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2014 ADA Posters 1319-2206.Indd INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO 1738-P increase in tumor size and pulmonary metastasis is observed, compared Sustained Action of Ceramide on Insulin Signaling in Muscle Cells: to wild type mice. In this study, we aimed to determine the mechanisms Implication of the Double-Stranded RNA Activated Protein Kinase through which hyperinsulinemia and the canonical IR signaling pathway drive RIMA HAGE HASSAN, ISABELLE HAINAULT, AGNIESZKA BLACHNIO-ZABIELSKA, tumor growth and metastasis. 100,000 MVT-1 (c-myc/vegf overexpressing) RANA MAHFOUZ, OLIVIER BOURRON, PASCAL FERRÉ, FABIENNE FOUFELLE, ERIC cells were injected orthotopically into 8-10 week old MKR mice. MKR mice HAJDUCH, Paris, France, Białystok, Poland developed signifi cantly larger MVT-1 (353.29±44mm3) tumor volumes than Intramyocellular accumulation of fatty acid derivatives like ceramide plays control mice (183.21±47mm3), p<0.05 with more numerous pulmonary a crucial role in altering the insulin message. If short-term action of ceramide metastases. Western blot and immunofl uorescent staining of primary tumors inhibits the protein kinase B (PKB/Akt), long-term action of ceramide on insulin showed an increase in vimentin, an intermediate fi lament, typically expressed signaling is less documented. Short-term treatment of either the C2C12 cell in cells of mesenchymal origin, and c-myc, a known transcription factor. Both line or human myotubes with palmitate (ceramide precursor, 16h) or directly vimentin and c-myc are associated with cancer metastasis. To assess if insulin with ceramide (2h) induces a loss of the insulin signal through the inhibition and IR signaling directly affects the expression these markers, in vitro studies of PKB/Akt. Extended periods of treatment with palmitate (48h) or ceramide were performed on MVT-1 and human MCF7 cells. 10nM of insulin signifi cantly (16h), however, shows an inhibition of insulin signaling through increased-IRS1 increased the expression of c-myc at 60 minutes and vimentin at 48 hours serine 307 phosphorylation. The double-stranded RNA-dependent protein in MVT-1 cells. Silencing the IR and inhibiting IR signaling decreased c-myc kinase (PKR) could play a central role to mediate long-term ceramide effects on expression in both cell lines. These results imply that the hyperinsulinemia IRS1, as recent studies showed that PKR acts as a key modulator of metabolic may drive tumor growth and metastasis through the IR by increasing vimentin infl ammation, insulin sensitivity and glucose homeostasis in obesity. Here, we and c-myc expression. These observations allow us to begin to understand the show that both PKR mRNA and PKR phosphorylation are increased in muscle different key players that contribute to tumor progression in the setting of T2D. of high fat diet fed mice compared to control mice as well as in myotubes These downstream elements could open the fi eld to new targets for therapy to from diabetic patients compared to human control myotubes. These results improve survival in women with breast cancer and hyperinsulinemia. are confi rmed in vitro in both human and C2C12 myotubes in response to either Supported By: ADA (1-13-BS-108) palmitate or ceramide. Pre-treatment of C2C12 or human myotubes with PKR inhibitors prevents the inhibitory effect of either palmitate or ceramide on IRS1. Finally, we show that c-Jun kinase (JNK) mediates ceramide-activated INTEGRATED PHYSIOLOGY—INSULIN SECRETION PKR inhibitory action on IRS1. Altogether, our data show that ceramide inhibits IN VIVO effi ciently insulin signalling by targeting in a time dependent manner two important actors, e.g. PKB/Akt and IRS1 in myotubes. Guided Audio Tour: Dynamic Regulation of Insulin Secretion (Posters: Supported By: Société Francophone du Diabète 1741-P to 1748-P), see page 13. 1739-P & 1741-P Defective Autophosphorylation of the Insulin Receptor with a Novel A Novel Long-Acting Analogue of Xenin-25 with Promising Anti- 3-basepair In-frame DeletionWITHDRAWN (ΔArg1027 Glu1028) Found in a Patient diabetic Potential with Severe Insulin Resistance NIGEL IRWIN, CHRISTINE MA MARTIN, PETER R. FLATT, VICTOR A. GAULT, Coler- BOLORMAA ENKHTUVSHIN, HIROYUKI TAMEMOTO, SHUICHI NAGASHIMA, aine, United Kingdom NAOKO SAITO, KENT SAKAI, MANABU TAKAHASHI, DAISUKE YAMAMURO, Xenin-25 is a peptide co-secreted with glucose-dependent insulinotropic JUN-ICHI OSUGA, SHIN-ICHI TOMINAGA, SHUN ISHIBASHI, Shimotsuke, Japan polypeptide (GIP) from intestinal K-cells following a meal. Xenin-25 is Type A insulin resistance (IR) syndrome is caused by genetic mutations believed to play a role in glucose homeostasis and possibly potentiate the in the insulin receptor (INSR) gene. We aimed to identify the molecular biological action of GIP. We have investigated the effects of sub-chronic mechanism of severe IR in a 35-years-old nonobese woman who was administration of a longer-acting xenin-25 analogue, xenin-25[Lys13PAL], in diagnosed as having type 2 diabetes at age 31 during pregnancy. She mice fed a high fat (45%) diet. Initial acute studies confi rmed the superior presented acanthosis nigricans, hyperglycemia (fasting plasma glucose- persistent glucose lowering (p<0.05) and insulin releasing (p<0.05) actions of 173mg/dl, HbA1c-10.3%), severe hyperinsulinemia (fasting insulin-66µU/ xenin-25[Lys13PAL] compared to native xenin-25. Twice daily intraperitoneal ml), high C-peptide (2.1ng/ml), normal lipid profi le and absence of polycystic injection of xenin-25[Lys13PAL] for 14 days had no signifi cant effect on energy ovary syndrome. Tests for insulin and INSR antibodies were both negative. intake or body weight. Circulating plasma glucose and insulin levels were To explore the underlying molecular defect of IR, we sequenced the INSR also unchanged. However, on day 14, overall plasma glucose levels during gene. We found a 3-basepair in-frame deletion in exon 17 of one allele of the a glucose tolerance and oral nutrient challenge were signifi cantly (p<0.05) INSR, which is predicted to substitute Glutamine for Arginine and Glutamic lowered by xenin-25[Lys13PAL] treatment. These changes were accompanied acid (ΔArg1027 Glu1028) in the kinase domain. The same mutation was by signifi cant enhancement of intraperitoneal (p<0.05) and oral (p<0.001) found in father’s INSR, who also showed severe IR with diabetes. To clarify nutrient-stimulated insulin concentrations when compared to controls. how the mutation impairs the receptor function, we generated plasmid Moreover, xenin-25[Lys13PAL] treated high fat mice had markedly improved vectors expressing the wild-type (WT) and ΔArg1027 Glu1028 mutants under insulinotropic (p<0.01) and glucose-lowering (p<0.01) actions in response to CMV promoter and transfected them to CHO-KI cells. Blasticidine was used exogenous GIP administration on day 14 when compared to saline controls. for selecting stable transformants. Clones with comparable (expression However, no appreciable change in insulin sensitivity was observed with levels) insulin binding levels (as demonstrated by Western blot analyses) xenin-25[Lys13PAL] treatment. Finally, ambulatory activity was signifi cantly revealed by Insulin binding assays were chosen for further experiments. (p<0.05 to p<0.001) increased during the dark phase in xenin-25[Lys13PAL] Scatchard analyses of insulin binding assay using 125I-insulin showed that mice compared to controls. These data indicate that sustained administration Bmax and Kd were comparable between the two receptors. Western blot of a stable analogue of xenin-25 exerts a spectrum of benefi cial metabolic analysis revealed that the expression levels and proteolytic processing effects in high fat fed mice. This demonstrates the utility of long-acting of the INSR were comparable. Treatment with insulin robustly increased analogues of xenin-25 as novel treatments for type 2 diabetes. autophosphorylation of WT, but not of the mutant INSR. Supported By: ERDF Integrated POSTERS In conclusion, we found defective autophosphorylation of the INSR with ΔArg1027 Glu1028 mutation, which might cause severe IR. Physiology/Obesity & 1742-P 1740-P Insulin-like Growth Factor Binding Protein (IGFBP1)-1: Favorable In Insulin Increases the Expression of Vimentin and C-Myc, and Vivo Actions in Glucose Regulation Enhances Breast Cancer Metastasis NATALIE J. HAYWOOD, NADIRA Y. YULDASHEVA, AMIR AZIZ, JESSICA SMITH, ZARA ZELENKO, MARILYN STASINOPOULOS, ROSALYN FERGUSON, RAN PAUL A. CORDELL, MARK T. KEARNEY, STEPHEN B. WHEATCROFT, Leeds, United ROSTOKER, DEREK LEROITH, EMILY J. GALLAGHER, New York, NY, Haifa, Israel Kingdom Women with Type 2 diabetes (T2D) have a 49% increase in breast cancer In humans, the circulating concentration of IGFBP1 has been proposed as related mortality compared with women without T2D. Epidemiological a marker of insulin sensitivity. In prospective studies, low circulating levels studies report that increased endogenous insulin levels and increased insulin of IGFBP1 predict the development of type 2 diabetes. IGFBP1 can impact on receptor (IR) expression are associated with poor survival in breast cancer cellular functions via an RGD (α5β1 integrin binding) motif independent of IGF patients. We used the non-obese female MKR mouse to study the effects of binding. However, whether IGFBP1 is causally implicated in glucose counter- hyperinsulinemia on breast cancer progression. In the MKR mice a signifi cant regulation and could be exploited therapeutically remains unexplored. For author disclosure information, see page A743. & Guided Audio Tour poster ADA-Funded
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