bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipocyte EGFL6 Expression from Subcutaneous Adipose Tissue Alters Glucose Homeostasis and Affects Human Obesity
Authors: BRADLEY DAVID , YIN ZHENG , LIU JOEY Z. , BLASZCZAK ALECIA M. , WONG STEPHEN T. , HSUEH WILLA 
Published: June 2018

Recent data suggests that the adipose tissue (AT) extracellular matrix (ECM) may be a key player in the pathogenesis of obesity-related T2D. HFD feeding to collagen VI knockout mice reduces AT fibrosis (a hallmark of abnormal ECM) and improves insulin sensitivity despite an expansion of adipocyte volume. Epidermal growth factor-like-domain, multiple 6 (EGFL6) is a secreted protein best characterized for its role in tumor endothelial cell angiogenesis. Although previous studies have shown increased EGFL6 expression in whole fat of obese and insulin resistant subjects, its precise role in metabolic disease, the subtypes of cells within AT that overexpress EGFL6, and the mechanism(s) by which AT EGFL6 could modulate insulin sensitivity are entirely unknown. We obtained SAT from twenty-five lean (BMI 22.8±0.3 kg/m2) and twenty-nine obese (BMI 50.2±1.6 kg/m2) human subjects. Adipocytes and stromal vascular fraction were isolated for gene expression and co-culture experiments. We found that both adipocyte (37.21±7.55 vs. 7.44±3.67,p=0.001) and macrophage (4.69±0.79 vs. 1.15±0.45,p=0.024) EGFL6 expression was highly upregulated in human obesity; yet, only adipocyte-derived EGFL6 related significantly to insulin sensitivity (r=+0.775,p&lt;0.001), even independent of BMI (Beta=+0.676,p&lt;0.001). We also noted a marked difference in adipocyte EGFL6 (13.0±4.0 vs. 45.1±17.3,p=0.043) between those subjects who were insulin sensitive (HOMA-IR&lt;3) compared to those who were insulin resistant (HOMA-IR≥3). Mechanistically, we further show that recombinant EGFL6 can directly disrupt insulin signaling in cultured adipocytes, hepatocytes, and skeletal muscle cells. Our findings linking adipocyte EGFL6 with systemic IR may lead to novel pathways involving adipocyte-derived EGFL6 and additional therapeutic targets for human T2D.

Disclosure
D. Bradley: None. Z. Yin: None. J.Z. Liu: None. A.M. Blaszczak: None. S.T. Wong: None. W. Hsueh: Advisory Panel; Self; Merck & Co., Inc., AstraZeneca, Novo Nordisk Inc..
FSP27-Rab18-Vimentin Regulates Lipid Droplet Trafficking and Insulin Signaling in Adipocytes
Authors: PURI VISHWAJEET , BANERJEE SAYANI , JASH SUKANTA 
Published: June 2018

Increased free fatty acid flux from white adipocytes exacerbates insulin resistance and increases the risk of its progression to type 2 diabetes. Distinct intracellular organelles called lipid droplets (LDs) in adipocytes play a key role in storing fatty acids (FAs) as triglycerides (TGs), hence protecting against FA-induced lipotoxicity. A highly coordinated cascade of LD-associated proteins and lipases is known to regulate the catabolism of stored TGs in LDs, but the molecular components of LDs that determine their dynamics and TG storing capacity in adipocytes remains understudied. Previously, we showed that Fat specific protein 27 (FSP27) is a lipid droplet associated protein that is positively associated with insulin sensitivity in humans, and plays a crucial role in lipid droplet dynamics by clustering and then fusion of LDs. The present investigation was designed to identify the molecular mechanism through which FSP27 mediates LD trafficking to regulate the initial step of LD clustering—a prerequisite of LD fusion. We found that a direct interaction between FSP27, Vimentin and Rab18, and FSP27-mediated activation of Rab18 GTPase activity is important for lipid droplet trafficking. Our results reveal a complex bi-directional cross-talk that takes place between LD-associated proteins and cytoskeletal elements that maintain lipid droplet dynamics in a highly organized manner. Our study provides a new insight in the regulation of LD dynamics and insulin signaling in adipocytes.

Disclosure
V. Puri: None. S. Banerjee: None. S. Jash: None.
Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT)—A Link between Adipocytes, Inflammation, and Glucose Intolerance
Authors: KAHN JONATHAN , GODDI ANNA A. , COHEN RONALD N. 
Published: June 2018

Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor, which regulates the transcriptional activity of metabolically essential transcription factors. While SMRT has been shown to modulate adipocyte function, in vivo experiments utilizing knock-out (KO) models have led to conflicting results. To more rigorously define the role of SMRT in the adipocyte, we generated adipocyte-specific SMRT KO (adSMRT KO) mice by crossing adiponectin-Cre mice with floxed SMRT mice on a C57/BL6 background. When adSMRT KO mice are challenged with a 45% high-fat diet, we observe 20% increase in glucose intolerance (p=0.006) compared to wild type (WT) counterparts. Additionally, RNA-Seq data of adipose tissue from these mice indicate a dramatic up-regulation of inflammatory gene expression. To further characterize the pro-inflammatory phenotype, we utilized flow cytometry to identify infiltration of specific populations of adipose tissue inflammatory cells. We found that overall macrophage infiltration in the adipose tissue of KO mice increased two-fold (p=0.026), with anti-inflammatory M2 macrophages infiltrating in significantly lower proportions (p=0.017), indicating a higher ratio of M1:M2 cells in the KO mice compared to WT. In contrast, body weight and total fat mass were not altered. These data suggest a role for SMRT in the cross-talk between adipocytes and pro-inflammatory macrophages for the regulation of systemic glucose tolerance, distinct from the development of obesity. SMRT therefore integrates metabolic and inflammatory signals to maintain physiological homeostasis.

Disclosure
J. Kahn: None. A.A. Goddi: None. R.N. Cohen: None.
Remodeling of Myocardial Metabolism by Cardiac Mitochondrial Akt Signaling through Modulation of Pyruvate Dehydrogenase Complex
Authors: CHEN YU-HAN , CHEN YUMAY , TA ALBERT , LEE HSIAOCHEN , LIN HUGO YOU-HSIEN , WANG PING H. 
Published: June 2018

Mitochondria play a critical role in the regulation of myocardial metabolism and function. Diminished insulin-activated Akt translocation into mitochondria matrix contributed to the development of diabetic cardiomyopathy. However, its mechanisms of actions are not fully understood. Using an inducible heart specific transgenic mice harboring a mitochondria-targeting dominant Akt (CAMDAKT), we have observed 50% attenuation of pyruvate dehydrogenase activity in mitochondria. Proteomic study revealed insulin injection promoted formation of pyruvate dehydrogenase supercomplex in the control mice, however, insulin-stimulated formation of pyruvate dehydrogenase supercomplex was inhibited in the CAMDAKT mice. We next used a novel small molecular inhibitor (SMI) to disrupt binding of Akt to the E3 subunit of pyruvate dehydrogenase to dissect how active Akt interacted and modulated pyruvate dehydrogenase complex (PDC). Insulin stimulation of PDC activity and complex formation were inhibited by the SMI. Acetyl-CoA, which bridges PDC to the TCA cycle, was significantly reduced by 40% in the cardiac mitochondria of CAMDAKT mice. Interestingly, this was accompanied by reduced NAD+ and NADH levels (40-50% reduction) and NAD+/NADH ratio (30-40% reduction). Therefore the redox state was compromised. In CAMDAKT mice, cardiac mitochondria underwent adaptive changes once mitochondrial Akt became inhibited, with biphasic alteration of mitochondria abundance (up and down). The expression of PPARγ and PGC1α, showed a similar pattern of changes, suggesting compensatory mitochondria biogenesis.
In summary, mitochondrial Akt action in the heart is at least partially mediated through its direct interaction with the E3 subunit of PDC, and inhibition of this pathway led to metabolic remodeling and compensatory mitochondria biogenesis. These data shed new light into the mechanism of mitochondrial Akt actions and how it modulated cardiac metabolism.

Disclosure
Y. Chen: None. Y. Chen: None. A. Ta: None. H. Lee: None. H. Lin: None. P.H. Wang: None.
Identification of Mitochondrial Pyruvate Carrier Modulators to Treat Diabetes
Authors: MCCOMMIS KYLE S. , HODGES WESLEY T. , CHEN YANA , CHAMBERS KARI , FINCK BRIAN N. 
Published: June 2018

Recent work conducted in knockout mouse models or using small molecule modulators of the mitochondrial pyruvate carrier (MPC) have suggested that targeting this protein complex may have efficacy for treating diabetes as insulin sensitizers. To begin to identify other small molecules that interact with the MPC and could potentially be new therapeutic leads, we used a BRET-based MPC reporter assay (reporter sensitive to pyruvate; RESPYR) system that responds to molecules that interact with the pyruvate binding site of the complex. Screening of a 1600 molecule chemical library generated a number of hits for compounds that activated RESPYR activity. Some hits in this unbiased screen confirmed previous reports of MPC interacting drugs, including the insulin-sensitizing thiazolidinediones, pioglitazone and rosiglitazone. Another hit in this screen was Zaprinast, an inhibitor of phosphodiesterase 5 (PDE5). Zaprinast affected RESPYR activity in a dose-dependent manner and at high nM concentrations. Zaprinast also potently inhibited pyruvate-mediated respiration in isolated WT, but not MPC-deficient mitochondria, demonstrating a direct mitochondrial effect and MPC-dependence for this inhibition of pyruvate metabolism. Analyses conducted using other PDE5 inhibitors (Sildenafil, Tadalafil, and Vardenafil) showed no effect on RESPYR activity or mitochondrial respiration. Consistent with the concept that hepatic gluconeogenesis from pyruvate requires mitochondrial pyruvate import, Zaprinast reduced production of glucose from pyruvate in WT, but not MPC-deficient hepatocytes in vitro. Studies are ongoing to determine whether Zaprinast treatment will lower blood glucose in vivo.
In conclusion, these data demonstrate the feasibility of screening for novel MPC interacting compounds to identify novel therapeutics for treating diabetes and other metabolic diseases and also suggests that the orphan drug Zaprinast may be a novel antidiabetic agent.

Disclosure
K.S. McCommis: None. W.T. Hodges: None. Y. Chen: None. K. Chambers: None. B.N. Finck: Board Member; Self; Cirius Therapeutics.
One-Year Follow-Up of Medicare Advantage Enrollees with Type 2 Diabetes and an Initial Elevated HbA1c Value
Authors: CORDIER TRISTAN A. , CHIGULURI VINAY , HINES HUYI , CLARK SARA H. , HAUGH GIL , GUMPINA RAJIV , GOPAL VIPIN , PREWITT TODD G. 
Published: June 2018

Introduction: Blood glucose control is critical to slowing the onset of T2DM complications for individuals. National guidelines encourage clinicians and payers to ensure patient HbA1c lab results are less than 8.0%. Understanding the longitudinal patterns of HbA1c control among individuals with lab results over 8.0% is therefore an important undertaking. This study aims to characterize the proportion of individuals returning to HbA1c control within a one year period after an uncontrolled result.
Population and Study Design: Medicare Advantage (MA) patients with a large, national health and wellness company residing in Florida with a diagnosis of type 2 diabetes were included if they had an HbA1c lab value greater than or equal to 8.0% in 2016. Patients had at least one year of continuous coverage prior to the uncontrolled result and were followed until disenrollment, death, or a controlled HbA1c lab value, up to a maximum of one year. Cox regression stratified by initial HbA1c value (8.0-8.9%, 9.0-9.9%, 10.0-10.9%, 11.0-11.9%, 12.0%+) was used to assess the adjusted proportion of persons returning to control over the one year follow-up period. Confounders in the model included: demographic factors, supply of insulin, and comorbidities.
Results: The study cohort consisted of 28,026 persons who met the inclusion criteria (50.7% female, 57.4% white, mean age 71.9 years). Overall, 50.5% (95% CI: 50.0%, 51.1%) of persons achieved HbA1c control within the 1 year follow-up. Inability to return to control was driven by higher initial Hba1c [8.0-8.9% return rate: 61.6% (60.9%, 62.4%) vs. 9.0-9.9%: 39.4% (38.1%, 40.7%) vs. 12.0+%: 27.7% (25.1%, 30.2%)].
Implications: MA patients with HbA1c results greater than 9.0% experienced challenges resuming controlled status suggesting increased attention to this population may be warranted.

Disclosure
T.A. Cordier: Employee; Self; Humana Inc.. Stock/Shareholder; Self; Humana Inc.. V. Chiguluri: None. H. Hines: None. S.H. Clark: None. G. Haugh: None. R. Gumpina: None. V. Gopal: None. T.G. Prewitt: None.
Diabetes and Liver Cancer Risk—A Stronger Effect in Whites than Blacks?
Authors: CONWAY BAQIYYAH , BLOT WILLIAM J 
Published: June 2018

Both diabetes and liver and biliary tract cancer are overrepresented among African Americans, but limited information is available on the interrelationship of these two diseases among African Americans. We tested the relationship of diabetes with the incidence of liver cancer and whether this relationship varied between blacks and whites. Using the Southern Community Cohort Study, we conducted a cancer follow-up (2002-2015) of a cohort of mostly low income black and white participants aged 40-79 with (n=17,644) and without diabetes (n=64,870) at cohort entry. Mean age and diabetes duration of those with diabetes was 55.0 and 9.5 years, respectively. Mean age of those without diabetes was 51.6 years. Logistic regression was used to compute ORs (95% CIs) for the risk of incident liver and biliary tract cancer. There were 429 incident cases of these cancers. In univariate analyses, diabetes was associated with an increased risk of liver and biliary tract cancer (OR=1.73, 95% CI=1.36-2.21). Upon further controlling for age, sex, race, BMI, current and former smoking, total alcohol consumption, and any hepatitis infection, diabetes remained a significant risk factor for liver and biliary tract cancer (OR=1.49, 95% CI= 1.18-1.89). However, when stratified by race, risk associated with diabetes was significantly greater among whites (OR = 2.67, 95% CI = 1.71-4.19) than blacks (OR= 1.28, 0.98-1.68) (pinteraction=.002). Furthermore, controlling for diabetes greatly attenuated the higher risk of liver and biliary tract cancer among blacks; indeed, while the cancer risk among those without diabetes was twice as high among blacks than whites (OR=2.01, 95% CI = 1.50-2.69), no racial disparity was observed among those with diabetes (OR = 0.95, 95% CI= 0.62-1.45). The findings raise the possibility of markedly different impacts of diabetes on hepatic carcinogenesis between blacks and whites.

Disclosure
B. Conway: None. W.J. Blot: None.
Persistence with Insulin Glargine 300 IU/ml Compared with Other Basal Insulins—A Canadian Retrospective Cohort Study
Authors: QUANSAH KOBINA A. , SAURIOL LUC , KUKASWADIA ATIF A. , BREMNER SAMANTHA , MILLSON BRADLEY 
Published: June 2018

Introduction: Insulin glargine (300 units/mL) is a long-acting insulin approved in Canada on 28-May-2015 for once-daily administration in the treatment of T1DM or T2DM requiring basal insulin therapy. Made of the identical molecule as insulin glargine (100 unit/mL), insulin glargine (300 units/mL) delivers the same amount of insulin in one third of the dose. Four pivotal trials compared GLA-300 to GLA-100 with changes in HbA1C from baseline to 6 months. However, persistence is another important medication metric. Persistence with antihyperglycemic therapies have been associated with positive clinical outcomes and reduced health care costs.
Objective: To assess 12-month persistence on neutral protamine Hagedorn (NPH), insulin detemir, and insulin glargine using Canadian private claims data.
Methods: The study utilized longitudinal private drug plan claims data from IQVIA’s Canadian Private Drug Plan Database. The study was performed looking at persistence for T1DM and T2DM patients combined, without any treatment cessation or change to a different basal insulin. Patients were indexed on their first claim for any of the basal insulins of interest between May 28th 2014 and June 30th 2016, patients’ basal insulin therapy was tracked for 12 months plus a 3 month look-forward period. Patients who did not have continuous coverage or with fewer than 3 claims for an insulin were excluded from the analysis.
Results: At 12 months using a 90 day grace period, 63% of insulin glargine 300 IU/ ml (Toujeo®) patients persisted with therapy compared to 54% of insulin glargine 100 IU/ml (Basaglar), 50% for insulin glargine 100 IU/ml (Lantus), 45% insulin detemir 100 IU/ml (Levemir) and 29% of NPH patients.
Conclusion: A retrospective cohort study of real-world claims data demonstrated insulin glargine 300 IU/ml (Toujeo ®) had the highest persistence among all basal insulins.

Disclosure
K.A. Quansah: Consultant; Self; Sanofi. Employee; Self; Allergan. L. Sauriol: Employee; Self; Sanofi. A.A. Kukaswadia: Consultant; Self; Sanofi. S. Bremner: Consultant; Self; Sanofi. B. Millson: Consultant; Self; Sanofi.
Insulin Acutely Regulates Gene Expression in Brain–A New Potential Major Level of Control of Metabolism and Neurotransmission
Authors: CAI WEIKANG , RAMIREZ ALFRED , DREYFUSS JONATHAN , BATISTA THIAGO M. , MARTIN RUBEN GARCIA , PAN HUI , LI MENGYAO E. , O'NEILL BRIAN T. , KIM JASON K. , RONALD KAHN C. 
Published: June 2018

While the brain is now recognized as an insulin sensitive tissue, and impaired insulin signaling in brain can lead to many metabolic and behavioral abnormalities, effects of insulin on gene expression in the brain remain largely unknown. To understand now this aspect of insulin action may impact physiology in vivo, we performed hyperinsulinemic-euglycemic clamps at low (4 mU/kg/min) and high (12 mU/kg/min) physiological doses of insulin in C57BL/6 mice, and after 3 hours collected different brain regions and analyzed their transcriptomes using RNA Seq. In response to low dose insulin infusion, 1851 genes were up- or down-regulated in the hypothalamus by at least 50% (all P &lt; 0.01). This was more than 4-fold as the number of genes regulated in liver or muscle under the same conditions. Other regions showed different responses with 2significantly regulated by at least 50% in hippocampus and 131 regulated in nucleus accumbens. The most upregulated pathway in all three regions was that for very long chain fatty acyl-CoA synthesis, indicating an important role of insulin action on brain fatty acid metabolism. Most other insulin responsive genes in these three brain regions were distinct. In the hypothalamus, insulin played a key role in modulating genes involved in neurotransmission in the hypothalamus, including enhancing the GABA-A receptor signaling pathway and suppressing neuropeptide signaling pathways. Insulin also modulated metabolism in the hypothalamus by suppressing the glycolysis and pentose phosphate pathways, while increasing the pyruvate dehydrogenase complex and cholesterol biosynthesis. Thus, insulin action in the brain acutely and potently regulates expression of genes involved in brain metabolism, neurotransmission and neuromodulation. In this way, insulin re-routes the carbon source to the biogenesis of plasma membrane for neuronal and glial function and synaptic remodeling.

Disclosure
W. Cai: None. A. Ramirez: None. J. Dreyfuss: None. T.M. Batista: None. R. Garcia Martin: None. H. Pan: None. M.E. Li: None. B.T. O'Neill: None. J.K. Kim: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.
Lack of Brain Insulin Receptor Substrate-1 (IRS1) Causes Growth Retardation via Growth Hormone Releasing Hormone
Authors: HAYASHI TAKANORI , KUBOTA NAOTO , KUBOTA TETSUYA , KADOWAKI TAKASHI 
Published: June 2018

Background and Purpose: We previously revealed that systemic Irs1 deficient mice showed growth retardation, indicating that Irs1 plays an important role in growth. Irs1 is main substrate of not only insulin receptor (IR) but also IGF-1 receptor (IGF-1R) tyrosine kinase. Recently, brain specific IGF-1 receptor knockout mice were reported to become growth impairment. We hypothesized that brain Irs1 may regulate growth via IGF-1.
Methods: We generated NIrs1KO mice and analyzed growth related parameter and immunohistochemistry (IHC) study.
Result: The body weight of NIrs1KO mice was significantly smaller than control mice. NIrs1KO mice also showed shorter body length and bone length. On the other hand food intake and gene expression of appetite-related neuropeptides (POMC, AgRP and NPY) were not different between two groups. We next confirmed that plasma IGF-1 and growth hormone (GH) levels of NIrs1KO mice were lower than control mice. Hypothalamic GHRH mRNA expression levels of NIrs1KO mice were also lower than those of control mice although hypothalamic somatostatin mRNA expression was not different between two groups. These data strongly suggest that lack of brain Irs1 causes growth retardation via GHRH. IHC study indicated that Irs1 colocalized with GHRH neuron in hypothalamus. We next investigated the IGF-1-induced proliferation in hypothalamic neural cells by using siIrs1. Downregulation of Irs1 significantly inhibited IGF-1-induced neural cell proliferation.
Conclusion: Our results suggest that IGF-1-Irs1 pathway promotes the proliferation of GHRH neurons and regulate growth.

Disclosure
T. Hayashi: None. N. Kubota: None. T. Kubota: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.