bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prdx6 Prevents Diabetic Myopathy by Improving Skeletal Muscle Cell Differentiation
Authors: PACIFICI FRANCESCA , CAPUANI BARBARA , PIERMARINI FRANCESCA , PASTORE DONATELLA , ARRIGA ROBERTO , COPPOLA ANDREA , REA SILVIA , DONADEL GIULIA , BELLIA ALFONSO , DELLA-MORTE DAVID , LAURO DAVIDE 
Published: June 2018

Diabetes mellitus is characterized by a state of hyperglycemia resulting from altered insulin secretion by pancreatic beta cell, insulin action or both. This pathological condition is frequently associated with muscle mass loss, a condition defined as sarcopenia, and diabetic myopathy, represented by an impairment of the regenerative power of muscle fiber and by an altered differentiation of progenitor cells. Oxidative stress has been identified as the main cause of muscular alterations typical of diabetic patients. We showed that Peroxiredoxin 6 (Prdx6), a relatively new antioxidant enzyme belonging from the Peroxiredoxin family, has a central role in glucose homeostasis by exerting a potent antioxidant role. Based on these results, in the present study we aimed to verify whether Prdx6 modulates the association between diabetes and the progression of myopathy and sarcopenia. Firstly, we evaluated the gene expression of the main factors involved in the differentiation of myogenic muscle cells such as MyoD and Myogenin in murine knockout models for Prdx6 (Prdx6-/-). We observed significant decreased levels of both genes in Prdx6-/- mice compared to controls, suggesting an impairment of the regenerative potential of muscle fibers. These data were, also, confirmed by using in vitro cell model of murine myoblasts (C2C7) knockdown for Prdx6. Moreover, in the murine models, the process of muscle atrophy was studied by evaluating the gene expression of MuRF1 and Atrogin-1 that finely regulate protein degradation at skeletal muscle level. According to our hypothesis, the expression levels of both enzymes were significantly increased confirming the presence of muscle atrophy. Our study, for the first time, highlights a fundamental role of Prdx6 in the preservation of muscle mass, suggesting how Prdx6 can be considered a potential therapeutic target for diabetic myopathy and sarcopenia. However, further studies are needed in order to understand the molecular mechanism underlying this phenomenon.

Disclosure
F. Pacifici: None. B. Capuani: None. F. Piermarini: None. D. Pastore: None. R. Arriga: None. A. Coppola: None. S. Rea: None. G. Donadel: None. A. Bellia: None. D. Della-Morte: None. D. Lauro: None.
Transient Activation of Skeletal Muscle Rac1 in Obesity-Related Insulin Resistance
Authors: STIERWALT HARRISON D. , BERGMAN BRYAN , EHRLICHER SARAH E. , ROBINSON MATTHEW M. , NEWSOM SEAN A. 
Published: June 2018

Rac1 is required for normal insulin-stimulated glucose transport in skeletal muscle and may be negatively regulated by lipids. We investigated if insulin stimulation of Rac1 was impaired with the accumulation of lipids in skeletal muscle, serving as a mechanism of insulin resistance with obesity. Male C57BL/6J mice consumed a 60% high-fat diet (HFD) for 12 weeks to induce obesity compared with low-fat diet (LFD). Insulin sensitivity and signaling were assessed using hyperinsulinemic-euglycemic (INS) or saline (CON) clamps (n=7-10 per diet/clamp). Rac1 activation and other insulin signaling was measured in quadriceps muscle harvested following the clamp conditions. Muscle lipids were assessed via liquid chromatography, tandem mass spectrometry. Activation of Rac1 (via GTP binding) was not increased in INS compared with CON conditions (P = 0.60) in either LFD or HFD. Further, insulin-stimulated pAktSer473 was similar between groups (P = 0.90) despite HFD mice having greater fat mass (P &lt; 0.01), lower glucose infusion rates during a 2-hour INS clamp (P &lt; 0.02), and greater skeletal muscle lipid content, including total ceramide (P = 0.03) and numerous 1,2 diacylglycerols (P &lt; 0.05). We considered if Rac1 activation is transient since Rac1 activity was not changed after the 2-hour INS condition. Time-course experiments in cultured L6 myotubes revealed that 2-min of insulin stimulation was sufficient to increase Rac1-GTP binding (P &lt; 0.01 vs. basal) and activation returned to basal by 10-min (P = 0.23 vs. basal). Modeling insulin resistance using overnight fatty acid treatments did not alter insulin-stimulated Rac1-GTP binding compared with no fatty acid control cells (P = 0.44).
In summary, skeletal muscle Rac1 activation by insulin is transient, but may be a key determinant of impaired glucose uptake with obesity in mice given the lack of impairment in Akt activation. In contrast, overnight fatty acid incubation was not sufficient to inhibit activation of Rac1 by insulin in L6 myotubes.

Disclosure
H.D. Stierwalt: None. B. Bergman: Research Support; Self; Eli Lilly and Company. Advisory Panel; Spouse/Partner; Novo Nordisk Inc., Merck & Co., Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. S.E. Ehrlicher: None. M.M. Robinson: None. S.A. Newsom: None.
Skeletal Muscle Mitochondrial Fission Is Increased after an Overnight Lipid Infusion in Healthy Humans
Authors: FEALY CIARAN E. , AXELROD CHRISTOPHER L. , ERICKSON MELISSA L. , HUANG EMILY , HARI ADITHYA , MULYA ANNY , FUJIOKA HISASHI , HOPPEL CHARLES L. , KIRWAN JOHN P. 
Published: June 2018

The role of mitochondria in insulin resistance and type 2 diabetes (T2D) is the subject of much debate. Recent evidence has suggested the presence of altered skeletal muscle mitochondrial dynamics, both increased fission and reduced fusion, in the etiology of insulin resistance and T2D, however, it is unclear what role, if any, changes in mitochondrial dynamics play in the induction of insulin resistance. We have proposed that increased mitochondrial fission may represent an early mechanistic link between the mitochondria and the onset of skeletal muscle insulin resistance. To test this hypothesis we recruited healthy humans to receive, in a randomized crossover design, an overnight saline (control) or lipid infusion (20% Intralipid) at 0.55 ml/kg/h, followed by a 2h, 90 mg/dL, 40 mU/m2 hyperinsulinemic-euglycemic clamp to assess insulin sensitivity. Changes to mitochondrial dynamics protein expression were assessed by western blot, ex vivo mitochondrial membrane potential (TMRM staining) by confocal microscopy, oxidative capacity by respirometry (Oroboros O2k), and mitochondrial morphology by transmission electron microscopy, in skeletal muscle biopsy samples following the overnight infusions. Preliminary data (n=8; 5M, 3F; Age: 26±1 years; BMI: 22.6±0.7; VO2max: 44.0±2.5) indicate that lipid infusion results in a tendency for reduced insulin sensitivity (P=0.08) and mitochondrial membrane potential (P=0.09), and an increase in Complex I state 3 respiration (P&lt;0.05). Dynamin related protein 1 (Drp1) activation (P&lt;0.05) by phosphorylation at serine 616—a key step in mitochondrial fission, and the Drp1 adaptor protein MiD49 (P=0.10) were increased after lipid infusion. No changes to mitochondrial fusion (Mfn1, Mfn2, OPA1), or mitophagy (Pink1, Parkin) proteins were observed following the lipid infusion. These data support our hypothesis that increased mitochondrial fission is an early adaptation to lipid induced insulin resistance in healthy humans.

Disclosure
C.E. Fealy: None. C.L. Axelrod: None. M.L. Erickson: None. E. Huang: None. A. Hari: None. A. Mulya: None. H. Fujioka: None. C.L. Hoppel: None. J.P. Kirwan: None.
Circulating Pigment Epithelium-Derived–Factor Levels—Hyperglycemia vs. Insulin Resistance
Authors: MASER RAELENE E. , LENHARD JAMES , POHLIG RYAN , BABU BALAGOPAL P. 
Published: June 2018

Serum pigment epithelium-derived factor (PEDF) levels are correlated with adiposity, dyslipidemia, and renal dysfunction in type 2 diabetes (T2D) men. Major sources of circulating PEDF include the liver and adipose tissue. Cross-sectional studies have reported higher serum PEDF levels in T2D vs. controls. Although studies have suggested PEDF’s role in mediating insulin resistance, its potential role with regard to glycemic control remains unclear. We examined the association of serum PEDF and glycemic control in individuals with T2D (n=50; 21 men/29 women; age=63±10 years; CKD&lt;stage 3b). PEDF was higher for those in poor (HbA1c≥7%; n=26) glycemic control (12.8±3.3 vs. 11.2±2.2 µg/mL; p=0.047) and for those that were insulin resistant (HOMA-IR&gt;1.8; n=23; p&lt;0.05). Spearman rank correlations of PEDF included: HbA1c≥7% (r=0.27, p=0.059), HOMA-IR&gt;1.8 (r=0.30, p=0.037), triglycerides (r=0.53, p&lt;0.001), creatinine (r=0.51, p&lt;0.001), and AST (r=0.33, p=0.02). Linear regression, with PEDF as the dependent variable, revealed that AST (p=0.003), creatinine (p=0.001), triglycerides (p&lt;0.001), and poor glycemic control (HbA1c≥7%) (p=0.009) were significant correlates (model R2=0.63, p&lt;0.001); whereas insulin resistance (HOMA-IR&gt;1.8) was not (p=0.70). There was also a significant interaction of AST x creatinine (p=0.02). While some suggest that elevated PEDF levels are associated with insulin resistance, the lack of an association in our data is intriguing. It is possible that gluconeogenesis by the liver and kidney is associated with elevation in circulating PEDF and PEDF may be part of an incomplete self-defensive regulatory mechanism to limit hyperglycemia. The significant interaction suggests that the relationship between creatinine and PEDF depends on AST. Taken together, the association between PEDF and poor glycemic control in persons with T2D may suggest a preferentially protective compensatory response of PEDF against hyperglycemia but not insulin resistance.

Disclosure
R.E. Maser: None. J. Lenhard: Speaker's Bureau; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi. R. Pohlig: None. P. Balagopal: None.
Comparative Study on Glucose Metabolism Before and After Surgery in Patients with Adrenal Cushing's Syndrome
Authors: MIYOSHI KENGO , TSURUTANI YUYA , SUZUKI AKIHIKO , TAKIGUCHI TOMOKO , SUGISAWA CHIHO , SAITO JUN , NISHIKAWA TETSUO 
Published: June 2018

Adrenal Cushing’s syndrome (CS) is caused by cortisol-producing adrenal adenoma (CPA) and is frequently accompanied with impaired glucose tolerance (IGT) or diabetes mellitus (DM). Previous cross-sectional studies showed that glucose metabolism disorders in CS are characterized by insulin resistance and insufficient β-cell compensation. However, because of the rarity of CS, there are few studies that assessed whether glucose metabolism disorders could be ameliorated by surgical treatment. We evaluated the changes in glucose metabolism before and after surgery for CPA. The participants were 11 (10 female and 1 male) patients with overt adrenal CS, treated with unilateral adrenalectomy for CPA between 20and 2017. Patients with pre-diagnosed DM were excluded. A 75 g oral glucose tolerance test (OGTT) was performed before and after surgery. Using the data from OGTT, insulin resistance and insulin secretion indices were calculated. After surgery, cortisol secretion and body mass index decreased significantly (24 h urinary free cortisol: 582 [321-743] to 31.3 [23.6-40.6] μg/day, p = 0.001, and 25.8 [20.6-26.2] to 21.4 [19.6-24.2], p = 0.0077, respectively). The type of OGTT was largely improved (normal glucose tolerance/IGT/DM: 2/8/1 to 8/3/0). The immunoreactive insulin and glucose levels during the OGTT decreased significantly. The homeostatic model assessment of insulin resistance decreased significantly (2.4 [1.4-2.8] to 1.0 [0.6-1.1], p = 0.002), and the Matsuda index increased significantly (3.0 [2.3-4.5] to 8.2 [6.3-11.4], p &lt; 0.001). In addition, the insulinogenic and disposition indices increased significantly (0.70 [0.22-1.51] to 1.22 [0.78-1.64], p = 0.04, and 609.1 [237.8-1095.2] to 1286.0 [1034.6-1857.6], p = 0.001, respectively).
In conclusion, our study showed that insulin resistance and insulin secretion were largely ameliorated after surgery for CPA, indicating that β cell dysfunction caused by cortisol overproduction is reversible.

Disclosure
K. Miyoshi: None. Y. Tsurutani: Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Astellas Pharma US, Inc., Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda. A. Suzuki: None. T. Takiguchi: None. C. Sugisawa: None. J. Saito: None. T. Nishikawa: None.
The Influence of Metabolic Surgery and Endoscopy on Serum Proteome in Subjects with Obesity and Type 2 Diabetes Mellitus
Authors: MRAZ MILOS , HARANT KAREL , KRATOCHVILOVA HELENA , CINKAJZLOVA ANNA , KLOUCKOVA JANA , KAVÁLKOVÁ PETRA , LACINOVÁ ZDENA , BENES MAREK , VLASAKOVA ZUZANA , DOLEZALOVA KARIN , FRIED MARTIN , PELIKANOVA TEREZIE , HALUZIK MARTIN 
Published: June 2018

Metabolic surgery and endoscopy are associated with long-term reduction in body weight and amelioration of glucose control; however, exact mechanisms responsible for these effects remain unclear. We performed a complex serum proteomic analysis in obese subjects with type 2 diabetes mellitus undergoing endoscopic duodenal-jejunal by-pass liner implantation (DJBL) or gastric plication (GP) to identify potential factors involved in postprocedural metabolic improvements. Thirty-one obese diabetic subject - 20 undergoing DJBL implantation and 11 GP - were examined at baseline and 10 months after DJBL or 6 months after GP, respectively. Serum proteomic analysis was performed using LC-MS (liquid chromatography-mass spectrometry) and the results were compared with human Uniprot reference database. Both procedures resulted in reduction in body weight (BMI 41.5 ± 1.0 vs. 37.6 ± 1.0 kg/m2, p=0.01 for DJBL and 41.6 ± 1.1 vs. 35.4 ± 1.2 kg/m2, p&lt;0.001 for GP) and HbA1C (72.5 ± 4.3 vs. 53.9 ± 3.3 mmol/mol, p=0.002 for DJBL and 55.4 ± 4.1 vs. 45.3 ± 2.3 mmol/mol, p=0.046 for GP). Proteomic analysis involving 600+ proteins revealed a significant change in 27 proteins after DJBL, including increase in IGFBP2, lyzosyme C and the islet cells regeneration factor lithostatine-1-α and decrease in C1q and serum amyloid A4. GP was associated with a change in 13 proteins including elevation of paraoxonase 1 and reduction of matrix metalloproteinase 2. To conclude, despite better weight-reducing efficacy of GP DJBL had a more profound effect on serum proteome, which might at least partially explain the stronger reduction in HbA1C observed in DJBL.

Disclosure
M. Mraz: None. K. Harant: None. H. Kratochvilova: None. A. Cinkajzlova: None. J. Klouckova: None. P. Kaválková: None. Z. Lacinová: None. M. Benes: None. Z. Vlasakova: None. K. Dolezalova: None. M. Fried: None. T. Pelikanova: None. M. Haluzik: None.
The Preprohormone Expression Profile of Enteroendocrine Cells following Roux-en-Y Gastric Bypass in Rats
Authors: RUDKJAER LISE BIEHL , ZHANG CHEN , RIGBOLT KRISTOFFER , PEDERSEN SØREN L. , FALKENHAHN MECHTHILDE , HÜBSCHLE THOMAS , SCHMIDT THORSTEN , VRANG NIELS , JELSING JACOB 
Published: June 2018

It is well-known that Roux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes and a marked and long-term body weight loss, but the molecular mechanisms driving these desirable effects are not fully understood. RYGB results in increased plasma levels of several gut peptidergic hormones with either anorexigenic and/or antidiabetic effects. However, the potent effects of RYGB cannot solely be ascribed to these, and it is therefore likely that additional factors play a role.
To gain further insight we have characterized the mRNA expression profile in enteroendocrine cells in the gut at day 9, 22 and 60 following surgery in a RYGB rat model. The enteroendocrine cells were identified by chromogranin-A immunohistochemistry staining, and isolated by laser capture microdissection from five locations covering the full rostrocaudal extent of the gastrointestinal tract. The mRNA expression profiles were analyzed by RNAseq, and bioinformatic analyses were applied to identify known and predicted preprohormones differentially regulated following RYGB. In total 64 putative preprohormones were identified in the secretome of rat enteroendocrine cells, of which 40 were shown to be differentially regulated at one or more time-points post surgery, including several well-known preprohormone genes (GCG, CCK, GHRL, GIP, NMU, SCT, NPY, and VIP). Only six preprohormones were differentially regulated at all time-points (NMU, TAC3, FAM3D, SCT1, SCT and ADM).
We present the full mRNA expression profile of the secretome of chromogranin A positive enteroendocrine cells following RYGB surgery in rats. The data provides a region-specific characterization of all preprohormone encoding genes in the rat gut, including 23 not hitherto known. This comprehensive catalogue of gut peptide hormone expression might help our understanding of hormone mediated effects of RYGB on diabetes remission and body weight lowering.

Disclosure
L. Biehl Rudkjaer: Employee; Self; Gubra. C. Zhang: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. S.L. Pedersen: None. M. Falkenhahn: None. T. Hübschle: Employee; Self; Sanofi-Aventis Deutschland GmbH. T. Schmidt: None. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Jelsing: Stock/Shareholder; Self; Gubra. Research Support; Self; Sanofi.
Discover and Track Obesity Relevant Research Resources Using dkNET (NIDDK Information Network)
Authors: LIN KO-WEI , BANDROWSKI ANITA , GO JAMES , OZYURT IBRAHIM BURAK , GILLESPIE TOM , GRETHE JEFFREY S. , MARTONE MARYANN E. 
Published: June 2018

The NIDDK Information Network (dknet.org) is a portal for basic and clinical investigators that makes it easier to discover, obtain, and reuse scientific research resources. Here we demonstrate how dkNET can connect researchers to resources for obesity research. A search for “obesity” returns 264,498 results (Table 1), including physical resources (i.e., antibodies, cell lines, model organisms), digital resources, data, models, funding, and knowledge bases. dkNET facilitates discovery not only within well known databases like GEO, Mouse Phenome Database, or model organism databases such as MMRRC, but also many unique but less well known databases, such as Animal Quantitative Trait Loci or Aging Gene/Interventions databases. dkNET provides some basic analytic tools, e.g., word clouds, category graphs, to aid exploration. dkNET provides in depth information on how resources are used through Research Resource Identifier (RRID), a unique ID allowing dkNET to aggregate and provide information, e.g., about known problems with antibodies or cell lines. To assist researchers in complying with NIH guidelines on rigor and transparency, dkNET provides a tool to suggest authentication plans for key research resources. dkNET also provides reports to track resource utilization. These new services aim to not only enhance transparency of research but also ensure that resource creators are appropriately credited.

Disclosure
K. Lin: None. A. Bandrowski: None. J. Go: None. I. Ozyurt: None. T. Gillespie: None. J.S. Grethe: None. M.E. Martone: None.
Loss of Adipocyte MDM2 Causes Lipodystrophy by Inducing P53-Dependent Apoptosis and Senescence
Authors: LIU ZHUOHAO , JIN LEIGANG , WANG BAILE , CHENG KENNETH K.Y. , XU AIMIN 
Published: June 2018

Adipose tissue is crucial for the maintenance of metabolic health. Activation of tumor suppressor p53 is known to induce adipose tissue dysfunction and its related metabolic diseases in obesity and aging. Here we show that murine double minute 2 (MDM2) acts as a gatekeeper of adipose health by restraining p53-mediated apoptosis and senescence. Adipocyte-specific deletion of MDM2 induces chronic and unrestrained activation of p53, which in turn triggers progressive loss of adipose tissues. Similar to other mouse models with lipodystrophy, mice lacking of adipocyte MDM2 develop hyperglycemia, hyperinsulinemia, hyperlipidemia and massive nonalcoholic fatty liver. Adiponectin-Cre-mediated deletion of MDM2 has no obvious effect on adipogenesis in cell-autonomous manner but induces apoptotic and senescent program in white and brown adipocytes. To ascertain whether the activation of p53 is responsible for the MDM2-null phenotypes, we generated an adipocyte specific MDM2-p53 double knockout mouse model. As expected, lipodystrophy and its associated metabolic disorders are not observed in adipocyte-MDM2-p53 double knockout mice. In addition, transplantation of subcutaneous white adipose tissue largely reverses diabetes, dyslipidemia and nonalcoholic fatty liver in adipocyte-specific MDM2 knockout mice. Together, our data suggest that the balance of MDM2-p53 signaling axis is crucial for proper functions and turnover of adipose tissues.

Disclosure
Z. Liu: None. L. Jin: None. B. Wang: None. K.K.Y. Cheng: None. A. Xu: None.
Stimulation of the ß3-Adrenergic Receptor via Mirabegron Induces Lipolysis and Thermogenesis in Human Adipocytes
Authors: CERO CHERYL , O'MARA ALANA , JOHNSON JAMES W. , BASKIN ALISON S. , LINDERMAN JOYCE D. , CYPESS AARON 
Published: June 2018

In rodent models, the β3-adrenergic receptor (AR) is responsible for thermogenesis in brown adipose tissue (BAT) and lipolysis in white adipose tissue (WAT). In contrast, the contribution of β3-AR in human adipocytes is controversial due to the low expression of the β3-AR in WAT and access only to partial β3-AR agonists. Mirabegron, an FDA-approved drug for overreactive bladder, is a selective human β3-AR agonist. In a recent clinical trial, mirabegron activated human BAT thermogenesis and WAT lipolysis. Therefore, we investigated the distribution and relative contribution of β1/2/3-AR in (i) whole white (hWAT) and brown (hBAT) adipose tissue from human autopsies and (ii) immortalized human white (hWA) and brown (hBA) adipocytes. Among the three β-ARs, β1-AR and β2-AR are similarly expressed in brown and white adipose tissue, whereas β3-AR has the highest expression in hBAT. In immortalized differentiated cells, hBA have a significantly higher expression of β3-AR compared to hWA. To assess the functionally of these receptors in adipocytes, dose-response curves of agonist-stimulated lipolysis were investigated in differentiated human and mouse adipocytes. We observed that stimulation of any one of the three β-ARs in human adipocytes induces a significant increase in glycerol release, a lipolytic byproduct. However, the effective dose of mirabegron to activate β3-AR-mediated lipolysis in white and brown adipocytes via mirabegron was significantly lower (hWA: EC50 2.55E-09; hBA: EC50 6.31E-09) compared to specific activators of β1-AR or β2-AR.
In summary, we identify a major role played by the β3-AR in the regulation of human BAT thermogenesis and WAT lipolysis, both in vivo and in vitro. Due to the comparatively minimal effects of mirabegron treatment on the cardiovascular system, selective β3-AR agonists may be the optimal choice for targeted stimulation of human WAT and BAT.

Disclosure
C. Cero: None. A. O'Mara: None. J.W. Johnson: None. A.S. Baskin: None. J.D. Linderman: None. A. Cypess: None.