bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 &lt;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 &lt;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 &lt;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 &lt;0.01 and p &lt;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
180-LB: Impact of a Multidisciplinary Diabetes Care Team in Primary Care Settings on Glycemic Control
Authors: HANDLOW NICOLE E. , NOLTON BRITTANY , WINTER SARAH E. , WESSEL CYNTHIA M. , PENNOCK JENNIFER 
Published: June 2019

Purpose: A multidisciplinary team approach to diabetes management involves various healthcare members to optimize patient outcomes. However, there are limited studies that look at the effect of a multidisciplinary team on diabetes outcomes outside of endocrinology services. This study aimed to evaluate the impact of a primary care multidisciplinary team on glycemic control and additional risk reduction during a 12-week diabetes program.
Methods: Retrospective review of medical records for patients who completed the 12-week diabetes program at three primary care clinics from January to August of 2018 occurred. The primary outcome was mean change in hemoglobin A1c (HbA1c). Secondary outcomes included 24-week HbA1c, mean change in blood pressure, weight, Diabetes Distress Scale (DDS) score, and Patient Health Questionnaire (PHQ9) score. Other secondary objectives included the number of patients on statin therapy and ACE inhibitor or angiotensin receptor blocker therapy as indicated. Patients enrolled in the diabetes program were seen by a provider, pharmacist, dietician, and behavioral health specialist at an initial visit and a 12-week follow-up visit. Follow-up occurred either telephonically or face-to-face in the interim for lifestyle counseling and medication adjustments.
Results: In total, 85 patients were included in the final analysis. At 3 month follow-up, the mean A1c was significantly decreased (2.1+/-2.3, p &lt; 0.001), 54.1% of patients met their A1c goal (p &lt; 0.001), 80.5% were on statin therapy (p &lt; 0.001), and the mean change in weight (kg) was -1.96+/- 3.9 (p = 0.001) from baseline.
Conclusion: This study demonstrates that a multidisciplinary approach to diabetes management can reduce HbA1c and other risk factors. A multidisciplinary model can be replicated in primary care offices to allow for comprehensive care and improvement in health outcomes for a broader patient population who may not have access to specialty services.

Disclosure
N.E. Handlow: None. B. Nolton: None. S.E. Winter: None. C.M. Wessel: None. J. Pennock: None.

Funding
R.K. Mellon Foundation
181-OR: ADA Presidents' Select Abstract: Fox01 Deficiency Impedes Beta-Cell Compensation for Maternal Insulin Resistance and Causes Gestational Diabetes in Female Mice
Authors: YAMAUCHI JUN , ZHANG TING , LEE SOJIN , DONG H. HENRY 
Published: June 2019

Beta-cell compensation is an adaptive mechanism by which beta-cells increase insulin secretion to overcome insulin resistance for maintaining euglycemia in obesity. Likewise, beta-cell compensation occurs during pregnancy, a physiological state that is characterized by increased insulin demand from the fetus. This effect, along with acquired insulin resistance in the mother, promotes beta-cell compensation for maintaining glucose homeostasis during gestation. Insufficient beta-cell compensation for maternal insulin resistance contributes to gestational diabetes. To understand the underlying mechanism of gestational diabetes, we determined the role of FoxO1 in regulating beta-cell mass and function in response to maternal insulin resistance. FoxO1 is a key transcription factor that mediates insulin action on cell metabolism, survival, proliferation, differentiation and oxidative stress. We found that beta-cell FoxO1 expression becomes markedly upregulated, coinciding with the induction of beta-cell compensation in pregnant mice. To gain mechanistic insight into FoxO1-mediated induction of gestational beta-cell compensation, we generated FoxO1-KO mice, in which FoxO1 is conditionally deleted in mature islets of adult mice using an inducible Pdx1-Cre-ERT system. We showed that prior to gestation, female FoxO1-KO mice exhibited normal blood glucose metabolism. However, at gestational day 14.5, pregnant FoxO1-KO mice exhibited fasting hyperglycemia and glucose intolerance. These effects were attributable to abnormal glucose-stimulated insulin secretion profiles in pregnant FoxO1-KO vs. control female mice. Using in vivo Brdu-labeling assay, we showed that FoxO1-deficient islets were associated with impaired abilities to mount a compensatory induction in beta-cell mass during pregnancy. Our data characterize FoxO1 as a pivotal factor for regulating the adaptive changes of beta-cell mass and function during pregnancy.

Disclosure
J. Yamauchi: None. T. Zhang: None. S. Lee: None. H. Dong: None.

Funding
National Institutes of Health
1816-P: Sex-Specific Metabolic Imbalance and Hypothalamic Inflammation Triggered by Low-Grade Benzene Exposure
Authors: DEBARBA LUCAS K. , MULKA ADAM , AWADA ABEAR A. , DIDYUK OLESYA , KLUEH ULRIKE , SADAGURSKI MARIANNA 
Published: June 2019

Current studies have shown that insulin resistance, T2D have been associated with long- term exposure to air and traffic pollution. Benzene is a highly volatile liquid, which is a constituent of crude petroleum. Given its ubiquitous utilization in industry as well as consumer products, it is classified as a common airborne pollutant. We hypothesized that benzene, at levels below carcinogenic contributes to insulin resistance and inflammatory responses linking persistent organic pollutants exposure to T2D mellitus. For this purpose, C57BL/6 mice in inhalation chambers were exposed to benzene concentration of 50 ppm for 6h/day for 4 weeks. We found that under these conditions, exposure to benzene did not significantly influence mice body weight, neither had it trigger any toxic responses in these animals. Despite normal fasting glucose and insulin levels, benzene-exposed male mice displayed significantly impaired glucose tolerance. Consequently, we detected an increase in hepatic genes associated with gluconeogenesis, G6Pase and Pck1, and the expression of SREBP-1c and SREBP-2, genes associated with lipid synthesis was significantly elevated in livers from benzene exposed male mice as compared to control mice. Female mice were completely resistant to the negative metabolic consequences of chronic benzene exposure. Further sex differences were apparent in neuroinflammatory responses, with greater male vulnerability observed in the hypothalamus of benzene- exposed animals. Benzene exposure promoted hypothalamic gliosis and robust neuronal activation in the arcuate, paraventricular, ventromedial and dorsomedial hypothalamic nucleus. These findings demonstrate male vulnerability to air pollution, and provide evidence that exposure to benzene induces metabolic imbalance and severe neuroinflammatory responses in a sex-specific manner. Persistent ambient benzene exposure may be a heretofore unrecognized contributor to metabolic diseases with male bias.

Disclosure
L.K. Debarba: None. A. Mulka: None. A.A. Awada: None. O. Didyuk: None. U. Klueh: Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC. M. Sadagurski: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust