bluuebunny/crossref_metadata_2025_split huggingface dataset:
1744-P: DBI-500 Significantly Increases Adipose Tissue Expression of PPAR-gamma and Adiponectin in DIO Mice and Significantly Decreases Markers of Fibrosis in Two Murine NASH Models
Authors: LEIGHTON ANTON 
Published: June 2019

Introduction and Aims: The aims of these studies were to explore the scope of activity of oral DBI-500, an atypical glycolipid, in a murine model of prediabetic type 2 diabetes and obesity, and in two models of NASH.
Methods: Part 1. Male C57BL/6 mice (14 weeks old) that received a high fat diet were divided into 3 groups (8 - 9 per group) and were either dosed with up to 144 mg/kg, 72 mg/kg or matching placebo via once daily oral gavage for 7 days. Fasting glucose, body weight and gene expression analyses were performed. Part 2. NASH was induced in male C57BL/6 mice using a standard methionine/choline deficient diet. Concomitant with initiation of diet, 4 groups of 8 mice received either placebo, 80 or 40 mg/kg DBI-500 or 40 mg/kg + metformin every other day for 4 weeks per gavage. Part 3. NASH was induced by diet in apolipoprotein-E-deficient mice using western diet (WD). Dose groups of 5 dose groups of 8 mice were dose with DBI-500 (100, 50 or 25mg/kg, or 25mg+metformin).
Results: Part 1. Gene expression analysis of epidymal fat samples showed significant increases in PPAR-gamma and adiponectin expression with concomitant significant reduction in CD8+ expression. Blood glucose and body weight were reduced. Plasma levels of PAI-1 and CD40L were also significantly reduced. Part 2. MCD mice showed significant and dose dependent reduction in hepatic collagen. Part 3. In ApoE deficient mice, DBI-500 significantly reduced expression of hepatic alpha-SMA and TGF-beta1, and significantly increased PPAR-delta. BDI-500 also significantly increased HNF4-alpha.
Conclusions: DBI-500 is a potential once daily novel therapy for type two diabetes and NASH that also significantly reduces markers of cardiovascular risk. DBI-500’s capacity to increase expression of HNF4-alpha strongly indicates potential as combination treatment with FXR agonists.

Disclosure
A. Leighton: Stock/Shareholder; Self; Dale Biotech, Inc.
1745-P: Inhibition of Soluble Epoxide Hydrolase 1 (sEH1) Improves Glucose Tolerance and Decreases Diabetes Incidence
Authors: WHITE TAYLEUR , RAMANADHAM SASANKA , HAMMOCK BRUCE 
Published: June 2019

Type 1 diabetes (T1D) is the result of autoimmune-mediated destruction of pancreatic islet β-cells by activated autoreactive inflammatory cells, effecting insulin production from β-cells. The Ca2+-independent phospholipase A2β(iPLA2β), a member of PLA2 family, hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid, which can be metabolized to bioactive lipids. Our work has revealed that iPLA2βactivation shifts macrophage polarization towards an inflammatory phenotype and that inhibition of iPLA2βreduces the development of T1D. We have now identified that iPLA2βactivation induces generation of select pro-inflammatory lipids in the non-obese diabetic (NOD) mice, including prostaglandins (PGs) and DHETs that accompany T1D development. To assess the role of these lipids in T1D development, NOD mice were administered (ip) polyethylene glycol 400 (vehicle), TPPU (sEH inhibitor, 3mg/ml), or PTUPB (dual antagonist of COX2/sEH, 9mg/ml) for up to 30 weeks. Measurement of blood concentrations of TPPU and PTUPB confirmed availability of the inhibitors between dosages. As expected, over the study-period glucose tolerance was impaired in the PEG group. Whereas glucose tolerance was not improved by PTUPB, it was significantly ameliorated by TPPU. These findings suggest that sEH1 inhibition, and thus the production of DHETs, can have beneficial effects in mitigating T1D development. Because different PGs can have pro- or anti-inflammatory effects, they further suggest that inhibition of COX2 may not be as effective as it may also lead to reductions in anti-inflammatory PGs. Overall, our findings support a role for select iPLA2β-derived lipids (iDLs) in T1D development and suggest developing strategies to target iPLA2βor the generation of select iDLs to prevent onset/progression of T1D.

Disclosure
T. White: None. S. Ramanadham: None. B. Hammock: None.

Funding
University of Alabama at Birmingham, Iacocca Family Foundation; U.S. Department of Veterans Affairs (BX001792, 13F-RCS-002); National Institutes of Health (R01DK69455, R01DK110292 to S.R.), (R01HL125353), (U01HD087198), (RR031535), (R01AI139072)
1748-P: Brucine Topical Administration Promotes Wound Healing through Downregulation of Proinflammatory Markers and Chemokine Expressions in Alloxan-Induced Diabetic Mice
Authors: MADKHALI HASSAN , GANAIE MAJID , ANSARI MOHD N. 
Published: June 2019

Diabetes mellitus is a complex metabolic disease and delayed wound healing constitutes one of the most serious diabetes-associated complications. Diabetes can impede the wound healing process by inducing inflammation which can lead to delayed maturation of granulation tissues and reduced wound parallel tension. Brucine, one of the major constituents in Strychnos nux-vomica has antioxidant and anti-inflammatory properties. In this study, we investigated the effects of topical administration of brucine on the key mediators of wound healing, namely T cell subsets, glucocorticoid-induced tumor necrosis factor receptor expressing cells, CD4+CD25+Foxp3+ regulatory T (Treg) cells, Th17 cells, Th1 cytokines, and inflammatory mediator mRNA expression.In current study, 5 groups of mice were used (10/group): group 1, the nondiabetic normal control; group 2, wound in nondiabetic mice; group 3, wound in diabetic mice; group 4, brucine 20mg/kg treated wounds in diabetic mice. Wound size was recorded on every third day and after 14 days of treatment, the heparinized whole blood and the wound tissue of all the groups was collected and tested. Brucine administration showed a significant reduction in wound size, the levels of GITR-expressing cells, and Th1 cytokines as well as substantial down regulation of mRNA expression of the inflammatory mediators compared with the diabetic mice. Brucine also significantly up regulated the number of Tregs or also induced Th17/Treg balance and modulated various pro-inflammatory and anti-inflammatory cytokines and the mRNA expression of their mediators. Furthermore, histopathological examination showed complete re-epithelization, decreased inflammatory cells and presence of granulation tissue in the brucine treated mice. Therefore, our results suggest the beneficial effect of brucine in enhanced wound healing and rebalancing the wound environment in diabetes.

Disclosure
H. Madkhali: None. M. Ganaie: None. M.N. Ansari: None.
176-LB: Long-Term Glycemic Variability in Diabetic Patients According to Their Glycemic Control in Follow-Up
Authors: GARCIA-ALCALA HECTOR 
Published: June 2019

Long term glycemic variability is linked to a higher rate of chronic complications and mortality in diabetic population and is also regarded a synonymous of poor glycemic control. However, the relationship between glycemic variability and glycemic control has not been studied properly.
Aims to describe differences in glycemic variability in diabetic patients according to their trends in glucose level during follow-up.
Methods from our database we selected those patients identified as diabetic (fasting glucose ≥ 126 mg/dl and/or Hba1c≥ 6.5%) who attended to our laboratory from January 2010 to august 2016 for a simultaneous Hba1c and glucose determinations. From the whole sample we selected those with at least 3 Hba1c determinations for 2 years. In all cases mean (M), standard deviation (SD) and variation coefficient (VC) were calculated from Hba1c during follow-up. Patients were categorized in four groups according to their first (i) and last determination (f) of Hba1c: group 1: i and f &lt; 7%, group 2: i &lt; 7% and f &gt; 7%, group 3: i &gt; 7% and f &lt; 7% and group 4 i and f &gt; 7%. We compared between groups VC.
Results we studied results from 1589 patients (men 52%, age 60.95 (SD 14.83) years, mean number of determinations: 6.65 (95% CI 6.39-6.84). The percent of patients in group 1 to 4 respectively were : 22.7%, 10.2%, 23.5% and 43.6% . The mean (SD) Hba1c i and f were for group 1: 6.33% (0.41), 6.26% (0.43), group 2: 6.30% (0.55), 8.71% (1.99) , group 3: 8.96% (2.01), 6.23% (0.49) and group 4: 9.4% (2.01), 8.78% (1.71) . Mean VC (SD) were from group 1 to 4: 9.16(9.53), 18.36(11.17), 18.37(11.41), 12.68(8.09))(p &lt;0.05 groups 1 vs. 2,3 and 4, group 2 vs. 1, 4, group 3 vs. 1 and 4, group 4 vs. 1, 2 and 3, P NS group 2 vs. 3).
Conclusions: long term glycemic variability measured by VC is very similar in groups that migrates from their original glycemic level, no matter if their final Hba1c is within the goal. High VC is not necessarily related to poor metabolic control.

Disclosure
H. Garcia-Alcala: None.
1767-P: Inflammatory Triggers of Lipolysis Act through IRE1 in Adipocytes
Authors: FOLEY KEVIN P. , CHEN YONG , KWOK KIERAN , BARRA NICOLE G. , TAMRAKAR AKHILESH K. , LIU YONG , SCHERTZER JONATHAN D. 
Published: June 2019

Hormones and inflammation can promote adipocyte lipolysis. Inflammation-induced insulin resistance can favor lipolysis, but the cellular mediators of unique lipolytic triggers are ill-defined. We found that ER stress discriminates inflammation-induced adipocyte lipolysis versus adrenergic-mediated lipolysis typical of hormones. Tauroursodeoxycholic acid (TUDCA) blocked adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial peptidoglycan (PGN), lipopolysaccharide (LPS) and tumor necrosis factor (TNF). TUDCA did not alter isoproterenol-induced lipolysis. Inhibiting inositol-requiring protein 1 (IRE1) kinase activity was sufficient to block lipolysis caused by inflammatory triggers and thapsigargin-induced ER stress. Tissue-specific deletion of IRE1 in mice confirmed that adipocyte-resident IRE1 was required for inflammatory ligand-induced lipolysis in adipose tissue. IRE1 kinase activity was dispensable for isoproterenol-induced lipolysis in adipocytes and adipose tissue. We found no role for typical unfolded protein responses as a mechanism linking ER stress to lipolysis, since IRE1 Rnase activity was not associated with changes in adipocyte lipolysis and adipose tissue from GRP78/BiP+/- mice had no change in lipolysis compared to littermate mice. Inhibiting IRE1 kinase activity blocked adipocyte NF-κB activation and Interleukin-6 (IL6) production in response to inflammatory ligands. However, inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signaling in adipocytes, which further supported the concept that inflammatory triggers of lipolysis can work independent of hormone responses, including insulin resistance. Our results are consistent with IRE1-linked ER stress mediating an inflammation-induced lipolytic program independently from hormonal regulation of lipolysis. Targeting components of IRE1-kinase signaling may have value in obesity and inflammatory lipid disorders.

Disclosure
K.P. Foley: None. Y. Chen: None. K. Kwok: None. N.G. Barra: None. A.K. Tamrakar: None. Y. Liu: None. J.D. Schertzer: None.

Funding
Canadian Institutes of Health Research
1768-P: Inflammation in Visceral and Subcutaneous Fat and Human Insulin Resistance
Authors: MCLAUGHLIN TRACEY , ZANLEY ELIZABETH J. , PETLURA CHRISTINA I. , TOLENTINO LORNA L. , CHOI OKMI , CHUANG JESSICA , XU YUE , MORTON JOHN , ENGLEMAN EDGAR 
Published: June 2019

Background/Methods: Visceral adipose tissue (VAT) is associated with increased risk for T2D and CVD. This depot, which accounts for only 5-10% of total fat mass, may play a relatively important role in determining insulin resistance (IR) due to its proximity to gut lymphatics and liver. Immune cells in fat respond to adipocyte stress and bacterial antigens from the gut with cytokine release, adversely affecting hepatic and systemic glucose metabolism. Few human studies have examined inflammation in VAT with regard to systemic IR. We hypothesized that inflammation in VAT vs. SAT would be associated with IR. To test this hypothesis we recruited 25 nondiabetic bariatric surgery patients who underwent whole-body insulin sensitivity testing via steady-state plasma glucose (SSPG) test prior to surgery. Samples of SAT and VAT were harvested for collagenase digestion and flash freezing for flow cytometry and gene expression.
Results/Conclusion: The cohort was 80% female, 20% male, age 48±10 years, BMI 43.7±6.1 kg/m2, fasting glucose 103±15 mg/dL. IR was defined as SSPG &gt; 200, and IS as SSPG &lt; 160 mg/dL. Comparison of immune cell profiles revealed greater frequency of macrophages in both SAT and VAT in IR vs. IS subjects, and higher expression of proinflammatory marker CD44 in IR vs. IS subjects. Macrophage number and phenotype (M1, M2, CD44+) did not differ between depots, suggesting systemic rather than localized inflammation contributes to IR.

Disclosure
T. McLaughlin: Advisory Panel; Self; January. Stock/Shareholder; Self; Eiger BioPharmaceuticals. E.J. Zanley: None. C.I. Petlura: None. L.L. Tolentino: None. O. Choi: None. J. Chuang: None. J. Morton: None.

Funding
American Heart Association
1769-P: Development of Adipose Fibrosis and Dysfunction in Aged Rxfp1-/- Mice
Authors: BENNETT ROBERT , HAMEL FREDERICK , SIMPSON RONDA L. , AGOULNIK ALEXANDER I. 
Published: June 2019

The hormone relaxin has roles in insulin sensitivity and age-related fibrosis in several organs, but the effect on adipose is unknown. Given the association of adipose fibrosis to dysfunction and progression of metabolic disease, we analyzed adipose tissue in aged mice lacking the relaxin receptor RXFP1. Male and female Rxfp1-/- or age-matched wild type (WT) mice were used at full adulthood (5-7 months) or when aged (12-18 months). Total fat and lean mass was determined, then gonadal white adipose tissue (gWAT) or inguinal white adipose tissue (iWAT) was collected. Sections were stained with Sirius red to visualize collagen. Gene expression was determined by qPCR, and serum adiponectin measured by ELISA. There were no significant differences in total body fat or lean mass between WT and Rxfp1-null mice at either age. All mice had similar adipose collagen content at age 5-7 months. In aged male mice, there was a remarkable increase in collagen in the iWAT of Rxfp1-/- mice, including pericellular deposits and thick collagen fibrils, and modestly elevated gWAT collagen compared to WT. In aged female mice, Rxfp1-null mice had modestly increased pericellular collagen in iWAT, but no apparent difference in gWAT. In aged male iWAT, the expression of the collagen types I, III, and VI genes, and the lysyl oxidase genes Lox, Loxl1, and Loxl2 were all significantly elevated. Serum adiponectin was significantly reduced in Rxfp1-/- mice compared to WT (12.6±1.6 vs. 23.9±2.8 ug/ml respectively, p&lt;.02).
In summary, Rxfp1-/- mice developed age-related adipose fibrosis, particularly in the iWAT. The effect was sex-specific, in that the fibrosis was much more extensive in male mice. The Rxfp1-/- mice had increased expression of fibrotic collagen and lysyl oxidase genes, and decreased serum adiponectin, suggesting adipose dysfunction. These results suggest that disruption of relaxin signaling plays a role in preventing age-related adipose fibrosis, which could contribute to the development and progression of metabolic dysfunction.

Disclosure
R. Bennett: None. F. Hamel: None. R.L. Simpson: None. A.I. Agoulnik: None.

Funding
U.S. Department of Veterans Affairs
1775-P: Impact of Acetyl-CoA Carboxylase 2 Inhibition on Skeletal Muscle Diacylglycerol and Ceramide Levels and Its Potential Contribution to Improved Glucose Metabolism
Authors: TAKAGI HIROYUKI , IKEHARA TATSUYA , HASHIMOTO KUMI , SHIMAZAKI ATSUYUKI , KASHIWAGI YUTO , NISHIURA YUJI , NOTOYA MITSURU , YUKIOKA HIDEO 
Published: June 2019

Intramyocellular lipid (IMCL) accumulation in skeletal muscle is closely associated with the development of insulin resistance. In particular, bioactive lipids such as diacylglycerol (DAG) and ceramide (Cer) have great impact on muscle insulin action. We have recently demonstrated that inhibition of acetyl-CoA carboxylase 2 (ACC2), which negatively modulates mitochondrial fatty acid oxidation in skeletal muscle, reduced IMCL levels and improved glucose metabolism in rodents. To further investigate the underlying mechanism, we examined the impact of pharmacological ACC2 inhibition on bioactive lipid composition and metabolic functions in skeletal muscle of rats, using an ACC2 selective inhibitor, compound A. As compared with vehicle treatment, chronic treatment with compound A significantly reduced both DAG and Cer levels in skeletal muscle of nondiabetic rats, which were strongly correlated with IMCL levels. Compound A also reduced the acyl-CoA pool along with enhanced acylcarnitine formation in skeletal muscle, while there were no differences in other bioactive lipid levels and DAG or Cer synthetic gene expression levels. Similarly, in Zucker diabetic fatty (ZDF) rats, compound A reduced both DAG and Cer levels in skeletal muscle without suppressing the synthetic gene expression levels. Treatment with compound A led to improved hyperinsulinemia and upregulated expression of key regulators in energy metabolism, such as Glut4 and Pgc1α, in skeletal muscle. Moreover, these positive effects on glucose metabolism were strongly correlated with diacylglycerol and ceramide reductions. Collectively, these findings suggest that ACC2 inhibition leads to preferential reductions of DAG and Cer by directly decreasing acyl-CoA pool via fatty acid oxidation in skeletal muscle, and these lipid reductions are closely linked to the improvement of glucose metabolism by ACC2 inhibition.

Disclosure
H. Takagi: None. T. Ikehara: None. K. Hashimoto: None. A. Shimazaki: None. Y. Kashiwagi: None. Y. Nishiura: None. M. Notoya: None. H. Yukioka: None.
1780-P: In High-Fat Diet-Induced Mice Skeletal Muscles, Iron Overload Plays a Critical Role in Leading Insulin Resistance
Authors: CHOI SUNGE , LEE NAMI , MOON HYUN UK , KIM HAE JIN , JEON JA YOUNG , KANG YUP , KIM TAE HO , LEE KWANWOO 
Published: June 2019

Aim/Hypotheses: Iron plays an important role in many physiological processes, including redox balance, inflammation, and mitochondrial respiratory metabolism. Abnormalities in iron metabolism lead to insulin resistance as well as diabetes. However, the abnormal mechanism of iron metabolism in the muscles of insulin resistance animal models is not precisely well known. Therefore, we investigated the molecular mechanism underlying iron dysregulation in high fat diet-induced C57BL/6J mice skeletal muscles.
Methods: We measured intracellular iron content in skeletal muscle tissues and iron metabolism related protein levels, such as transferrin receptor1, heavy chain ferritin, light chain ferritin, DMT1, and ferroportin. To investigate the association between iron content and insulin resistance, we treated iron donor or chelator in an animal model and performed insulin tolerance tests and measurement of insulin signaling.
Results: Interestingly, intracellular iron levels were increased in high fat diet-induced mice skeletal muscles. We also observed up-regulation of transferrin receptor 1 (TfR1), ferritin, but did not observe a change of DMT1 and ferroportin. Treatment with iron dextran, an iron donor, in C57BL/6J normal mice induced insulin resistance. However, treatment of desferrioxamine, an iron chelator, in high fat diet-induced insulin resistance mice recovered insulin resistance. Iron overload with iron dextran impaired insulin signaling in skeletal muscles, while iron chelation with desferrioxamine recovered high fat-induced dysregulated insulin signaling.
Conclusions/interpretation: Therefore, we consider fine-tuning of skeletal muscle iron levels and highly suggest the use for preventing and/or treating insulin resistance and diabetes.

Disclosure
S. Choi: None. N. Lee: None. H. Moon: None. H. Kim: None. J. Jeon: None. Y. Kang: None. T. Kim: None. K. Lee: None.
1782-P: Mechanism of Lipid-Induced White Adipose Tissue Insulin Resistance
Authors: ZHANG YE , ZHANG DONGYAN , LYU KUN , SONG JOONGYU D. , LI XIRUO , PERRY RACHEL J. , SAMUEL VARMAN , SHULMAN GERALD I. 
Published: June 2019

White adipose tissue (WAT), as an energy storage organ, plays a major role in regulating peripheral insulin resistance and hepatic gluconeogenesis, but the mechanism by which lipid induces insulin resistance in WAT is poorly understood. To examine the potential role of the diacylglycerol (DAG) - protein kinase Cε (PKCε) - insulin receptor (INSR) pathway in mediating lipid-induced WAT insulin resistance, we assessed insulin action in liver, muscle and WAT in 7-day high fat diet (HFD) and regular chow (RC) fed rats by hyperinsulinemic-euglycemic clamp (HEC) combined with [3-3H] glucose, [14C] deoxyglucose and [2H5]glycerol infusions. Using this approach, we found that HFD induced WAT insulin resistance as reflected by impaired suppression (∼20%, P&lt;0.05 vs. RC) of WAT lipolysis during the HEC. WAT insulin resistance was associated with increased PKCε translocation (P&lt;0.05 vs. RC) and increased phosphorylation of perilipin, HSL and ATGL (all P&lt;0.05 vs. RC). To investigate if PKCε induced Thr1150phosphorylation mediates lipid-induced WAT insulin resistance by inhibiting INSR kinase activity, we studied mice with a threonine-to-alanine knockin mutation at INSR Thr1150(InsrT1150Amice). InsrT1150Amice were protected from HFD-induced WAT insulin resistance as reflected by normalization of insulin’s ability to suppress WAT lipolysis and normalization of insulin’s ability to stimulate INSR and Akt2 phosphorylation in WAT, as well as a restoration of insulin’s ability to suppress phosphorylation of perilipin, HSL and ATGL (all P&lt;0.05 vs. WT).
Conclusion: The DAG-PKCε-INSR Thr1150pathway plays a major role in mediating lipid-induced WAT insulin resistance and represents a potential therapeutic target to improve insulin sensitivity in WAT.

Disclosure
D. Zhang: None. K. Lyu: None. J.D. Song: None. X. Li: None. R.J. Perry: Research Support; Self; AstraZeneca. V. Samuel: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.

Funding
National Institutes of Health (R01DK116774)