bluuebunny/crossref_metadata_2025 huggingface dataset:
1735-P: Oral Exposure to Air Pollutants Mediates Diabetes via Innate Immunity
Authors: BOSCH ANGELA J.T. , ROHM THERESA V. , ALASFOOR SHEFAA , BAUMANN ZORA , CAVELTI-WEDER CLAUDIA
Published: June 2019

Background: Besides classical risk factors such as sedentary lifestyle and unhealthy diet, air pollution has emerged as an unexpected risk factor for type 2 diabetes. However, the causal mechanism remains poorly understood. Air pollution particles are known to reach the gastrointestinal tract by mucociliary clearance. Underlining the clinical relevance of oral exposure, air pollution has been associated with a variety of gastrointestinal diseases. Therefore, we aim to study the effects of oral air pollution exposure on glucose metabolism and a potential immune-mediated mechanism.

Research Design and Method: Male C57B6/N, Rag2-/- and CCR2-/- mice or mice on a diet supplemented with a Csfr1-inhibitor were exposed to diesel exhaust particles (DEP; 12µg 5 days/week) or PBS by gavage for up to 6 months. Glycemia, tissue inflammation and immune cells were assessed.

Results: Mice orally treated with DEP developed impaired glucose tolerance with reduced insulin secretion, while insulin resistance, systemic, adipose tissue and liver inflammation were not induced. This effect was independent of the adaptive immunity as Rag2-/- mice, which are devoid of B and T cells, also became glucose intolerant. In contrast, glucose intolerance did not develop in CCR2-/- mice and mice treated with a Csfr1-inhibitor. Supporting a causative role of intestinal macrophages in air pollution-induced diabetes, wild type mice exposed to oral DEP had reduced anti-inflammatory, resident macrophages in the lamina propria of the gut.

Conclusion: Oral exposure to air pollutants results in impaired glucose tolerance, which is mediated by innate immunity as we found a loss of anti-inflammatory, resident macrophages in the gut. Moreover, mice devoid of macrophages are protected from air pollution-induced diabetes. Our findings provide a new understanding how environmental pollutants affect metabolic health, which is crucial for preventing the worldwide disease burden of air pollution-induced diabetes.

Disclosure

A.J.T. Bosch: None. T.V. Rohm: None. S. AlAsfoor: None. Z. Baumann: None. C. Cavelti-Weder: None.
1740-P: Gene-Editing of FOXP3 in Antigen-Specific CD4+ T Cells for Restoration of Immune Tolerance in Type 1 Diabetes
Authors: XIANG YUFEI , SOMMER KAREN , HONAKER YUCHI , SMITH JESSICA , TORGERSON TROY R. , BUCKNER JANE , RAWLINGS DAVID
Published: June 2019

Clinical trials for type 1 diabetes (T1D) using expanded, autologous natural regulatory T cells (nTreg) have demonstrated safety and sustained engraftment. Limitations to this approach include the requirement for potential instability in vivo, lack of antigen specificity, and intrinsic Treg defects in some patients. As an alternative strategy, we used gene editing to convert primary human or mouse CD4+T cells into immunosuppressive Treg-like cells. Our approach utilizes co-delivery of designer nucleases and AAV6 homology-directed repair templates to enforce the expression of FOXP3, a transcription factor determining Treg development. These edited (ed)Treg exhibit a phenotype and functional activity similar to nTreg and ameliorate the inflammatory xenograft response of effector T cells in NOD-scid-Il2rgnull (NSG) mice. In the current study, we hypothesized that antigen-specific edTreg would exhibit increased potency in treatment of autoimmune diseases including T1D. As an initial test of feasibility, we generated edTreg from flu- or tetanus-specific human CD4+ T cells and demonstrated antigen-specific suppressive activity. Next, we show proof-of-concept for antigen (Ag)-specific edTreg in a T1D mouse model. Using mouse-specific nucleases and donor templates, we edited CD4+T cells from transgenic NOD mice expressing the diabetogenic, BDC2.5, TCR. BDC2.5 edTreg were similar to nTreg on the basis of key cell markers and cytokine production. BDC2.5 edTreg or polyclonal edTreg from NOD mice were co-transferred with effector BDC2.5 T cells (CD4+CD25-) into NSG mice. Recipients of only effector cells exhibited rapid diabetes onset. In contrast, edTreg delayed disease and, as hypothesized, Ag-specific edTreg exhibited much greater suppression and longer delays in T1D onset. Together, our findings demonstrate the capacity to generate functional, Ag-specific, edTreg with potential therapeutic application in promoting immune tolerance in T1D.

Disclosure

Y. Xiang: None. K. Sommer: None. Y. Honaker: None. J. Smith: None. T.R. Torgerson: Consultant; Self; CSL Behring, Grifols, Shire, UCB, Inc. Research Support; Self; CSL Behring. J. Buckner: None. D. Rawlings: None.

Funding

Seattle Children’s Research Institute, Seattle Children's Center for Immunity and Immunotherapies; Seattle Children's Program in Cell and Gene Therapy; Seattle Children's Guild Association (to D.R.); The Leona M. and Harry B. Helmsley Charitable Trust (to D.R.); National Institutes of Health (DP3DK111802-01 to D.R.)
1741-P: Overexpression of the Type 1 Diabetes-Associated IFIH1 A946T Single Nucleotide Polymorphism in Coxsackievirus B Infection
Authors: TAYLOR JARED P. , TSE HUBERT M.
Published: June 2019

Type 1 diabetes (T1D) is a multifactorial autoimmune disease with a strong genetic basis. However, evidence suggests a role for environmental factors such as viral infections in triggering disease onset. One viral infection that is highly correlated with T1D is the Coxsackievirus B (CVB) serotype. Sensing of CVB is mediated by the melanoma differentiation-associated protein 5 (MDA5), a cytosolic sensor of dsRNA, which is encoded by the IFIH1 gene. Stimulation of the MDA5 signaling pathway activates the transcription factors IRF3 and NFκB p65, which induce type I IFNs synthesis. Type I IFNs can signal in an autocrine manner through the JAK/STAT pathway to initiate an antiviral transcriptional program. Single nucleotide polymorphisms (SNP) in the IFIH1 gene such as rs1990760, which results in a non-synonymous mutation that changes alanine at position 946 to a threonine, is highly associated with increased risk for T1D. Studies in human PBMCs and mice have demonstrated that the A946T SNP results in an increased sensitivity to viral ligands and subsequently a stronger downstream IFN response. We hypothesize that cells overexpressing the type I diabetes-associated variant 946T will have enhanced downstream signaling and subsequent type I IFN secretion in response to viral ligands and CVB infection. To test this, we stably overexpressed MDA5 with the 946A or 946T variants in HeLa cells. We anticipate that signaling events downstream of CVB infection and synthetic ligand poly (I:C) treatment, such as levels of phosphorylated IRF3 and NFκB p65 will be increased in cells expressing the T1D-associated allele 946T in contrast to cells overexpressing the non-risk allele 946A. Corroborating the increase in IRF3 and NFκB p65 pathway activation, we expect to observe enhanced production and secretion of type I IFNs were measured using HEK Blue IFN reporter cells that may partly explain how CVB infections can trigger autoimmune diabetes.

Disclosure

J.P. Taylor: None. H.M. Tse: None.

Funding

National Institutes of Health
1742-P: Blockade and Reversal of Autoimmunity and Type 1 Diabetes through Gene-Therapeutic and Nutritional Intervention of Elevating ω-3 PUFAs
Authors: BI XINYUN , LI XIAOXI , ZHAO ALLAN ZIJIAN
Published: June 2019

Despite the benefit of insulin injection, blockade of autoimmune attack and regeneration of pancreatic islets remain to be the ultimate sought-after goal for the complete cure of type 1 diabetes(T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for both prevention and amelioration of autoimmune diseases. Herein, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, readjusted the population of Th1, Th2, Th17 and Treg, balanced the ratio of Th1/Th2, decreased the levels of such cytokines as IFN-γ, IL-17, IL-6 and TNF-α. In T1D patients, ω-3 PUFAs also regulated CD4+ T-cell differentiation isolated from peripheral blood mononuclear cells (PBMCs) in a manner similar to that observed in NOD mice. The regulation of CD4+ T-cell differentiation was mediated at least in part through some of their eicosanoid derivatives and by inhibition of mTORC1. Importantly, therapeutic intervention in NOD mice through nutritional or gene-therapeutic supplementation completely normalized blood glucose and insulin levels for at least 182 days, blocked autoimmune development, prevented lymphocyte infiltration into regenerated islets, and sharply elevated expression of Pdx1 and Pax4. The findings revealed herein can potentially become a novel and cost-effective therapeutic modality in the cure of T1D.

Disclosure

X. Bi: None. X. Li: None.

Funding

National Natural Science Foundation of China
1757-P: Ginsenoside Rb2 Alleviates Obesity by Activation of Brown Fat and Induction of Browning of White Fat
Authors: GU XUEJIANG
Published: June 2019

Ginsenoside Rb2 (Rb2), the most abundant saponin contained in Panax ginseng, has been used to treat variety of metabolic diseases. However, its effects in obesity and potential mechanism are not well understood. In the present study, we investigate the metabolic performances with Rb2 supplement in diet induced obese (DIO) mice, focusing on assessing the effects and mechanisms of Rb2 on brown and beige fat functions. Our results demonstrated that Rb2 effectively reduced body weight, improved insulin sensitivity, as well as induced energy expenditure in DIO mice. Histological and gene analysis revealed that Rb2 induced activation of brown fat and browning of white fat as shown by reduced lipid droplets, increased UCP1 staining and increased thermogenic and mitochondrial genes, which could be recapitulated in 3T3-L1, C3H10T1/2 and primary adipocytes. In addition, Rb2 induces AMPK phosphorylation both in vitro and in vivo and these effects were shown to be dependent on AMPK since its inhibitor blocked Rb2 induced expressions of Pgc1α and Ucp1. Overall the present study revealed that Rb2 activates brown fat and induces browning of white fat, which increases energy expenditure and thermogenesis and consequently ameliorates obesity and metabolic disorders, suggesting Rb2 to be a promising beneficial compound treating obesity.

Disclosure

X. Gu: None.
1759-P: Effects of High-Fat Feeding on Adipose Tissue Matrisome Composition in Female Mice
Authors: BAILEY JENNIFER L. , ELKS CARRIE M.
Published: June 2019

Alterations in adipose tissue (AT) extracellular matrix (ECM) organization and/or composition accompany several pathologies, including obesity and diabetes. The need to better understand overall AT ECM composition and structure is essential to unraveling the pathogenesis of obesity, especially when considering that a given tissue ‘matrisome’ (a protein signature comprised of core ECM proteins plus ECM-associated proteins) can consist of several hundred proteins. Recent methods have exploited the insolubility of ECM proteins to allow their enrichment from decellularized tissues and subsequent proteomic analysis, but to our knowledge these methods have not been performed in AT. In this study, we used this methodology to characterize the AT matrisome in female mice fed control or high-fat diets. Female C57BL/6J mice were fed control (n=6) or high-fat (n=6) diets for 8 weeks. Body weights were obtained weekly and body composition was analyzed biweekly via NMR. At study end, AT samples were decellularized and enriched for ECM proteins using a commercially available kit. The ECM-enriched fractions were digested, deglycosylated, fractionated into peptides, LC-MS/MS performed, and raw data analyzed using Proteome Discoverer v2.2. Our data reveal that high-fat feeding does not significantly affect AT collagen levels in female mice, but does significantly increase glycoprotein levels (spondin 1, SPARC, adiponectin). Conversely, a significant decrease in the proteoglycan, PRG3, was also observed in AT with high-fat feeding. Several additional ECM-associated proteins, which have undefined roles AT, were differentially regulated by high-fat diet feeding in female mice. Current studies are focused on determining how these proteins influence AT metabolism.

Disclosure

J.L. Bailey: None. C.M. Elks: None.

Funding

National Institutes of Health
1760-P: Tetrahydrobiopterin Regulates Developmental Differentiation of Brown Adipose Tissue
Authors: MINAMINO HIROTO , FUJITA YOSHIHITO , OGURI YASUO , GOTO TSUYOSHI , OHASHI AKIKO , FURUYA FUTOSHI , ISOMURA NOZOMI , KAWARASAKI SATOKO , KAWADA TERUO , HASEGAWA HIROYUKI , INAGAKI NOBUYA
Published: June 2019

Brown adipose tissue (BAT) is a key organ that produces heat and increases energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity and diabetes. Tetrahydrobiopterin (BH4) is an essential co-factor of tyrosine hydroxylase and nitric oxide synthase. Our group recently showed that BH4 activates BAT function and regulates systemic energy metabolism using Hph-1 mice, a mouse model of BH4 deficiency in which GTP-cyclohydrolase I (GTPCH I), a rate-limiting enzyme of BH4, synthesis is deficient. Interestingly, we found that dysplasia of BAT already has been confirmed in the neonatal period. We investigated the role of BH4 in the development and differentiation of BAT using the mouse model of BH4 deficiency. Compared with control mice, Hph-1 neonatal mice exhibited lower weight of BAT as well as attenuated thermogenesis-related gene expressions (UCP1, Dio2, Pgc1a). We also evaluated the role of BH4 in brown adipocyte differentiation using brown pre-adipocytes isolated from control and Hph-1 mice. Compared with control mice, brown pre-adipocytes from Hph-1 mice reduced differentiation capacity measured by accumulated lipid droplets and thermogenesis-related gene expressions. In addition, inhibition of GTPCH I by 2,4-Diamino-6-Hydroxypyrimidine (DAHP) reduced differentiation capacity in brown pre-adipocytes. These data strongly suggest that BH4 is required for brown adipocyte differentiation. Furthermore, supplementation of BH4 in brown pre-adipocytes from Hph-1 mice dose-dependently increased accumulation of lipid droplets, thermogenesis-related gene expressions, and nitric oxide production. Taken together, BH4 plays an integral role in developmental differentiation of BAT, and has therapeutic potential for metabolic disorders such as obesity and diabetes.

Disclosure

H. Minamino: None. Y. Fujita: None. Y. Oguri: None. T. Goto: None. A. Ohashi: None. F. Furuya: None. N. Isomura: None. S. Kawarasaki: None. T. Kawada: None. H. Hasegawa: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
177-OR: Genome-Wide Association Study of Lipid Traits in Youth with Type 2 Diabetes: The ProDiGY (Progress in Diabetes Genetics in Youth) Consortium
Authors: CHEN LING , SRINIVASAN SHYLAJA , SANTORO NICOLA , TODD JENNIFER , DIVERS JASMIN , SHAH AMY SANGHAVI , GIDDING SAMUEL , BURKE BRIAN K. , HAYMOND MOREY W. , LANGE LESLIE , MARCOVINA SANTICA M. , CHAIT ALAN , FLANNICK JASON , CAPRIO SONIA , FLOREZ JOSE C.
Published: June 2019

Type 2 diabetes (T2D) in youth is associated with a pro-atherogenic lipid profile characterized by high triglycerides (TG), high low-density lipoprotein cholesterol (LDL-c), and low high-density lipoprotein cholesterol (HDL-c). Genome wide association studies (GWAS) in adults have discovered more than 100 variants associated with lipid traits, but the association of genetic variants to dyslipidemia in youth with T2D remains unknown. Therefore, we genotyped 206,928 variants and imputed 17,642,824 variants in 1,076 youth with T2D from the Treatment Options for type 2 diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) as part of ProDiGY, a collaboration with type 2 diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES). Using a linear mixed model, we performed association testing for TG, LDL-c and HDL-c adjusted for age, sex, body mass index (BMI) Z-score, HbA1c, and genetic relationship matrix within each sub-study followed by meta-analyses for each lipid trait. We identified a novel variant between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) that was associated with TG levels at genome wide level of significance (P-value=2.26×10-8, β=0.21±0.09). We also identified a genome-wide significant variant rs247617 (P-value=5.12×10-9, β=2.52±0.43) between HERFUD1 and CETP for association with HDL-c. This variant has been previously reported to be associated with HDL-c in adults in the Global Lipids Genetics Consortium (GLGC). We did not find any genome-wide significant variants in the LDL-c analysis.

In summary, our genetic analyses of lipid traits in youth with T2D identified one novel and one previously known locus. Further multi-phenotype analysis may uncover additional loci associated with lipid traits in youth with T2D.

Disclosure

L. Chen: None. S. Srinivasan: None. N. Santoro: None. J. Todd: None. J. Divers: None. A.S. Shah: None. S. Gidding: Research Support; Self; Color Genomics. B.K. Burke: None. M.W. Haymond: Advisory Panel; Self; Daiichi Sankyo Company, Limited, Zealand Pharma A/S. Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca. L. Lange: None. S.M. Marcovina: None. A. Chait: Consultant; Self; MedImmune. J. Flannick: Consultant; Self; Decibel Therapeutics. S. Caprio: None. J.C. Florez: None.

Funding

National Institutes of Health
1771-P: Upregulation of RETN, TNFα, and CCL2 mRNAs in Adipocytes by Intermittent Hypoxia and Its MicroRNA-Mediated Mechanism
Authors: UCHIYAMA TOMOKO , ITAYA-HIRONAKA ASAKO , YAMAUCHI AKIYO , MAKINO MAI , SAKURAMOTO-TSUCHIDA SUMIYO , SHOBATAKE RYOGO , OTA HIROYO , TAKEDA MAIKO , OHBAYASHI CHIHO , TAKASAWA SHIN
Published: June 2019

Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for insulin resistance/type 2 diabetes. IH is considered to cause adipose tissue inflammation, leading to insulin resistance. In this study, we exposed mouse 3T3-L1 and human SW872 adipocytes to experimental IH (1% O2, 5% CO2 [5 min], 21% O2, 5% CO2 [10 min]) or normoxia (21% O2, 5% CO2) for 24 h, and analyzed mRNA expression of adipokines (leptin, adiponectin, resistin [RETN], tumor necrosis factor α [TNFα], IL-6, and C-C motif chemokine ligand 2 [CCL2]). We found that the mRNA levels of RETN, TNFα and CCL2 in SW872 cells (P=0.0257, P=0.0312, and P<0.0001, respectively) and 3T3-L1 adipocytes (P=0.0498, P=0.0237, and P=0.0002, respectively) were significantly increased by IH. RETN, TNFα, and CCL2 in IH-treated cell medium were also increased (P=0.0256, P=0.0215, and P<0.0001, respectively). We next prepared reporter plasmids containing human RETN (-979∼+20), TNFα (-966∼+19) and CCL2 (-3455∼+25) upstream of luciferase reporter gene, and transfected them into SW872 cells. The promoter activities of these genes were not increased by IH. Target mRNA search of microRNA (miR)s using MicroRNA.org program revealed that all the mRNAs have a potential target sequence for miR-452. The miR-452 level of IH-treated cells was significantly decreased than that of normoxia-treated cells (P=0.0458). To clarify the role of miR-452, miR-452 mimic and non-specific control RNA (miR-452 mimic NC) were introduced into SW872 cells, and the IH-induced up-regulation of RETN, TNFα, and CCL2 was abolished by introduction of miR-452 mimic but not by miR-452 mimic NC. These results indicate that IH stress down-regulates the miR-452 in adipocytes, resulting in the increased levels of RETN, TNFα, and CCL2 mRNA via the inhibition of the miR-452-mediated mRNA degradation, leading SAS patients to insulin resistance.

Disclosure

T. Uchiyama: None. A. Itaya-Hironaka: None. A. Yamauchi: None. M. Makino: None. S. Sakuramoto-Tsuchida: None. R. Shobatake: None. H. Ota: None. M. Takeda: None. C. Ohbayashi: None. S. Takasawa: None.
1773-P: Beta-Catenin Is a Key Player in Insulin-Stimulated Skeletal Muscle Glucose Transport
Authors: MASSON STEWART W.C. , SHEPHERD PETER R. , MERRY TROY L.
Published: June 2019

Recent work has identified β-catenin as a potential regulator of vesicle trafficking within various tissues including synapses, pancreatic β-cells, and adipocytes. The trafficking of GLUT4 vesicles to the cell membrane is essential for insulin-stimulated glucose uptake. Here we provide evidence for a role of β-catenin in regulating skeletal muscle glucose transport. In in vivo models, β-catenin is sensitive to insulin, which through PI3 kinase and Akt triggers phosphorylation of β-catenin at serine 552 (S552). Substituting S552 to alanine impairs glucose transport in L6-GLUT4-myc cells suggesting S552 is key in β-catenin-regulated glucose transport. Furthermore, inhibition of β-catenin in ex vivo models and cell culture impairs insulin-stimulated glucose transport. Using transcriptional inhibitors we demonstrate that β-catenin’s regulation of glucose transport is at least in part independent of its role in gene regulation. Finally, we investigated whether diet induced insulin-resistance alters insulin stimulated β-cateninS552 phosphorylation in vivo. Based on β-catenin’s structure and role in other cellular processes we believe that β-catenin regulates glucose transport via interactions with cytoskeletal proteins which ultimately regulate vesicle movement.

Disclosure

S.W.C. Masson: None. P.R. Shepherd: None. T.L. Merry: None.

Funding

Royal Society of New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery
1778-P: Delivery of the Insulin Gene Using an Integrating Adeno-Associated Viral Vector (AAV) to Diabetic NOD Mice
Authors: LA QUE T. , REN BINHAI , LOGAN GRANT J. , CUNNINGHAM SHARON C. , KHANDEKAR NEETA , NASSIF NAJAH T. , O'BRIEN BRONWYN A. , ALEXANDER IAN E. , SIMPSON ANN M.
Published: June 2019

Previously we introduced furin-cleavable human insulin (INSFUR) to the livers in several animal models using a lentiviral vector. Reversal of diabetes with normal glucose tolerance and pancreatic transdifferentiation was seen. The aim of the present study was to ascertain if we could similarly reverse diabetes in the non-obese diabetic (NOD) mouse using a clinically-applicable AAV system to deliver INSFUR ± the β-cell transcription factor (TF) Pdx1 to the livers of the diabetic mice. The traditional AAV8 that allows predominantly episomal expression, and the hybrid AAV8/piggyBac that results in transgene integration into the host genome were used. Weight and blood glucose levels were monitored. Intraperitoneal glucose tolerance tests (IPGTTs) were performed. Immunofluorescence was carried out to monitor transduction utilising marker genes Venus and mCherry. RT-PCR was used to identify expression of pancreatic genes. Diabetic mice that received intraperitoneal (IP) injections of AAV8-INSFUR-mCherry (2.3x 1010-4.5x1010vg) became hypoglycaemic with abnormal responses to IPGTTs. No β-cell TF could be detected in the livers. Reversal of diabetes could not be achieved in the mice (n=8) that received combinations of AAV8-INSFUR-venus (5x1010 or 7.5x1010vg) and AAV8-Pdx1-mCherry (7.5x1010 vg). Both INSFUR and Pdx1 were detected using RT-PCR and immunofluorescence showed the expression of both marker genes. IPGTTs were abnormal; however, the β-cell TF MafA was detected by RT-PCR. Euglycaemia and normal IPGTTs were achieved in mice (n=4) that received AAV8/piggyBac-INSFUR-mCherry (transposase 4x1010 vg and transposon 3.5x1010 vg). The INSFUR gene and the β-cell TFs NKx6.1 and MafA were detected in the livers, however wider evidence of pancreatic transdifferentiation was not seen. This is the first in vivo study using the hybrid AAV8/piggyBac system to treat type 1 diabetes (T1D). The AAV system, with further development, may hold promise for gene therapy of T1D.

Disclosure

Q.T. La: None. B. Ren: None. G.J. Logan: None. S.C. Cunningham: None. N. Khandekar: None. N.T. Nassif: None. B.A. O'Brien: None. I.E. Alexander: Other Relationship; Self; LogicBio. A.M. Simpson: Consultant; Self; Pharmacyte Biotech.
178-LB: Use of Random Glucose Followed by HbA1c Improves the Accuracy of Opportunistic Screening
Authors: LEGVOLD BRIAN T. , STAIMEZ LISA R. , LI DONG , PHILLIPS LAWRENCE S. , RHEE MARY K.
Published: June 2019

The diagnostic accuracy of HbA1c to identify diabetes and dysglycemia as found in OGTTs is limited. Since opportunistic screening at health visits is cost-effective, and glucose is commonly included in metabolic panels obtained at such visits, we asked if use of glucose followed by HbA1c could improve the accuracy of screening. With the Screening for Impaired Glucose Tolerance (SIGT) study dataset of 1,573 adults without known diabetes, we used Receiver Operating Characteristic (ROC) analysis and OGTTs with ADA diagnostic criteria as a "standard" to evaluate screening; random plasma and capillary glucose (RPG and RCG) were measured on a separate day. Subjects were 58% female and 58% black, with mean age 47.9 year, BMI 30.3 kg/m2 and HbA1c 5.4%. Using OGTTs, 51.5% had normal glucose metabolism, 33.3% prediabetes (PreDM), 4.6% type 2 diabetes (DM), and 37.9% dysglycemia (PreDM or DM). For HbA1c to identify DM by ADA OGTT criteria, the ROC area under the curve (AUC) was 0.818 in all 1573 subjects. However, using an RPG cutoff of 100 mg/dl, the ROC was increased to 0.857 in the 576 with RPG >100 mg/dl but only 0.603 in the 997 with RPG <100 mg/dl (both p<0.001 vs. all subjects). There was similar improvement in identification of DM in the 756 subjects with RCG >100 mg/dl (ROC 0.841, p<0.001), and parallel improvement in identification of dysglycemia (ROC 0.671 for all subjects, vs. 0.740 and 0.741 for those with RPG or RCG >110 mg/dl, respectively, both p<0.001). Results were similar with RCG in a separate dataset (n=1,037). For identification of DM among those with RPG >100 mg/dl in the SIGT dataset, specificity and sensitivity were 79% and 74%, respectively, for HbA1c >5.7%, 84% and 69%, for HbA1c >5.8%, and 90% and 64% for HbA1c >5.9%.

Conclusions: Use of random glucose followed by HbA1c improves the accuracy and efficiency of screening, identifying both individuals who should and should not have an OGTT. Such a strategy might improve recognition of diabetes and prediabetes, permitting initiation of preventive management.

Disclosure

B.T. Legvold: None. L.R. Staimez: None. D. Li: None. L.S. Phillips: Advisory Panel; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; AbbVie Inc., GlaxoSmithKline plc., Kowa Pharmaceutical Europe Co. Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc. Stock/Shareholder; Self; Diasyst Inc. Other Relationship; Self; Diasyst Inc., Janssen Pharmaceuticals, Inc. M.K. Rhee: None.

Funding

U.S. Department of Veterans Affairs; National Institutes of Health
178-OR: Long-Term Treatment with Injectable Testosterone Undecanoate (TU) Improves Lipid Profile in Men with Hypogonadism and Type 2 Diabetes in Comparison to an Untreated Control Group: Ten-Year Data from a Urological Registry Study
Authors: SAAD FARID , HAIDER KARIM S. , HAIDER AHMAD
Published: June 2019

Background: In the literature, effects of testosterone on lipid pattern in men with hypogonadism are inconsistent.

Methods: Of 324 men with hypogonadism and T2DM in a registry, 152 received TU 1000 mg/12 weeks (T-group), 172 opted against treatment (CTRL). Mean changes over time between groups were compared by mixed effects model for repeated measures with random effect for intercept and fixed effects for time, group and their interaction. Changes were adjusted for age, weight, waist circumference, fasting glucose, blood pressure (BP), lipids and quality of life to account for baseline differences between the two groups.

Results: Mean age: 62.7±5.1 years.

Follow-up: Mean: 7.9, median: 9 years. All values are in mmol/L ±SE. Total cholesterol decreased by 2.8±0.1 at 10 years (T-group) and increased by 1.0±0.1 (CTRL). Estimated adjusted difference between groups: 3.9 (p<0.0001 for all). HDL increased by 0.3±0.0 (T-group) and decreased by 0.3±0.0 (CTRL), difference between groups: 0.6 (p<0.0001 for all). LDL decreased by 1.8±0.1 (T-group) and increased by 0.8±0.1 (CTRL), difference between groups: 2.7 (p<0.0001 for all). Triglyceride decreased by 1.1±0.1 (T-group) and increased by 0.4±0.0 (CTRL), difference between groups: 1.6 (p<0.0001 for all). Non-HDL decreased by 4.6±0.3 (T-group) and increased by 3.8±0.3 (CTRL), difference between groups: 8.4 (p<0.0001 for all). Remnant cholesterol decreased by 1.3±0.1 (T-group) and increased by 0.4±0.1 (CTRL), difference between groups: 1.8 (p<0.0001 for all). The lipid accumulation product (LAP, cm*mmol/L) decreased by 85.0±3.7 (T-group) and increased by 40.3±3.2 (CTRL), difference between groups: 125.3 (p<0.0001 for all).

Conclusions: Long-term TTh with TU in men with hypogonadism and T2DM sustainably improved lipid profile which worsened in untreated controls.

Disclosure

F. Saad: Employee; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Amgen Inc., Bayer AG. K.S. Haider: Speaker's Bureau; Self; Bayer AG. A. Haider: Research Support; Self; Bayer AG. Speaker's Bureau; Self; Bayer AG.

Funding

Bayer AG
1788-P: The Natural Product ZYM01 Exerts Antidiabetic and Islet-Protective Effects in Diabetic Mice and Promotes Glucagon-Like Peptide-1 Secretion
Authors: SUN YILI , LI JINGYA , LI JIA
Published: June 2019

Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1). Two classes of incretin-based therapies are available: GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. However, there are currently no clinical drugs that directly increase endogenous GLP-1 secretion. Although several nutrients induce GLP-1 secretion, there is little evidence to suggest that non-nutritive compounds directly increase GLP-1 secretion. In the present study, we demonstrated that the natural product ZYM01 from the Bougainvillea glabraChoisy (which was used for hypoglycemic by the Dai ethnic group in China) had a good hypoglycemic effect and a significant islet protection function in diabetic mouse model. ZYM01 treatment (50 mg•kg-1 •day-1) decreased plasma levels of glucose, body weight and food intake; ameliorated OGT and plasma lipid profiles; augmented plasma insulin levels; alleviated islets pathological morphology; and reduced liver lipid accumulation in db/db diabetic mouse model. Furthermore, ZYM01 enhanced GLP-1 release in C57BL/6 mice and exerted an acute hypoglycemic effect through the secretion of GLP-1 in vivo since the exendin 9-39, a GLP-1R antagonist could completely block the acute hypoglycemic effect of ZYM01. Also, in cultured STC-1 cells, ZYM01 increased intracellular calcium and promoted GLP-1 secretion in a dose- dependent manner accompanied by elevated levels of phosphorylated Erk signaling.

In summary, our study found that ZYM01 exerted the hypoglycaemic and islets protective effects, which were associated with an enhanced release of GLP-1 mediated by the activation of the Erk signaling. These findings firmly identified ZYM01 as a new viable therapeutic option for diabetes control.

Disclosure

Y. Sun: None. J. Li: None. J. Li: None.
179-LB: Confidence of Healthcare Providers to Prescribe Antihyperglycemic Agents with Cardiovascular Benefit
Authors: SHAY CHRISTINA M. , ROBB KAREN J. , MARTIN MEGAN T. , PETERSEN MATTHEW P. , SANCHEZ EDUARDO
Published: June 2019

Several antihyperglycemic agents have recently been demonstrated to provide additional glucose lowering and CVD risk reduction benefits in people living with type 2 diabetes (T2D). However, little is known about confidence of healthcare providers (HCPs) to utilize these agents in clinical practice. A national sample of 905 physicians and nurse practitioners (NPs) from primary care, cardiology, and endocrinology completed an online survey and were asked: “How confident are you that you can effectively prescribe and manage type 2 diabetes with the following medications?” Answer options included a 5-point Likert-type scale ranging from “Not at All Confident” to “Extremely Confident.” Results were weighted for representation by U.S. specialty-specific distributions of gender, race/ethnicity, years in practice, region, and employment. When compared to other HCPs, endocrinologists reported higher confidence in prescribing antihyperglycemic agents for people living with T2D (Table 1). Large proportions of HCPs in cardiology and primary care expressed low confidence prescribing many antihyperglycemic agents, particularly novel agents with CVD risk reduction benefit. Guideline-based professional education efforts may improve confidence of HCPs to utilize antihyperglycemic agents to optimize glycemic control and cardiovascular risk reduction when treating people living with T2D.

Disclosure

C.M. Shay: None. K.J. Robb: None. M.T. Martin: None. M.P. Petersen: None. E. Sanchez: None.
1793-P: Dopamine D1 plus D2 Receptor Coactivation Ameliorates Metabolic Syndrome (MS) and Nonalcoholic Fatty Liver Disease (NAFLD) in Mice
Authors: EZROKHI MICHAEL , LUO SHUQIN , COMINOS NICHOLAS , RAICHE BENJAMIN , GUSTAFSON MELANIE , CINCOTTA ANTHONY H.
Published: June 2019

The peak in circadian dopaminergic activity at the biological clock area, suprachiasmatic nucleus is diminished in insulin resistant states and daily co-administration of dopamine D1 and D2 receptor agonists to restore this circadian peak of hypothalamic dopaminergic activity reverses this insulin resistance (IR) in genetic animal models of MS. However, the impact of such dopamine D1D2 receptor agonist therapy on NAFLD in an obesogenic animal model of the disease has never been investigated and such was the focus of the present study. C57B6 mice were maintained on a 40% kcal fat and 29% kcal sucrose diet with 5% fructose in the drinking water for 12 weeks and then randomized to daily treatment with bromocriptine (BC, a D2 agonist) (10 mg/kg), SKF38393 (S, a D1 agonist) (10 mg/kg), BC + S, or vehicle (N=7-8/gr) for 3 weeks while maintained on the diet. At the end of treatment, animals were sacrificed for analyses of metabolic parameters and liver biochemistry. D1D2 but neither D1 nor D2 agonist therapy maximally improved IR, obesity, and NAFLD. The D1D2 improvement in NAFLD was associated with reduced hepatic expression of lipogenic, inflammatory, insulin resistance-inducing, and FFA oxidative genes while normalizing antioxidant gene expressions (Table). This study suggests that circadian-timed daily dopamine D1D2 agonist therapy may be a means of treating both type 2 diabetes and NAFLD.

Disclosure

M. Ezrokhi: Employee; Self; VeroScience LLC. S. Luo: Employee; Self; VeroScience LLC. N. Cominos: Employee; Self; VeroScience LLC. B. Raiche: Employee; Self; VeroScience LLC. M. Gustafson: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.
1796-P: A Ventral Medial Hypothalamus Estrogen Receptor a Neural Circuit Controlling Energy Expenditure
Authors: XU PINGWEN , HE YANLIN , WANG CHUNMEI , YANG YONGJIE , CAI XING , XU YONG
Published: June 2019

Multiple estrogen receptor α (ERα) neuron populations in the brain are required to maintain normal body weight. While the metabolic effects of these ERα neuron populations have been investigated, the neural circuit and associated neurotransmitter signaling underlying the regulatory effects of ERα neurons on energy balance are unknown. Here we combined retrograde and anterograde trans-synaptic tracers, chemogenetics, optogenetic circuit mapping, and genetic mouse models to functionally map the downstream neural circuits of ERα neurons. We found that selective activation of ERα neurons in the ventral medial hypothalamus (VMH) stimulated brown adipose tissue (BAT) thermogenesis and physical activity without affecting food intake. We also showed that VMH ERα neurons provide monosynaptic glutamatergic inputs to serotonergic neurons in the dorsal Raphe nuclei (DRN). Inhibition of DRN serotonergic neurons partially attenuated the stimulatory effects of VMH ERα neurons on BAT thermogenesis and physical activity. More intriguingly, specific deletion of ERα or vesicular glutamate transporter 2 (vGluT2) from a subpopulation of VMH neurons projecting to the DRN results in decreased BAT thermogenesis and physical activity with normal food intake. Together, these findings suggest a model that VMH ERα neurons activate BAT thermogenesis and physical activity by stimulating DRN serotonergic neurons.

Disclosure

P. Xu: None. Y. He: None. C. Wang: None. Y. Yang: None. X. Cai: None. Y. Xu: None.

Funding

American Diabetes Association (1-17-PDF-138 to Y.H.); National Institutes of Health (R01DK093587), (R01DK101379 to Y.X.); (R00DK107008 to P.X.); U.S. Department of Agriculture (3092-5-001-059 to Y.X.); American Heart Association (17GRNT32960003 to Y.X.)
18-OR: Efficacy and Safety of Chiglitazar vs. Sitagliptin in Patients with Type 2 Diabetes: A 24-Week, Randomized, Double-Blind, Noninferiority Phase 3 Trial (CMAS)
Authors: JIA WEIPING , MA JIANHUA , MIAO HENG , WANG CHANGJIANG , WANG XIAOYUE , LI QUANMIN , LU WEIPING , YANG JIALIN , ZHANG LIHUI , YANG JINKUI , WANG GUIXIA , ZHANG XIUZHENG , ZHANG MIN , SUN LI , YU XUEFENG , DU JIANLING , SHI BINGYIN , XIAO CHANGQING , ZHU DALONG , LIU HONG , ZHONG LIYONG , XU CHUN , XU QI , LIANG GANXIONG , ZHANG YING , LI GUANGWEI , GU MINGYU , LIU JUN , NING ZHIQIANG , JI LINONG
Published: June 2019

Chiglitazar, a novel PPARα/γ/δ pan-agonist, showed favorable effects on glycemic control and lipid modulation with well tolerated safety profile in phase 2 trials. This trial aimed to compare the efficacy and safety of chiglitazar with DPP-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with diet and exercise (ClinicalTrials.gov NCT02173457). Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or sitagliptin 100 mg once daily. The primary endpoint was change in HbA1c from baseline at week 24, with a non-inferiority of each chiglitazar dose versus sitagliptin. Analysis was done in all randomized patients who received at least one dose of study drug (n=739). Chiglitazar showed comparable HbA1c lowering effect compared with sitagliptin at 24 weeks (LS mean difference -0.04% [95% CI -0.22 to 0.15] and -0.08% [95% CI -0.27 to 0.10] for 32 mg and 48 mg, respectively), along with different trends in secondary endpoints. Overall adverse events were comparable across study groups. The incidences of weight gain and edema were generally low but relatively higher in chiglitazar 48 mg.

In conclusion, chiglitazar showed non-inferior effect compared with sitagliptin on HbA1c reduction with well tolerated safety profile.

Disclosure

W. Jia: None. J. Ma: None. H. Miao: None. C. Wang: None. X. Wang: None. Q. Li: None. W. Lu: None. J. Yang: None. L. Zhang: None. J. Yang: None. G. Wang: None. X. Zhang: None. M. Zhang: None. L. Sun: None. X. Yu: None. J. Du: None. B. Shi: None. C. Xiao: None. D. Zhu: None. H. Liu: None. L. Zhong: None. C. Xu: None. Q. Xu: None. G. Liang: None. Y. Zhang: None. G. Li: None. M. Gu: None. J. Liu: None. Z. Ning: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi.

Funding

Ministry of Science and Technology of the People´s Republic of China (2013ZX09401301)
1803-P: Role of Medial Amygdala Neurons in Glucose Regulation
Authors: STANLEY SARAH , DEVARAKONDA KAVYA , ALVARSSON ALEXANDRA , BAYNE MITCHELL
Published: June 2019

Nearly two-thirds of U.S. adults are overweight or obese, putting them at risk for other serious medical conditions, including diabetes and heart disease. The medial amygdalar nucleus (MeA) regulates the intersection of stress, social behavior, and metabolism. We found that MeA neuronal activity is regulated by glucose. Using viral tracers, we mapped the projections of glucose-sensing neurons in the MeA and found they project to multiple downstream sites that are known to play a role in glucose metabolism. MeA neurons also form part of polysynaptic pathways to organs such as the pancreas, that are critical for glucose regulation. Chemogenetic activation of MeA neurons in both male and female mice alters home cage feeding, an effect that is most prominent when animals are in the fed state and presented with palatable food. This phenotype is not affected by administration of propranolol, a beta adrenergic receptor antagonist that can alleviate hypneophagia. Activation of the MeA does not alter anxiety-related behavior on the elevated plus maze, open field, or light-dark box. Optogenetic activation of MeA neurons expressing glucokinase, a putative marker of glucose-sensing neurons in the brain, mimics the feeding phenotype, suggesting that MeA suppression of feeding may be mediate through these neurons. Future work will delineate the role of specific MeA neural populations in glucose metabolism.

Disclosure

S. Stanley: Consultant; Self; Redpin Therapeutics. K. Devarakonda: None. A. Alvarsson: None. M. Bayne: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-17-ACE-31 to S.S.); National Institutes of Health (1R01NS097184, OT2OD024912); Alexandrine and Alexander L. Sinsheimer Fund
1806-P: Improvement Brain Insulin Signaling in Antidiabetic Effect of Duodenal Jejunal Bypass Surgery
Authors: YAN QINGTAO , LI NA , PAN RUIYAN , WANG HUAI-JIE , JIANG BIN , WANG WEI-YU , GAO ZHIQIN , QU MEI-HUA
Published: June 2019

Duodenal-Jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction, while the mechanism underlying remains unclear. The most important characteristic of diabetes is hyperglycemia due to impaired glucose homeostatic regulation, increasing evidences have demonstrated that the brain can directly initiate behavioral and metabolic responses to control energy and peripheral glucose homeostasis. This study mainly focused on exploring the role of brain insulin signaling activation and brain glucose utilization in the antidiabetic mechanism of DJB. The diabetic rats that induced by Streptozotocin (STZ) injection were grouped and proceeded with DJB or Sham operation, respectively. Basal glycemic parameters, such as fasting glucose, fasting plasmid insulin, OGTT, HOMA-IR and Hb1Ac, were detected by ELISA kits. In different treated (DJB, Sham or Control) rats models, 18F-FDG PET scanning was used to detect the glucose uptake in different organs, and of the level of insulin as well as insulin signaling pathway related proteins (InsR, IRS1/2, PI3K, AKT) and glucose utilization related proteins (HK1, PFK2) was evaluated by Q-RT-PCR, Western blot or IHC in the brain. Results showed that DJB surgery significantly improved basal glycemic parameters (Blood glucose, Insulin, HOMA-IR, HbA1c and OGTT) and reversed the decreased glucose uptake in the brain which was caused by type 2 diabetes. DJB surgery not only induced the gene expression of the brain insulin as well activated the insulin related signals, but also increased the expression of glucose utilization enzymes, such as HK1 and PFK2 in the brain. These results indicated that activation of brain insulin signaling and elevation of brain glucose metabolism might play an important role in the antidiabetic effect of DJB.

Disclosure

Q. Yan: None. N. Li: None. R. Pan: None. H. Wang: None. B. Jiang: None. W. Wang: None. Z. Gao: None. M. Qu: None.

Funding

National Natural Science Foundation of China (81871892, 31671208, 81500798, 81471048); Shandong Province Natural Science Foundation (ZR2015HL128); Technology Development Plan of Weifang (2018YX027)
181-LB: Effect of Obesity and Physical Activity-Based Lifestyle Change on Circulating Amino Acids: A Randomized and Controlled Intervention Study in Adolescents
Authors: HOSSAIN MD JOBAYER , GEORGE DONALD E. , BALAGOPAL P. BABU
Published: June 2019

Objective: Circulating amino acids (AA) may serve as potential biomarkers for obesity and future type 2 diabetes (T2DM). In children and adolescents, the effects of obesity on circulating AAs are inconsistent. Data on the role of physical activity-based lifestyle (PAL) interventions on circulating AAs are also sparse. We aimed to address these gaps and determine the effect of obesity and PAL on circulating AAs in adolescents.

Method: Age (age,14-18 year) and maturity matched (Tanner stage>IV) adolescents with normal weight (NW, n=7) and obesity (OB, n=15) were studied at baseline; the 15 OB adolescents underwent a 3-month randomized controlled PAL intervention. AAs were measured using high performance liquid chromatography-based amino acid analyzer. Body composition by DXA and glucose, insulin, adiponectin, RBP4, hsCRP and IL-6 were measured and HOMA-IR calculated. Independent t-tests, analysis of covariance and mixed effect models were used for data analysis.

Results: Thirteen AAs were significantly (P<0.05) higher in the OB compared to the NW group. The branched chain AAs, leucine (28%), isoleucine (11%) and valine (17%) were higher (P<0.05) in the OB vs. NW. PAL intervention showed only negligible effects on AA concentration, except for glutamine and glycine; both deceased (P<0.05) post-intervention. Adiponectin increased and RBP4, hsCRP, IL-6 and HOMA-IR decreased (P<0.05 for all) post-intervention, but no correlation with changes in the concentration of AAs. BMI did not change; fat mass decreased; fat free mass increased (P<0.05).

Discussion: Obesity-related alterations in AAs warrant further studies to understand their role as potential biomarkers of obesity and T2DM in children. The post-PAL decrease in glutamine and glycine may suggest their increased demand by other organs in response to the intervention. Despite the beneficial changes in various metabolic factors, the lack of changes in several AAs is intriguing.

Disclosure

M. Hossain: None. D.E. George: None. P. Balagopal: None.

Funding

American Diabetes Association (1-14-CE-04 to P.B.B.); Nemours Biomedical Research
1812-P: Multitissue Single-Cell Analysis Reveals Differential Tissue, Cellular, and Molecular Sensitivity between Fructose and High-Fat Diets
Authors: ARNESON DOUGLAS , MAJID SANA , AHN IN SOOK , KURT ZEYNEB , DIAMANTE GRACIEL , ZHANG GUANGLIN , GOMEZ-PINILLA FERNANDO , YANG XIA
Published: June 2019

High fructose and high fat diets have been associated with increased prevalence of metabolic syndrome, yet our understanding of the tissue, cellular, and molecular sensitivities of these two risk diets remains limited. Using single cell RNA sequencing, we examined thousands of individual cells from hypothalamus, liver, adipose, and small intestine from mice fed a high fat diet, a high fructose diet, and a chow diet. We found significant differences between the two diets in terms of the vulnerable tissues, cell types, and molecular pathways: both diets had significant impact on liver hepatocytes; high fructose diet induced stronger gene expression perturbations in hypothalamic neurons; high fat diet had more prominent influence on adipose cell types. We also identified key differences in tissue-tissue and cell-cell interactions between diets. Our results indicate that high fat and high fructose diets engage different tissues, cell types and molecular pathways, and rewire cell-cell networks to promote metabolic syndrome.

Disclosure

D. Arneson: None. S. Majid: None. I. Ahn: None. Z. Kurt: None. G. Diamante: None. G. Zhang: None. F. Gomez-Pinilla: None. X. Yang: None.

Funding

National Institutes of Health (R01DK14363)