islet function was also comparable across transplant groups as measured by a glucose tolerance test. BAT thermogenic function during a cold challenge showed no difference in cold tolerance after transplantation. Histology and mRNA analysis revealed BAT engrafted islets expressed islet hormones, functional islet transcription factors, and CD31+ vascularization at the islet graft site. Overall, our data suggest BAT is a novel and efficacious site for islet transplantation. Future islet transplant studies will determine if the inherent properties of BAT can extend the longevity of transplanted islets by investigating the immunomodulatory capacity of BAT-resident mesenchymal stem cells and immune cells, compared to current transplantation sites.

Disclosure
J. Barra: None. J. Kepple: None. H.M. Tse: None. C.S. Hunter: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099550); JDRF (SRA-2016-270-S-B, 2-SRA-2019-692-S-B); National Institute of General Medical Sciences (T32GM008111)
1700-P: Exogenous a1-Antitrypsin A Enhances Insulin Sensitivity in Mice Fed a High-Fat Diet by Attenuation of Neutrophil Infiltration in Epididymal Fat
Authors: D’SOUZA RANDALL F. , WOODHEAD JONATHAN S.T. , MASSON STEWART W. , JAMES SAMUEL L. , HEDGES CHRISTOPHER , MERRY TROY L. 
Published: June 2020

Neutrophil elastase (NE) is a serine protease expressed by neutrophils which is inhibited endogenously by α1-Antitrypsin A (AAT). Obesity is associated with increased plasma NE:AAT ratios and adipose tissue NE accumulation, which may drive obesity-associated metabolic dysfunction. Exogenous AAT is now an FDA approved treatment for AAT deficiency, therefore we investigated whether AAT treatment may also have potential therapeutic benefits for diet induced metabolic dysfunction. Standard Chow and high-fat diet (HFD) fed male C57Bl6 mice were randomized to receive 3x weekly IP injections of either AAT (2mg) or vehicle (PBS) for 10 weeks. Chow fed mice treated with recombinant AAT showed no differences in plasma NE, body weight or metabolic phenotype compared to vehicle treated control mice. However, during HFD feeding AAT treatment attenuated increases in plasma NE and white adipose tissue (WAT) NE and neutrophil accumulation without affecting circulatory neutrophil levels or body weight. Consistent with NE knockout mice being partially protected from HFD glucose intolerance, treatment of HFD fed mice with AAT enhanced whole body insulin sensitivity which was attributed to higher insulin-dependent p-AktSer473 and reduced inflammation markers in WAT but no other peripheral tissues. Treatment of 3T3L1 adipocytes with recombinant NE impaired insulin-stimulated glucose uptake andp-AktSer473, suggesting that inhibition of NE in WAT is the primary mechanism through which AAT treatment enhances insulin sensitivity. Collectively, our data suggests AAT may play a potential role in mitigating diet-induced neutrophil infiltration in WAT insulin resistance.

Disclosure
R.F. D’Souza: None. J.S.T. Woodhead: None. S.W. Masson: None. S.L. James: None. C. Hedges: None. T.L. Merry: None.

Funding
Health Research Council of New Zealand