bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Lipidomics and Gestational Diabetes—A Longitudinal Study in a Multiracial Cohort
Authors: RAHMAN MOHAMMAD L. , ANNE FENG YEN-CHEN , FIEHN OLIVER , TSAI MICHAEL Y. , TEKOLA-AYELE FASIL , LIANG LIMING , ZHU YEYI , ZHANG CUILIN 
Published: June 2018

Dyslipidemia is implicated in glucose intolerance. Study of lipidomics in pregnancy may identify novel metabolites that may provide new insights to the etiology of gestational diabetes (GDM). Such studies, however, are sparse. We prospectively investigated lipidomics and GDM risk in a matched case-control study of 107 GDM and 214 non-GDM women nested in the NICHD Fetal Growth Studies. GDM diagnosis was based on Carpenter and Coustan Criteria. We measured plasma lipidome of 420 metabolites at gestational weeks (GW) 8-13, 16-22, 24-29 and 34-37 by gas chromatography mass spectrometry. Associations between individual lipids and GDM were assessed using linear mixed effect models at GW 8-13 and GW 16-22. At GW 8-13, 48 metabolites were significantly related to GDM risk (FDR &lt;0.05). Specifically, the mid-to-long carbon-chain (C) glycerolipids (34-38C diglycerides [DGs]; 48-58C triglycerides [TGs]) were positively related to GDM, while long carbon-chain cholesteryl esters (18-22C CEs) were inversely related. At GW 16-22, 87 metabolites (34-36 C DGs, 48-58C TGs, 18-22C CEs, glycerophospholipids) were significantly related to GDM. Mean levels of top-identified metabolites between cases and controls are presented (Figure). We identified novel metabolites related to GDM with relations differed by lipid structure and the timing of pregnancy. Future studies are warranted to evaluate their roles in GDM early prediction.

Disclosure
M.L. Rahman: None. Y. Feng: None. O. Fiehn: None. M.Y. Tsai: None. F. Tekola-Ayele: None. L. Liang: None. Y. Zhu: None. C. Zhang: None.
Flash Glucose Monitoring Reflects Graft Function after Clinical Islet Transplantation—An Initial Report
Authors: LAM ANNA , FORBES SHAREEN , HAMMING CECILIA , MALCOLM ANDREW J. , JAMES SHAPIRO A.M. , SENIOR PETER A. 
Published: June 2018

Metabolic assessment in clinical islet transplantation (CIT) has primarily been limited to the research setting. However, technological advances may now allow for this in routine practice. We describe here flash glucose monitoring (FGM) in islet transplant recipients with varying degrees of graft function as assessed by BETA-2 score (validated clinical index, range 0-42).
Method: Sensor data from 3 of 6 patients using FGM (Abbott FreeStyle Libre) at our center were available for this descriptive study. BETA-2 score was calculated from most recent A1c, insulin dose, fasting C-peptide and glucose.
Results: Patients (1,2,3) varied in age (68,49, 66 years), diabetes duration (59, 37, 48 years), total CITs (5, 2, 2), time from last CIT (28, 10, 1 months) and BETA-2 score (3.4, 10, 34). Patient 3 was insulin independent. FGM profile also varied and appeared to be related to BETA-2 score with improved mean glucose (7.8, 7.3, 5.2 mmol/L), time spent in target (4-8 mmol/L) (40,47, 97%) and decreased frequency/severity of hypoglycemia (Figure) with increasing BETA-2 score.
Conclusion: These observations are in line with previous studies showing an association between graft function (based on stimulated C-peptide) and continuous glucose monitoring and points to the potential of FGM and the BETA-2 score, which can be done in routine clinical care, to characterize graft function and glycemia post CIT.

Disclosure
A. Lam: None. S. Forbes: None. C. Hamming: None. A.J. Malcolm: None. A. Shapiro: Consultant; Self; Viacyte, Inc., Protokinetix. P.A. Senior: Consultant; Self; Abbott, AstraZeneca. Research Support; Self; AstraZeneca, Prometic Life Sciences Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., Abbott. Research Support; Self; Viacyte, Inc..
Impaired Insulin Resistance in IF1-Deficient Mice Subjected to a High-Fat Diet with Reduced-Fat Mass and Skeletal Muscle Lipid Accumulation
Authors: HUANG FENGYUAN , YANG KEVIN , SAJA KAMALAMMA , HUANG YICHENG , LONG QINGQIANG , YOSHIDA MASASUKE , YANG QINGLIN 
Published: June 2018

Mitochondrial ATP synthase catalyzes the coupling step of oxidative phosphorylation. Under pathologic conditions, ATP synthase hydrolyzes ATP to replenish protons from the matrix into the intermembrane space, sustaining mitochondrial membrane potential. ATPase inhibitory factor 1 (IF1) is an ATP synthase-interacting protein that selectively inhibits the hydrolysis activity of ATP synthase to preserve ATP. The role of IF1 in patients with obesity and type 2 diabetes(T2D) has been reported recently but the in vivo role of IF1 in metabolic regulation in obesity and T2D remains unclear. To understand IF1 in the development of insulin resistance and T2D, we first assess IF1 expression in adipose and skeletal tissues in mice subjected to a high-fat diet (HFD). We found that IF1 transcript expression is upregulated in adipose, but reduced in skeletal muscle of the HFD-fed mice. IF1 knockout mice subjected to HFD showed a substantially slower increase of body weight in adult mice despite a similar food intake and body composition analysis using Magnetic resonance imaging(MRI) revealed that IF1 KO mice had less fat mass than WT mice littermates .Morphometric measurements showed that gonadal, subcutaneous and mesenteric fat mass were relatively lower than those of WT mice. Glucose and insulin tolerance assay revealed that IF1 KO mice impaired glucose and insulin tolerances after HFD feeding. Biochemical assays further revealed that the relatively lower fat mass in the IF1 KO mice was concomitant with increased circulating triglyceride and free fatty acids (FFA) levels. As a result, Gastrocnemius skeletal muscles showed increased triglyceride and FFA contents. Taken together, studies on the IF1 KO mice subjected to HFD uncover that IF1 is an important metabolic regulating factor that affects the development HFD-induced insulin resistance, probably due to an impairment in adipogenesis and skeletal muscle lipid accumulation.

Disclosure
F. Huang: None. K. Yang: None. K. Saja: None. Y. Huang: None. Q. Long: None. M. Yoshida: None. Q. Yang: None.
Depletion of CD2M2-Like Macrophages Promotes the Browning of the White Adipose Tissue
Authors: NAWAZ ALLAH , FUJISAKA SHIHO , USUI ISAO , YAGI KUNIMASA , NAKAGAWA TAKASHI , KADO TOMONOBU , TOBE KAZUYUKI , IGARASHI YOSHIKO , OKABE KEISUKE , SAEKI KUMIKO 
Published: June 2018

We have previously shown that CD2M2-like macrophages constitute a microenvironment for adipocyte progenitors (APs), in a Tgfβ-dependent manner, to retain systemic insulin sensitivity by tuning the quiescence/proliferation balance of APs to adapt to changes in nutritional status. Previously we generated CD206DTR transgenic mice and CD206-CreERT2/ Tgfβ1flox/flox (Tgfβ1 KO) mice to determine the role of CD2M2-like macrophages a role of CD206+ cell specific Tgfβ1 respectively, in the APs proliferation. Previous reports have shown that M2-like macrophages play a key role in the browning of WAT via activation of type 2 cytokines production during cold exposure. These findings revealed the relationship between the occurrence of beige adipocytes and M2-like macrophage recruitment. In order to investigate the role of CD2M2-like macrophages in the induction of browning into the WAT, we extended our study to see the browning phenomenon by using CD206DTR and Tgfβ1 KO mice. Here, we show that depletion of CD2M2-like macrophages promotes the browning of WAT. We report that cold stimulation resulted in the generation of smaller adipocytes, upregulation of UCP1 and CD137, a marker for beige progenitors, in the WAT of CD206-ablated mice. Flow cytometry analysis further confirmed enhanced beige progenitors in the WAT. Since blocking of Tgfβ is known to promote browning of the WAT. Mechanistically, we assume that enhanced browning into the WAT of CD206DTR mice might be due to the deletion of Tgfβ1 from CD206-M2-like macrophages. Taken together, we concluded that CD2M2-like macrophages induce the proliferation of beige progenitors in the WAT, which may serve as effective therapeutic tools for the prevention and treatment of obesity.

Disclosure
A. Nawaz: Research Support; Spouse/Partner; Kobayashi Foundation, Kobayashi Foundation, Kobayashi Foundation. S. Fujisaka: Research Support; Self; Mochida Pharmaceutical Co., Ltd., Eli Lilly and Company, MSD K.K., Toyama First Bank. I. Usui: None. K. Yagi: None. T. Nakagawa: None. T. Kado: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura & Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co. Y. Igarashi: None. K. Okabe: None. K. Saeki: None.
Adipose Tissue–Specific Knockout of AMPK alpha1/alpha2 Results in Normal AICAR Tolerance and Glucose Metabolism
Authors: CHOI RAN HEE , MCCONAHAY ABIGAIL , JOHNSON MACKENZIE B. , KOH HO-JIN 
Published: June 2018

AMP-activated protein kinase (AMPK) is a member of Ser/Thr kinases that has been shown to regulate energy balance. Although recent studies have demonstrated the function of AMPK in adipose tissue using different fat-specific AMPK knockout mouse models, the results were somewhat inconsistent. Our previous study has shown that exercise training increases AMPK activity in mouse adipose tissue, whereas high fat diet decreases its activity. For this study, we tested the hypothesis that AMPK in adipose tissue regulates whole body glucose metabolism. To determine the role of adipose tissue AMPK in vivo, we generated fat-specific AMPKα1/α2 knockout mice (AMPKFKO) using the Cre-loxP system. AMPK α1 and α2 protein expression in epididymal, inguinal, and brown adipose tissues was reduced by &gt;90% in AMPKFKO mice compared to wild type littermates. Body weights of AMPKFKO mice were not different between 8-27 weeks of age. Furthermore, tissue weights (liver, kidney, muscle, heart and white and brown adipose tissue) were similar to wild type littermates and DEXA scan analysis revealed no differences in percentages of body fat and lean mass. Knockout of AMPKα1/α2 in adipose tissue abolished basal and AICAR-stimulated AMPK phosphorylation. Basal and AICAR-stimulated phosphorylation of Acetyl-CoA Carboxylase, a downstream of AMPK, was also reduced by 90% in AMPKFKO mice. Despite of the ablation of AICAR-stimulated AMPK phosphorylation, the blood glucose lowering effect of AICAR injection (i.p.) was normal in AMPKFKO mice. In addition, AMPKFKO displayed normal fasting blood glucose, glucose tolerance, and insulin tolerance, indicating normal whole body glucose metabolism. These data demonstrate that adipose tissue AMPK plays a minimum role in whole body glucose metabolism under normal condition.

Disclosure
R. Choi: None. A. McConahay: None. M.B. Johnson: None. H. Koh: None.
Role of Adenylyl Cyclase-Associated Protein 1 (CAP1) in Mediating Resistin Actions in Mouse Liver Cells
Authors: AVTANSKI DIMITER , GARCIA ANABEL , THANGESWARAN PRIYANTHAN , BORDON BEATRIZ CARABALLO , PORETSKY LEONID 
Published: June 2018

Resistin is a pro-inflammatory adipokine produced by the white adipose tissue (WAT) adipocytes and macrophages. Obesity results in chronic inflammation of the WAT, marked by an increase in resistin and other inflammatory cytokines, and by infiltrating leukocytes. Elevated resistin levels are believed to play a major role in the development of insulin resistance in the peripheral tissues. Adenylyl cyclase-associated protein 1 (CAP1) was recently identified as a receptor for resistin. In the present study we aimed to investigate whether CAP1 mediates resistin actions which may affect insulin sensitivity in the liver. As a model we used BNL CL.2 mouse liver cell line. Concentration- and time-dependent experiments demonstrated that resistin upregulated TNFα, SOCS3, IL-1α, and IL-6 mRNA expression maximally when used in concentration of 12.5 ng/ml for 6 hours. In order to determine the CAP1 involvement in mediating resistin actions in the liver, we transfected BNL CL.2 cells with CAP1 siRNA and performed a real-time PCR array measuring the expression of 84 key genes involved in insulin signaling, adipokine signaling, and inflammation. Results demonstrated that resistin upregulated mRNA expression of IL-6; this effect was ameliorated when CAP1 was downregulated. Knock-down of CAP1 facilitated mRNA expression of genes involved in insulin signaling and adipokine signaling pathways, while it resulted in downregulation of infiltrating leukocyte markers expression. Taken together these results indicate that CAP1 is a mediator of resistin actions in the liver.

Disclosure
D. Avtanski: None. A. Garcia: None. P. Thangeswaran: None. B. Caraballo Bordon: None. L. Poretsky: None.
Mitochondrial DNA DAMPs Induce Inflammation and Insulin Resistance
Authors: YUZEFOVYCH LARYSA , PASTUKH VIKTOR M. , RACHEK LYUDMILA 
Published: June 2018

Increasing evidence showed that mitochondrial DNA (mtDNA), as a part of mitochondrial damage-associated molecular patterns (DAMPs), induces an immune response and inflammation in immune, as well as in cells of nonnimmune origin. As insulin resistance and type 2 diabetes are characterized by a persistent chronic inflammation, the aim if this study was to evaluate if mtDNA DAMPs induce an inflammatory responses in skeletal muscle cells and induce insulin resistance both in vitro and vivo. In vitro study showed that exogenous mtDNA fragments induced TLR9-mediated NF-κB activation in primary muscle cells. Also, we found that mtDNA DAMPs and palmitate increased TLR9 content in muscle cells. Furthermore, mtDNA DAMPs reduced insulin signaling and insulin stimulated glucose uptake in primary muscle cells. Importantly, administration of exogenous mtDNA DAMPs induced inflammatory signaling, hyperglycemia and insulin resistance in vivo, providing a direct causative role for mtDNA DAMPs in the development of insulin resistance. Parallel studies in vivo showed that high fat diet-induced insulin resistant mice (Yuzefovych et al, 2013, PLOS One) have elevated circulating mtDNA DAMPs contents which were associated with increased mtDNA damage in skeletal muscle and liver, increased oxidative stress and content of TLR9 in skeletal muscle. Collectively, this study identifies a novel role for mtDNA as a pro-inflammatory molecule which promotes insulin resistance. Ultimately, this can provide new clinical implications both to design novel therapeutic strategies and cost-effective biomarkers of insulin resistance progression.

Disclosure
L. Yuzefovych: None. V.M. Pastukh: None. L. Rachek: None.
Hierarchical Brain and Physiological Responses to Hypoglycemia and HAAF
Authors: LEE JOHN J. , TANENBAUM AARON , ARBELAEZ ANA MARIA ,   HYPOGLYCEMIA AND HAAF IN T1DM STUDY GROUP HIERARCHICAL BRAIN AND PHYSIOLOGICAL RESPONSES TO
Published: June 2018

Glycemic control is essential for the management of diabetes. However, intensive glycemic control brings increased morbidity and mortality associated with hypoglycemia. This work tested the hypothesis that human brain networks have functional patterns of hierarchical recruitment in physiologic responses to induced hypoglycemia.
Design and Methods: Glycemic levels were clamped to 90, 65, 55 and 45 mg/dL in seven normal subjects and six persons with T1DM. Cerebral blood flow (CBF) was measured by arterial spin labelling with MRI.
Results: The thalamus, medial prefrontal (MPFC) and orbital prefrontal cortices (OPFC), and striatum have differential changes in CBF with progressive hypoglycemia. Significances were verified using threshold-free cluster enhancement methods.
Discussion: With progressively induced hypoglycemia, specific cortical and subcortical regions demonstrate characteristic alterations of CBF. These changes confirm existing data regarding the roles of the thalamus, MPFC, OPFC and striatum in responses to hypoglycemia. Furthermore, regional CBF reactivity to progressive, induced hypoglycemia has distinctive features for acute/recurrent hypoglycemia and hypoglycemia in T1DM. These characteristic features suggest mechanistic roles for human brain networks in physiologic responses to severe hypoglycemia and hypoglycemia-associated autonomic failure (HAAF).

Disclosure
J.J. Lee: None. A. Tanenbaum: None. A. Arbelaez: None.
Impact of Hepatic Mig6 on Glucose Homeostasis and Oxidative Stress
Authors: IRIMIA-DOMINGUEZ JOSE M. , LUTKEWITTE ANDREW J. , FUEGER PATRICK T. 
Published: June 2018

Hepatic epidermal growth factor receptor (EGFR) expression and activation are decreased during steatosis in humans and several animal models of obesity. Restoring EGFR activation in obesity-induced endoplasmic reticulum (ER) stress and diabetes is a potential therapy to improve liver function in type 2 diabetes (T2D). Mitogen-inducible gene 6 (Mig6) is an inducible feedback inhibitor of EGFR activity and, therefore, a target for enhancing EGFR signaling during diet-induced obesity and T2D. We previously observed that liver Mig6 expression was increased during obesity-induced insulin resistance in C57Bl/6J mice fed a high fat diet and by both pharmacological- and fatty acid-driven ER stress in hepatocytes, leading to decreased EGF-mediated EGFR activation. To test the hypothesis of Mig6 as a target to treat insulin resistance in T2D, we examined liver-specific Mig6 knockout mice (LKO) and their littermate controls (CON) during diet-induced obesity. We identified enhanced whole-body glucose tolerance and hepatic insulin action in LKO compared to CON mice. Moreover, liver ballooning, an oxidative stress marker, was also improved in LKO mice. Using whole transcriptome sequencing, we sought to determine the molecular mechanisms leading to liver function improvement in obesity-induced insulin resistance in LKO mice. We identified that gene expression and protein accumulation of key enzymes of both peroxisomal (e.g., Acox1, Ehhadh) and mitochondrial (e.g., Cpt2, Acadl) beta-oxidation were decreased by Mig6 ablation. This observation correlated with a compromised gene expression of liver gluconeogenic enzymes.
In conclusion, we posit that hepatic Mig6 deficiency partially reverts the effects of obesity-induced diabetes by decreasing hepatic glucose output and reducing cellular oxidative stress, thereby establishing Mig6 as a therapeutic candidate for treating insulin resistance in obesity and T2D.

Disclosure
J.M. Irimia-Dominguez: None. A.J. Lutkewitte: None. P.T. Fueger: None.
Evaluating the Sub-chronic Effects of MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, on Weight Loss in Male ob/ob Mice
Authors: OLDHAM STEPHANIE , CHURCH CHRISTOPHER D. , WILL SARAH , KONKAR ANISH , TREVASKIS JAMES , DAVIES GRAEME R. 
Published: June 2018

MEDI0382, a balanced GLP-1/glucagon dual receptor agonist, is under development for the treatment of type 2 diabetes (T2DM). MEDI0382 reduces food intake and improves glucose control in lean and obese mice. Here, we determined the effects of MEDI0382 on body weight in leptin-deficient ob/ob mice. MEDI0382 (10, 20 or 30 nmol/kg), liraglutide (30 nmol/kg; a GLP-1 analog), or G1437 (30 nmol/kg; a lipidated glucagon receptor agonist) was administered to ob/ob mice for 21 days. Body weight was reduced by MEDI0382 treatment compared to vehicle controls, with 15% weight loss observed in the highest dose group. In comparison, liraglutide reduced body weight by 8% and G1437 by 29% (both p&lt;0.0001 vs. vehicle and high-dose MEDI0382). Glucose tolerance was improved by MEDI0382 (30 nmol/kg), similar to liraglutide, whereas G1437 worsened glucose tolerance. Additionally, 4-h fasted glucose on day 7 and 14 in high-dose MEDI0382- and liraglutide-treated groups was lower than vehicle, whereas G1437-treated mice exhibited higher glucose levels. Overnight fasting glucose was also reduced in all groups relative to vehicle except G1437. Liver fat was reduced in a dose-dependent manner (11%, 14% and 22%, respectively) by MEDI0382 compared to vehicle. Both liraglutide (12%) and G1437 (10%) also reduced liver fat (both p&lt;0.vs. vehicle and MEDI0382 30 nmol/kg dose). Serum ALT levels were also dose-dependently reduced by MEDI0382 and liraglutide, but not G1437. Expression of thermogenic genes (Ucp1, Ppargc1a and/or Adrb3) tended to be increased in brown and white adipose tissue by MEDI0382 administration, whereas negligible effects were observed following liraglutide or G1437 administration.
In summary, these data indicate that high-dose MEDI0382 produced superior body weight loss and improved liver health compared to liraglutide but the improved glucose homeostasis was similar to liraglutide.

Disclosure
S. Oldham: Stock/Shareholder; Self; AstraZeneca. Employee; Self; MedImmune. C.D. Church: Employee; Self; MedImmune. S. Will: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. A. Konkar: Employee; Self; Sanofi. Other Relationship; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. G.R. Davies: Employee; Self; MedImmune.
Sarcolipin, an Uncoupler of SERCA, Protects against Lipotoxicity and Insulin Resistance
Authors: MAURYA SANTOSH K. 
Published: June 2018

Obesity is strongly associated with insulin resistance and type 2 diabetes, and increased consumption of high-caloric diet combined with decreased physical activity have made type 2 diabetes a worldwide epidemic. Excess accumulation of lipid and fatty acid metabolites has been shown to interfere with insulin signaling in skeletal muscle. Increasing energy expenditure and mitochondrial metabolism in muscle is an attractive strategy to protect against fat-induced insulin resistance. We have previously shown that sarcolipin (SLN), an uncoupler of SERCA pump, promotes futile cycling, increases ATP utilization and heat generation thereby contributing to muscle thermogenesis. When fed with high-fat diet (HFD), Sln-KO mice developed massive obesity whereas SLN overexpression (SlnOE) mice showed resistance to obesity. In this study, we investigated if SLN based uncoupling mechanism can be targeted to enhance muscle energy expenditure and protects against fat-induced lipotoxicity and insulin resistance in skeletal muscle. Here we show that SLN overexpression increases fatty acid oxidation in skeletal muscle by reprogramming mitochondria and upregulation of enzymes involved in fatty acid transport and oxidation. Interestingly, SlnOE mice fed on high-fat diet did not show intramuscular lipid accumulation and display improved insulin sensitivity. On the other hand, Sln-KO mice show excessive lipid accumulation in muscle and defects in insulin-stimulated glucose uptake, a sign of insulin resistance. Insulin resistant phenotype of Sln-KO muscle was associated with the increased intramuscular concentration of diacylglycerols (DAG), ceramides and acylcarnitines. These results suggest that sarcolipin mediated uncoupling of SERCA is a novel therapeutic target to increase energy expenditure and prevent insulin resistance in skeletal muscle.

Disclosure
S.K. Maurya: None.