bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Antidiabetic Drugs on Cerebral Metabolism in Mice with Central Insulin Resistance
Authors: CAO YUE , WANG GUIXIA , LI ZHUO 
Published: June 2018

Objectives: This study focused on the effects of antidiabetic drugs, alogliptin (Nesina), exenatide (Byetta) and pioglitazone (Actos), on astrocyte-neuron metabolic cooperation in mice with central insulin resistance. That may provide theoretical basis for clinical treatment of diabetes related cognitive dysfunction.
Methods: Male C57BL/6J mice were randomly divided into control group (Ctrl), high-fat group (HF), alogliptin (ALO) group, exenatide (EXE) group and pioglitazone (PIO) group. Ctrl group was served normal diet, and then the others were served high-fat diet for 12 weeks. Then ALO group, EXE group and PIO group were respectively treated with alogliptin (25mg/kg/day), exenatide (30ug/kg/day) and pioglitazone (10mg/kg/day) for 4 weeks. The memory was tested using the Morris Water Maze test after 16 weeks. Then mice were killed and the brains were removed to detect insulin signaling and metabolic parameters. All data were presented as mean±SD and P&lt;0.05 was considered statistically different.
Results: 1. Antidiabetic drugs improved insulin signaling, IRS1/PI3K/Akt pathway in hippocampus and cortex. 2. Comparative analysis indicated that the latency in finding the platform significantly decreased, while frequency of crossing platform were increased in ALO group (3.75±1.14), EXE group (3.33±1.07) and PIO group (4.00±1.71) compared to HF group (1.66±1.23) (P&lt;0.05). 3. The results showed that the expression of glucose transporter (GLUT) 1, GLUT3, monocarboxylate transporter (MCT)1, MCT2 and MCT4 in HF group were significantly lower than those in Ctrl group, no matter in hippocampus and cortex. ALO group, EXE group and PIO group obviously reversed metabolic parameters compared to HF group.
Conclusions: We demonstrated that reprogramming metabolic pathways is an elaborate way by which neural cells respond to central insulin resistance. And antidiabetic drugs can reverse metabolic pathways to protect memory.

Disclosure
Y. Cao: None. G. Wang: None. Z. Li: None.
Real-Time In Vivo Imaging of Whole Islet Ca2+ Dynamics Reveals Glucose-Induced Changes in Beta-Cell Connectivity in Mouse and Human Islets
Authors: SALEM VICTORIA , SUBA KINGA , ALONSO ALDARA MARTIN , CHABOSSEAU PAULINE L. , GEORGIADOU ELENI , STYLIANIDES THEODOROS , BRIANT LINFORD , HODSON DAVID , CARRAT GAELLE , LECLERC ISABELLE , GABORIAU DAVID C. , ROTHERY STEPHEN M. , RUTTER GUY A. 
Published: June 2018

Imaging of Ca2+ dynamics in the intact islet in vitro has recently been subjected to connectivity analysis informed by similar approaches in neuronal systems. This has revealed the existence of intercellular networks between individual β cells which are increased by high glucose. Here, we sought to investigate if network connectivity also exists in islets in vivo under conditions of near-normal vascularisation and innervation. Donor mouse (C57BL/6J) islets were infected with adenovirus expressing the Ca2+ sensor GCaMP6m and transplanted into the anterior chamber of the eye in syngeneic recipients. Under isofluorane anaesthesia, fully implanted islets were imaged using a spinning disk confocal microscope (Nikon Ti-E, 25 x water dipping 1.0 NA objective, 300ms exposure time, 1 frame per second, 488nm excitation). Mean baseline blood glucose was 19mM and rose to &gt;30mM following an IP bolus of 1.5g/L glucose. Human islets were infected with AV-GCaMP6m, transplanted into a nu/nu mouse recipient and imaged under conditions of normoglycaemia (blood glucose 3.9-4.9 mM followed by hyperglycaemia (blood glucose &gt;30 mM). As circulating blood glucose increased, the proportion of connected cells in mouse islets rose from 65.5% to 88.3% (n=3 islets in 3 different animals, p=0.02) whilst the coefficient of correlation (a measure of the strength of the connectivity) showed a tendency to increase from 0.34 to 0.44 (p=NS). Data from human islets also revealed a tendency towards a rise in connectivity from 58.3% to 63.9% in response to rising circulating glucose. These data demonstrate that functional connectivity of Ca2+ dynamics between β cells is conserved in vivo in both mouse and human islets, with enhanced connectivity patterns observed in response to rising blood glucose levels. This technique, which allows β cell connectivity to be examined prospectively over time, will provide a powerful new approach for assessing its significance in health and disease.

Disclosure
V. Salem: None. K. Suba: None. A. Martin Alonso: None. P.L. Chabosseau: None. E. Georgiadou: None. T. Stylianides: None. L. Briant: None. D. Hodson: None. G. Carrat: None. I. Leclerc: None. D.C. Gaboriau: None. S.M. Rothery: None. G.A. Rutter: Research Support; Self; Servier.
Malate Dehydrogenase 2 (MDH2) as a New Diabetogene Causing Hyperglycemia in Families with Multigenerational Diabetes
Authors: JUNGTRAKOON PRAPAPORN , PEZZILLI SERENA , PEZZILLI ANTONELLA , PANNONE LUCA , FLEX ELISABETTA , BIAGINI TOMMASO , BURANASUPKAJORN PATINUT , LUDOVICO ORNELLA , MERCURI LUANA , HASTINGS TIMOTHY , PAOLA ROSA DI , ALBERICO FEDERICA , MENDONCA CHRISTINE , CERON JULIAN , PORTA DE LA RIVA MONTSERRAT , MARSELLI LORELLA , MAZZA TOMMASO , MARTINELLI SIMONE , TRISCHITTA VINCENZO , DORIA ALESSANDRO , PRUDENTE SABRINA 
Published: June 2018

We are pursuing the identification of new diabetogenes by whole exome sequencing in families with multigenerational diabetes that do not carry MODY-gene mutations. Here we report two gain-of- function mutations (c.154 C&gt;T p.Arg52Cys and c.478 G&gt;A p.Val160Met) in the gene coding for Malate Dehydrogenase 2 (MDH2) that we have identified as segregating with hyperglycemia in two such unrelated families. The MDH2 enzyme is localized to the mitochondria where it catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the tricarboxylic acid cycle. MDH2 also plays a pivotal role in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. By molecular dynamic simulation, both the Arg52Cys and Val160Met substitutions were found to severely alter the atomic dynamics of the MDH2 structure. MDH2 enzymatic activity was significantly increased (p&lt;0.01) in HepG2 cells transfected with either MDH2_T154 or MDH2_A478 as compared to WT_MDH2, despite no differences in MDH2 protein expression levels. Increased MDH2 activity is known to decrease NAD/NADH ratio—a biochemical alteration reported to affect both insulin signaling and secretion. In genetically modified C. elegans strains obtained by means of CRISPR/Cas9, the Arg52Cys mutant exhibited a significantly (p&lt;0.05) prolonged lifespan and increased Paraquat resistance and lipid storage when compared to WT strains. These changes resemble those reported for C. elegans with defective insulin signaling—a condition which in humans predisposes to both insulin resistance and inadequate insulin secretion.
In conclusion, our data point to MDH2 as a new diabetogene, heterozygous mutations of which cause hyperglycemia in families presenting with multigenerational diabetes.

Disclosure
P. Jungtrakoon: None. S. Pezzilli: None. A. Marucci: None. L. Pannone: None. E. Flex: None. T. Biagini: None. P. Buranasupkajorn: None. O. Ludovico: None. L. Mercuri: None. T. Hastings: None. R. Di Paola: None. F. Alberico: None. C. Mendonca: None. J. Ceron: None. M. Porta de la Riva: None. L. Marselli: None. T. Mazza: None. S. Martinelli: None. V. Trischitta: None. A. Doria: Research Support; Self; Sanofi-Aventis. S. Prudente: None.
Effects of a High-Carb vs. High-Fat Meal on Glycemia, Insulin, Interleukin-6, TNF-Alpha, and Apo-B
Authors: STEINBERG HELMUT O. , STENTZ FRANKIE B. , SHANKAR NANDITA K. 
Published: June 2018

Past studies have shown that food ingestion modulates vascular function within the first two hours of consumption and that food composition such as the amount of carbohydrates vs. fat may play a role. The goal of this study was to assess the effect of a high-carbohydrate (HC) meal vs. a high-fat (HF) meal on potential modulators of vascular function, insulin, interleukin-6 (IL-6), TNF-alfa and Apo-B. We studied a group of healthy volunteers; n=6, age 38 ± 13 years, BMI 24.5 ± 3.8 kg/m2 and systolic blood pressure 125.3 ± 9.1 mmHg. The meals were commercially available; HC meal consisted of 120 gm of carbohydrates (∼60% sugars) and 8 gm fat, and the HF meal consisted of 54 gm of carbohydrates (∼ 15% sugars) and 28 gm of fat and contained slightly (∼20%) less total calories. The meals were ingested within 5 minutes.
Results: Glucose and insulin levels increased in response to either meal but more robustly with HC. Glucose and insulin levels peaked at 30 minutes in response to HC and at 60 minutes in response to HF. IL-6 levels nearly doubled in response to either meal, but the time course appeared different; it peaked at 180 minutes and 60 minutes in response to HC and HF, respectively. TNF-alpha levels remained overall unchanged after either HC and HF meal. Apo-B levels also remained overall unchanged after either HC and HF meal.
Conclusions: Our study shows that food composition differentially affects the magnitude and time course of changes in metabolites, hormones and markers of inflammation. Ingestion of a HF meal resulted in a delayed and lower peak of glucose and insulin and a much earlier peak in IL-6. This early elevation of IL-6 in response to HF may potentially impair vascular function as described in the “big Mac” study. It is unclear if higher insulin levels during this period would be vaso-protective. Further research is needed to better understand the link between food composition and changes in metabolites, hormones and pro/anti-inflammatory mediators and its relation to vascular function.

Disclosure
H.O. Steinberg: None. F.B. Stentz: None. N.K. Shankar: None.
Function of Deubiquitinating Enzyme USP1 in Adipogenesis
Authors: LEE JINAH 
Published: June 2018

Obesity and metabolic disorders are one of the most challenging issues to be solved in modern society. Adipogenesis, which is a cellular differentiation process of pre-adipocyte to become a fully differentiated adipocyte, is a key mechanism in increasing fat mass and lipid accumulation. This process is a very complex multistep and involves numerous cascades of transcriptional factor activation. Accordingly, adipogenesis is regarded as a crucial target in treating or preventing obesity. Post-translational modification is a significant process for a protein to acquire its functional diversity in cell signaling by the addition or cleavage of functional groups. Deubiquitination by deubiquitinating enzyme is one of the important post-translational modifications involved in various signaling pathways. In this study, we screened deubiquitinating enzymes with differentiating 3T3-L1 adipocytes and found out that the mRNA and protein expression of ubiquitin specific peptidase 1 (USP1) was gradually increasing during the adipogenesis process. Also, from the various mouse tissue mRNA sample, ubiquitin specific peptidase 1 displayed higher expression levels on adipose tissues compared to other tissues. From these data, we assumed that this enzyme might be an important factor involved in adipogenesis. In the knockdown study, when ubiquitin specific peptidase 1 is absent, all the adipogenic transcription factors (Peroxisome proliferator-activated receptor gamma, Ccaat-enhancer-binding proteins alpha, beta, fatty acid synthase, and fatty acid binding protein 4) were down regulated. Furthermore, according to the proliferation assay result, ubiquitin specific peptidase 1 3T3-L1 cells had lower proliferation rate which indicates significant effect of USP1 during the mitotic clonal expansion. In consequence, our results indicate that ubiquitin specific peptidase 1 plays an important role in adipogenesis process.

Disclosure
J. Lee: None.
Insulin Resistance and Type 2 Diabetes Mellitus Are Associated with Impaired Mitochondrial Function in Human Ventricular Myocardium
Authors: ZWECK ELRIC , SCHEIBER DANIEL , JELENIK TOMAS , HORN PATRICK , ALBERMANN SOPHIE , BOEKEN UDO , SAEED DIYAR , KELM MALTE , RODEN MICHAEL , WESTENFELD RALF , SZENDROEDI JULIA 
Published: June 2018

Type 2 Diabetes Mellitus (T2DM) is related to increased cardiac morbidity and mortality. Underlying mechanisms are yet unclear. Recent studies detected mitochondrial abnormalities in atrial tissue acquired during open-heart surgery of T2DM patients suffering from ischemic or valvular heart disease. We hypothesized that mitochondrial capacity and coupling efficiency are reduced in ventricular tissue of humans with T2DM and normal heart function. High resolution respirometry was performed in transcatheter ventricle biopsies of 29 healthy heart transplant recipients with normal left ventricular ejection fraction (64±8%) and no allograft rejection. We assessed oral glucose insulin sensitivity (OGIS) and redox potential (ORP) reflecting systemic oxidative stress. Glucose tolerant humans (CON; n=16) and T2DM (n=13) had comparable age (54±14 vs. 58±12 years; p=0.45), sex (81% vs. 85% male) and time since transplantation (26±24 vs. 25±26 months; p=0.93), while body mass index was higher in T2DM (25.0±2.9 vs. 28.1±4.9 kg/m2; p&lt;0.05). State 3 respiration on octanoyl-carnitine was 20% lower in T2DM (101±25 vs. 81±20 pmol/(s*mg); p&lt;0.05). Lipid-linked respiration related negatively to HbA1C (r=-0.45; p&lt;0.05) and fasting blood glucose levels (r=-0.41; p&lt;0.05), but positively to OGIS (r=0.56; p&lt;0.05). Respiratory control ratios (RCR) on lipids were 21% lower in T2DM compared to CON (1.6±0.4 vs. 1.2±0.3; p&lt;0.05) and correlated negatively with HbA1C (r=-0.44; p&lt;0.05). Substrates of mitochondrial complex I and II induced 22% lower RCR in T2DM (2.7±0.8 vs. 2.1±0.5; p&lt;0.05). ORP was 24% higher in T2DM (127±23 vs. 157±25 mV; p&lt;0.01). Ventricular myocardium of T2DM and insulin resistant humans shows diminished mitochondrial oxidative capacity and coupling efficiency for lipid and glycolytic substrates which is related to hyperglycemia and oxidative stress. This might indicate targets for treatment and prevention of T2DM-related heart failure.

Disclosure
E. Zweck: None. D. Scheiber: None. T. Jelenik: None. P. Horn: None. S. Albermann: None. U. Boeken: None. D. Saeed: None. M. Kelm: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. R. Westenfeld: None. J. Szendroedi: None.
The Novel Adipokine C1QTNF1 Significantly Predicts the Incidence of Future Major Cardiovascular Events in Patients with Type 2 Diabetes
Authors: MUENDLEIN AXEL , LEIHERER ANDREAS , SAELY CHRISTOPH H. , GEIGER KATHRIN , EBNER JANINE , BRANDTNER EVA-MARIA , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , DREXEL HEINZ 
Published: June 2018

Increased serum levels of the novel adipokine C1q and tumor necrosis factor related protein 1 (C1QTNF1) have been linked with type 2 diabetes (T2DM) and ischemic heart disease. The impact of circulating C1QTNF1 on the incidence of future major cardiovascular events (MACE) is unclear and is addressed in the present study. We measured C1QTNF1 serum levels in 542 patients undergoing coronary angiography for the evaluation of established or suspected coronary artery disease (CAD) using an enzyme-linked immunosorbent assay. Prospectively, MACE were recorded over a mean follow-up period of 6.3 years. C1QTNF1 serum levels at baseline were significantly increased in patients with T2DM (n=160) compared to those without diabetes (521.4 ± 224.8 vs. 429.5 ± 130.3 ng/ml; p&lt;0.001). Prospectively, the incidence of MACE increased significantly through tertiles of C1QTNF1 (17.8%, 24.7%, and 29.7% in the 1st, 2nd and 3rd tertiles, respectively; ptrend=0.010). Also after adjustment for age, sex, and T2DM as well as after additional adjustment for body mass index, hypertension, LDL cholesterol, HDL cholesterol, triglycerides, and angiographically determined baseline CAD, C1QTNF1 significantly predicted MACE, with adjusted HRs of 1.30 [1.04-1.61]; p=0.019 and 1.36 [1.09-1.70]; p=0.007, respectively. Patients with T2DM were at a significantly higher risk of MACE than those who did not have diabetes (48% vs. 26%; p=0.003). C1QTNF1 in subgroup analyses also in T2DM patients proved to be a strong predictor of MACE (adjusted HR 1.57 [1.10-2.24]; p=0.013). We conclude that high serum levels of C1QTNF1 significantly predict MACE, in particular in patients with T2DM.

Disclosure
A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. K. Geiger: None. J. Ebner: None. E. Brandtner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
Dynamic Changes in the Regulation of Energy Balance after Roux-en-Y Gastric Bypass Are Reflected in Time-Dependent Alterations in Liver Gene Expression
Authors: AGOSTINA SANTORO M. , BRANCALE JOSEPH , GARRISON JILL CARMODY , MACHINENI SRIRAM , LAJOIE SCOTT A. , KAPLAN LEE M. 
Published: June 2018

Roux-en-Y gastric bypass (RYGB) leads to long-term weight loss and diabetes remission. Animal studies have shown that RYGB changes the physiology of energy regulation to favor a lower defended fat mass. To explore these effects, we developed a mouse model of enhanced response to dietary change, where RYGB abrogates the rapid obesogenic effects of re-exposure to a high-fat diet (HFD). HFD-induced obese mice that underwent RYGB- or Sham operation were fed chow for 9 weeks and switched back to HFD for 8 weeks. Glucose regulation was improved in RYGB animals independent of diet or body weight. During the first 2 days on HFD, Sham animals gained significant weight (1.8 g, p&lt;0.05) due to a 10.6 kcal increase in energy intake (EI) compared to the chow period (p&lt;0.05). In RYGB mice, weight and EI remained unchanged. By week 8 of HFD, Sham controls were 24% heavier than before surgery (p&lt;0.05), while RYGB mice continued to maintain a lean weight. There was no difference in EI between groups, but RYGB mice exhibited 26% higher energy expenditure than Sham mice (p&lt;0.05). Given the widespread changes in physiology in RYGB animals, we sought to identify differentially expressed (DE) genes in RYGB vs. Sham livers during the dynamic response to HFD. RNA-Seq showed that the number of DE genes after long-term HFD was 5.6 times larger than after 2 days (1,409 vs. 251, respectively), reflecting adaptation to a new metabolic state in Sham mice after chronic HFD. Differential expression of inflammatory, lipogenic, and cell cycle genes was substantially altered over time. These data suggest that the means by which RYGB modulates energy balance to resist the obesogenic effects of HFD is time-dependent. Further assessment of the molecular basis of this dynamic physiological response will provide important insight into the mechanisms most relevant to the therapeutic effects of RYGB and therefore guide development of less invasive therapies for metabolic disease.

Disclosure
M. Santoro: None. J. Brancale: None. J. Carmody Garrison: None. S. Machineni: Consultant; Self; Johnson & Johnson Services, Inc., Rhythm Pharmaceuticals Inc.. Other Relationship; Self; Novo Nordisk Inc.. S.A. Lajoie: None. L.M. Kaplan: None.
Effects of the Diabetes-Induced MicroRNA-155 on Wound Healing and Fibroblast Growth Factor 7 Expression
Authors: DALGAARD LOUISE T. , LEAL ERMELINDO C. , SVENDSEN RIKKE , MOURA JOÃO , SØRENSEN ANJA E. , JØRGENSEN PER T. , CARVALHO EUGENIA 
Published: June 2018

Impaired wound healing is a serious late-diabetic complication resulting in significant morbidity. MicroRNAs (miRNAs), post-transcriptional gene-regulators, are differentially expressed in several conditions, such as diabetes. To assess the mechanistic action of miRNAs in diabetic wound healing streptozotocin (STZ)-induced diabetic and control mice (n=6/group, 6 weeks of diabetes) were subjected to 6-mm full-thickness excisional wounds. Biopsies were obtained at days 3 and 10 post-wounding. Wound healing was delayed in diabetic mice (p&lt;0.05). The skin miRNA profile was determined for up to 561 unique miRNAs using Taqman MicroRNA array cards. We identified 288 different robustly expressed miRNA in skin. While half of them were decreased more than 1.5 fold, 41 were increased more than 1.5 fold, during wound healing. MiR-155-5p was increased in diabetic skin (15.8 fold (95% CI: 3.5-28.1), however, it was 9.7 fold (95% CI: 4.2-15.2) decreased at day 10 post wounding, as compared to nondiabetic mouse skin. Scratch assays in HaCaT cells showed increased scratch closure after 24 hours, when miR-155 was inhibited (Ctrl: 31%, miR-155 inhibitor: 8.1% of scratch remaining, P&lt;0.001). In vivo, topical treatment of diabetic mouse wounds with miR-155 inhibitor dose-dependently accelerated wound closure with maximal effect at 2.5pmol (P&lt;0.03). Interestingly, reporter-gene analysis identified fibroblast growth factor (FGF) 7 mRNA as a target of miR-155-5p. Moreover, miR-155 inhibitor treated mouse wounds showed significant increase in FGF7 protein expression by immunofluorescence. We present evidence that miR-155-5p expression is altered in diabetic mouse skin and its suppression significantly improves wound healing under diabetic conditions, indicating its potential as a novel chronic diabetic foot ulcer treatment.

Disclosure
L.T. Dalgaard: Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. E.C. Leal: None. R. Svendsen: None. J. Moura: None. A.E. Sørensen: Research Support; Self; Danish Diabetes Academy, Merck Serono. P.T. Jørgensen: None.
Tannic Acid–Encapsulated Islets Suppress Autoimmunity and Restore Euglycemia following Transplantation
Authors: BARRA JESSIE , TSE HUBERT M. 
Published: June 2018

Type 1 diabetes (T1D) is an autoimmune disease of pancreatic β-cell death caused by islet-infiltrating leukocytes. Islet transplantation can restore β-cell function, however, limited islet availability, toxicity of immunosuppressants, and poor graft survival are major hurdles for clinical application. We hypothesize that islet encapsulation with a nanothin multilayer coating consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), will provide an immunoprotective barrier and maintain β-cell function after transplantation. In support of our hypothesis, we demonstrate that (PVPON/TA)-encapsulated syngeneic NOD.Rag islets restored euglycemia after transplantation under the kidney capsule of streptozotocin-treated diabetic NOD mice by more than 30 days in comparison to non-encapsulated islets. Encapsulated allogeneic B6 islets also restored euglycemia in diabetic NOD mice and delayed rejection by 7.5 days in contrast to non-encapsulated islets. Gene expression of allogeneic B6 islets at 5 days post-transplant displayed an increase in Ins2 (6-fold), Gcg (6-fold), Pdx1 (5-fold), Ccl22 (3-fold), and Arg1 (2.5-fold) mRNA accumulation with (PVPON/TA)-encapsulated islet grafts, suggesting a potential shift toward an alternatively-activated M2 macrophage phenotype. To address limited islet availability, the use of (PVPON/TA)-encapsulated differentiated neonatal porcine islets restored euglycemia and maintained β-cell function for more than 200 days after transplantation into diabetic NOD.scid mice. Our results support the hypothesis that islet encapsulation with (PVPON/TA) coatings maintain function and may elicit protection following islet allo- and xenotransplantation. Future studies will determine the immunological mechanism of protection following (PVPON/TA)-encapsulation of islets.

Disclosure
J. Barra: None. H.M. Tse: None.