77 results on '"Tennagels N"'
Search Results
2. Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle
- Author
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Eckardt, K., Sell, H., Taube, A., Koenen, M., Platzbecker, B., Cramer, A., Horrighs, A., Lehtonen, M., Tennagels, N., and Eckel, J.
- Published
- 2009
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3. Gene expression profiling in skeletal muscle of Zucker diabetic fatty rats: implications for a role of stearoyl-CoA desaturase 1 in insulin resistance
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Voss, M. D., Beha, A., Tennagels, N., Tschank, G., Herling, A. W., Quint, M., Gerl, M., Metz-Weidmann, C., Haun, G., and Korn, M.
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- 2005
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4. Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1
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Rakatzi, I., Mueller, H., Ritzeler, O., Tennagels, N., and Eckel, J.
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- 2004
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5. Insulin Treatment Induces Oxidative Stress in the Vascular Wall of Patients With Atherosclerosis Independently of Diabetes or Systemic Insulin Resistance: The Protective Role of DPP-IV Inhibition
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Akoumianakis, I, Herdman, L, Margaritis, M, Sanna, F, Sayeed, R, Krasopoulos, G, Tennagels, N, Wohlfart, P, Channon, K, and Antoniades, C
- Published
- 2019
6. Inhibitor κB kinase is involved in the paracrine crosstalk between human fat and muscle cells
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Dietze, D, Ramrath, S, Ritzeler, O, Tennagels, N, Hauner, H, and Eckel, J
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- 2004
7. Insulin induces oxidatives stress in the vascular wall of patients with atherosclerosis independently of systemic insulin resistance: the regulatory role of DPP4 inhibition
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Akoumianakis, I, Herdman, L, Margaritis, M, Sayeed, R, Krasopoulos, G, Petrou, M, Tennagels, N, Wohlfart, P, Channon, K, and Antoniades, C
- Published
- 2018
8. Erratum to: Differences in metabolic and mitogenic signalling of insulin glargine and AspB10 human insulin in rats
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Tennagels, N., Welte, S., Hofmann, M., Brenk, P., Schmidt, R., and Werner, U.
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- 2014
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9. The signalling conformation of the insulin receptor ectodomain
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Weis, F, Menting, JG, Margetts, MB, Chan, SJ, Xu, Y, Tennagels, N, Wohlfart, P, Langer, T, Mueller, CW, Dreyer, MK, Lawrence, MC, Weis, F, Menting, JG, Margetts, MB, Chan, SJ, Xu, Y, Tennagels, N, Wohlfart, P, Langer, T, Mueller, CW, Dreyer, MK, and Lawrence, MC
- Abstract
Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin's negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design.
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- 2018
10. Novel insights into the effects of insulin-like growth factor 1 and endothelin signalling on vascular redox state in patients with type 2 diabetes
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Akoumianakis, I, Herdman, L, Margaritis, M, Sanna, F, Sayeed, R, Petrou, M, Wohlfart, P, Tennagels, N, Channon, K, and Antoniades, C
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- 2017
11. Leucine-zippered human insulin receptor ectodomain with single bound insulin - ""upper"" membrane-distal part
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Weis, F., primary, Menting, J.G., additional, Margetts, M.B., additional, Chan, S.J., additional, Xu, Y., additional, Tennagels, N., additional, Wohlfart, P., additional, Langer, T., additional, Mueller, C.W., additional, Dreyer, M.K., additional, and Lawrence, M.C., additional
- Published
- 2018
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12. Leucine-zippered human insulin receptor ectodomain with single bound insulin - ""lower"" membrane-proximal part
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Weis, F., primary, Menting, J.G., additional, Margetts, M.B., additional, Chan, S.J., additional, Xu, Y., additional, Tennagels, N., additional, Wohlfart, P., additional, Langer, T., additional, Mueller, C.W., additional, Dreyer, M.K., additional, and Lawrence, M.C., additional
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- 2018
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13. 2437Insulin triggers oxidative stress in the vascular wall of patients with atherosclerosis, independently of systemic insulin resistance: the beneficial role of DPP-IV inhibition
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Akoumianakis, I, primary, Herdman, L, additional, Margaritis, M, additional, Sayeed, R, additional, Krasopoulos, G, additional, Petrou, M, additional, Tennagels, N, additional, Wohlfart, P, additional, Channon, K M, additional, and Antoniades, C, additional
- Published
- 2018
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14. Concentrations of insulin glargine and its metabolites during long-term insulin therapy in type 2 diabetic patients and comparison of effects of insulin glargine, its metabolites, IGF-I, and human insulin on insulin and IGF-I receptor signaling
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Varewijck, A.J. (Aimee), Yki-Jarvinen, H. (Hannele), Schmidt, R. (Reinhold), Tennagels, N. (Norbert), Janssen, J.A.M.J.L. (Joop), Varewijck, A.J. (Aimee), Yki-Jarvinen, H. (Hannele), Schmidt, R. (Reinhold), Tennagels, N. (Norbert), and Janssen, J.A.M.J.L. (Joop)
- Abstract
We investigated 1) the ability of purified glargine (GLA), metabolites 1 (M1) and 2 (M2), IGF-I, and NPH insulin to activate the insulin receptor (IR)-A and IR-B and IGF-I receptor (IGF-IR) in vitro; 2) plasma concentrations of GLA, M1, and M2 during longterm insulin therapy in type 2 diabetic patients; and 3) IR-A and IR-B activation in vitro induced by serum from patients treated with GLA or NPH insulin. A total of 104 patients (age 56.3 ± 0.8 years, BMI 31.4 ± 0.5 kg/m2, and A1C 9.1 ± 0.1% [mean ± SE]) were randomized to GLA or NPH insulin therapy for 36 weeks. Plasma concentrations of GLA, M1, and M2 were determined by liquid chromatography- tandem mass spectrometry assay. IR-A, IR-B, and IGF-IR autophosphorylation was induced by purified hormones or serum by kinase receptor activation assays. In vitro, M1 induced comparable IR-A, IR-B, and IGF-IR autophosphorylation (activation) as NPH insulin. After 36 weeks, M1 increased from undetectable (
- Published
- 2013
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15. Concentrations of Insulin Glargine and Its Metabolites During Long-Term Insulin Therapy in Type 2 Diabetic Patients and Comparison of Effects of Insulin Glargine, Its Metabolites, IGF-I, and Human Insulin on Insulin and IGF-I Receptor Signaling
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Varewijck, Aimee, Yki-Jarvinen, H, Schmidt, R, Tennagels, N, Janssen, J.A.M.J.L., Varewijck, Aimee, Yki-Jarvinen, H, Schmidt, R, Tennagels, N, and Janssen, J.A.M.J.L.
- Abstract
We investigated 1) the ability of purified glargine (GLA), metabolites 1 (M1) and 2 (M2), IGF-I, and NPH insulin to activate the insulin receptor (IR)-A and IR-B and IGF-I receptor (IGF-IR) in vitro; 2) plasma concentrations of GLA, M1, and M2 during long-term insulin therapy in type 2 diabetic patients; and 3) IR-A and IR-B activation in vitro induced by serum from patients treated with GLA or NPH insulin. A total of 104 patients (age 56.3 +/- 0.8 years, BMI 31.4 +/- 0.5 kg/m(2), and A1C 9.1 +/- 0.1% [mean +/- SE]) were randomized to GLA or NPH insulin therapy for 36 weeks. Plasma concentrations of GLA, M1, and M2 were determined by liquid chromatography-tandem mass spectrometry assay. IR-A, IR-B, and IGF-IR autophosphorylation was induced by purified hormones or serum by kinase receptor activation assays. In vitro, M1 induced comparable IR-A, IR-B, and IGF-IR autophosphorylation (activation) as NPH insulin. After 36 weeks, M1 increased from undetectable (<0.2 ng/mL) to 1.5 ng/mL (0.9-2.1), while GLA and M2 remained undetectable. GLA dose correlated with M1 (r = 0.84; P < 0.001). Serum from patients treated with GLA or NPH insulin induced similar IR-A and IR-B activation. These data suggest that M1 rather than GLA mediates GLA effects and that compared with NPH insulin, GLA does not increase IGF-IR signaling during long-term insulin therapy in type 2 diabetes.
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- 2013
16. Erratum to: Differences in metabolic and mitogenic signalling of insulin glargine and AspB10 human insulin in rats
- Author
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Tennagels, N., primary, Welte, S., additional, Hofmann, M., additional, Brenk, P., additional, Schmidt, R., additional, and Werner, U., additional
- Published
- 2013
- Full Text
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17. Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle
- Author
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Eckardt, K., primary, Sell, H., additional, Taube, A., additional, Koenen, M., additional, Platzbecker, B., additional, Cramer, A., additional, Horrighs, A., additional, Lehtonen, M., additional, Tennagels, N., additional, and Eckel, J., additional
- Published
- 2008
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18. Inhibitor ?B kinase is involved in the paracrine crosstalk between human fat and muscle cells.
- Author
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Dietze, D., Ramrath, S., Ritzeler, O., Tennagels, N., Hauner, H., and Eckel, J.
- Subjects
ADIPOSE tissues ,OBESITY ,BODY weight ,INSULIN resistance ,NF-kappa B ,FAT cells - Abstract
OBJECTIVE:: Adipose tissue is now considered as an endocrine and secretory organ, and some adipocyte factors are thought to play a major role in the induction of insulin resistance in skeletal muscle. Here we tested the hypothesis that the crosstalk between fat and muscle involves activation of inhibitor ?B Kinase (IKK) in the myocytes. MEASUREMENTS:: Adipocyte-conditioned culture medium was added to the muscle cells overnight, or human fat and muscle cells were kept in co-culture. Insulin signalling was subsequently analysed in the myocytes. Involvement of IKK was assessed using I229, a highly specific inhibitor of the IKK complex. RESULTS:: Adipocyte-conditioned medium strongly inhibited insulin-induced serine phosphorylation of Akt in myocytes with a rapid parallel activation of the nuclear factor ?B pathway in these cells. Conditioned medium lacking the perturbation of insulin signalling did not activate NF-?B. Insulin signalling to Akt was completely abrogated under co-culture conditions. The IKK inhibitor I229 did not affect protein expression of Akt, but fully restored insulin action in myocytes subjected to co-culture. CONCLUSION:: These data show that the release of fat cell factors may rapidly induce insulin resistance in human skeletal muscle cells. This process appears to be mediated by an IKK/NF-?B dependent pathway. We suggest that inhibitors of IKK would be of use to counteract the negative crosstalk between fat and muscle.International Journal of Obesity (2004) 28, 985-992. doi:10.1038/sj.ijo.0802701 Published online 22 June 2004 [ABSTRACT FROM AUTHOR]
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- 2004
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19. Autophosphorylation of the two C-terminal tyrosine residues Tyr1316 and Tyr1322 modulates the activity of the insulin receptor kinase in vitro
- Author
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Tennagels, N., Bergschneider, E., Al-Hasani, H., and Klein, H. W.
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- 2000
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20. Insulin triggers oxidative stress in the vascular wall of patients with atherosclerosis, independently of systemic insulin resistance: the beneficial role of DPP-IV inhibition
- Author
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Akoumianakis, I, Herdman, L, Margaritis, M, Sayeed, R, Krasopoulos, G, Petrou, M, Tennagels, N, Wohlfart, P, Channon, K, and Antoniades, C
21. 40 EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004
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Veitenhansl, M., Stegner, K., Hierl, F-X, Dieterle, C., Feldmeier, H., Gutt, B., Landgraf, R., Garrow, A. P., Vileikyte, L., Findlow, A., Waterman, C., Boulton, A. J. M., Shankhdhar, K., Shankhdhar, L., Shankhdhar, U., Petrova, N. L., Foster, A. V. M., Edmonds, M. E., Ferraresi, R., Caravaggi, C., Giglio, R., Cavaiani, P., Pogliaghi, I., Sommariva, E., Katz, I. A., Harlan, A., Miranda-Palma, B., Prieto-Sanchez, L., Armstrong, D. G., Bowker, J. H., Mizel, M. S., Cernea, S., Wohlgelernter, J., Kidron, M., Modi, P., Raz, I., Arbit, E., Nosek, L., Kapitza, C., Beckett, P., Gelfand, R., Goldberg, M., Heise, T., Testa, M. A., Turner, R. R., Hayes, J. F., Scranton, R. E., Simonson, D. C., Yang, Y-W, Hsu, Y-J, Naujok, O., Francini, F., Jorns, A., Tiedge, M., Lenzen, S., Abdel-Wahab, Y. H. A., Marenah, L., Orr, D. F., Shaw, C., Flatt, P. R., Chokkalingam, K., Mansell, P. I., Clausen, P., Ekbom, P., Damm, P., Feldt-Rasmussen, U., Nielsen, B., Mathiesen, E. R., Feldt-Rasmussen, B., Dewan, S., Da Silva, N., Ternan, P. Mc, Leong, K. S., Wilding, J. P. H., Asatiani, N., Kurashvili, R., Dundua, M., Shelestova, E., Pagava, K., Ramazashvili, M., Hod, M., Smirnov, S., Petersen, J. L. A., Justesen, T. I., Ringholm Nielsen, L., Muller, C., Hojlund, K., Wensaas, A., Kase, E. T., Aas, V., Rustan, A. C., Thoresen, G. H., Levin, K., Beck-Nielsen, H., Gaster, M., Im, S-S, Kang, S-Y, Kim, S-Y, Ahn, Y-H, Lihn, A. S., Schmoll, D., Werner, T., Kienitz, A., Meyer, M., Barthel, A., Ailett, F., Sutherland, C., Walther, R., Grempler, R., Sasson, S., Reich, R., Tenenbaum, T., Alpert, E., Anfossi, G., Russo, I., Traversa, M., Massucco, P., Mattiello, L., Doronzo, G., Trovati, M., Lally, S., Tan, C. Y., Owens, D., Tomkin, G. H., Porchay, I., Pean, F., Bellili, N., Betoulle, D., Balkau, B., Tichet, J., Marre, M., Fumeron, F., Group D.E.S.I.R., Chatellier, G., Alhenc-Gelas, F., Diabhycar, Study Group, Nichols, G. A., Brown, J. B., Hayes, R. P., Bowman, L., Drexel, H., Saely, C. H., Marte, T., Benzer, W., Langer, P., Hoefle, G., Moll, W., Aczel, S., Karagiannis, E., Lubben, G., Urquhart, R., Edwards, G., Bruce, S., Howlett, H. S. C., Cugnardey, N., Turner, K. C., Park, J-S, Fiedorek, F. T., Avogaro, A., Gallo, A., Pinton, P., Rizzuto, R., Murphy, E., Ceolotto, G., Caterson, I., Guy-Grand, B., Hill, J., Barone, M., Aiello, A., Allochis, G., Borzi, V., Cannata, F., Caronna, S., D Avanzo, A., Elli, R., Formoso, G., Paroli, A., Scardapane, R., Sorichetti, P., Tatti, P., Viviani, G., Santeusanio, F., Italian Repaglinide Study Group, Manzella, D., Grella, R., Abbatecola, A. M., Paolisso, G., Sondergaard, L. G., Monster, T. B. M., Johnsen, S. P., Olsen, M. L., Mclaughlin, J. K., Sorensen, H. T., Lervang, H. H., Rungby, J., Lyssenko, V., Fredriksson, J., Almgren, P., Anevski, D., Orho-Melander, M., Sjogren, M., Tuomi, T., Groop, L., Jaziri, R., Aubert, R., Tuomilehto, J., Hu, G., Jousilahti, P., Peltonen, M., Lindstrom, J., Laina, A., Alevizaki, M., Philippou, G., Souvatzoglou, A., Anastasiou, E., Alba, S., Metcalf, B. S., Voss, L. D., Jeffery, A. N., Wilkin, T. J., Gluimer, C., Colagiuri, S., Vistisen, D., Borch-Johnsen, K., Haynes, A., Bower, C., Bulsara, M. K., Jones, T. W., Davis, E. A., Mortensen, H. B., Hougaard, P., Holl, R., Swift, P., Pociot, F., Knip, M., Hansen, L., Szadkowska, A., Pietrzak, I., Zmyslowska, A., Wyka, K., Bodalski, J., Holl, R. W., Swift, R., Hougaard, R., Gerstl, E-M, Engelsberger, I., Rabl, W., Rosenbauer, J., Grobe, H., Hofer, S. E., Krause, U., DPV-Wiss-Study Group, Dabelea, D., Morgan, T., Pettitt, D. J., Dolan, L., Mayer-Davis, E. J., Pihoker, C., Hillier, T. A., Imperatore, G., Ruggiero, A., Hamman, R. E., Stylianou, A., Tentolouris, N., Perrea, D., Tselepis, A. D., Lourida, E., Kitsou, E., Katsilambros, N., Vedovato, M., Dodesini, A. R., Lepore, G., Tiengo, A., Trevisan, R., Penno, G., Miccoli, R., Pucci, L., Lucchesi, D., Bandinelli, S., Fotino, C., Triscornia, S., Baldassari, E., Del Prato, S., Reboldi, P., Santeusanio, E., Fuller, J., Langham, R. G., Gow, R. M., Zhang, Y., Kelly, D. J., Christensen, P. K., Parving, H-H, Gilbert, R. E., Chibalin, A. V., Zhong, Z., Kotova, O., Davidescu, A., Ehren, I., Ekberg, K., Wahren, J., Wassef, L., Buckley, A. J., Rooney, K. B., Briody, J., Thompson, M., Ozanne, S. E., Thompson, C. H., Chamson-Reig, A., Summers, K., Arany, E. J. R., Hill, D. J., Solerte, S. B., Gazzaruso, C., Locatelli, E., Precerutti, S., Schifino, N., Ferrari, E., Fioravanti, M., Phenekos, C. V., Ginis, A., Fragaki, I., Chalkiadaki, M., Tzioras, C., Powell, L. A., Mcguire, G. M., Jewhurst, V., Trimble, E. R., Rasmussen, B. M., Vessby, B., Uusitupa, M., Berglund, L., Pedersen, E., Riccardi, G., Rivellese, A. A., Tapsell, L., Hermansen, K., Kanwu, Study Group, Da Silva Xavier, G., Rutter, J., Rutter, G. A., Briaud, I. M., Lingohr, M. K., Dickson, L. M., Mccuaig, J. R., Lawrence, J. C., Rhodes, C. J., Wikstrom, J. D., Katzman, S. M., Shirihai, O. S., Yang, J., Deng, S., Wang, X., Hessner, M. J., Wu, J., Wong, R. K., Sukumvanich, S., Markman, J. F., Naji, A., Wolf, B. A., Gao, Z., Rubi, B., Del Arco, A., Satrustegui, J., Maechler, P., Del Guerra, S., Lupi, R., Bugliani, M., Sbrana, S., Torri, S., Boggi, U., Vistoli, F., Mosca, F., Marchetti, P., Rennings, A. J. M., Smits, P., Stewart, M. W., Tack, C. J. J., Li, L., Nystrom, T., Gutniak, M., Ahren, B., Holst, J., Sjoholm, A., Gomes, M. B., Cailleaux, S., Tibirica, E., Albertini, J-P, Chen, H., Mather, R., Valensi, P. E., Chisalita, S. I., Arnqvist, H. J., Kraenkel, N., Adams, V., Linke, A., Gielen, S., Schuler, G., Humbrecht, R., Cipollone, F., Iezzi, A., Fazia, M., Pini, B., Cucurullo, C., Cesare, D., Schmidt, A. M., Mazurek, T., Zang, L. F., Mannion, J., Diehl, J., Martin, J., Martella, A., Zalewski, A., Shi, Y., Otter, W., Winter, M., Doering, W., Standi, E., Schnell, O., Kragelund, C., Kober, L., Faber, J., Hildebrandt, P., Steffensen, R., Pankowska, E., Szypowska, A., Lipka, M., Herwig, J., Scholl-Schilling, G., Bohles, H., Robertson, K. J., Schonle, E., Gucev, Z., Mordhorst, L., Tamer, S. C., Gall, M-A, Ludvigsson, J., Hoogma, R. P. L., Hammond, P. J., Gomis, R., Kerr, D., Bruttomesso, D., Bouter, P., Wiefels, K. J., La Calle, H., Schweitzer, D. H., Pfohl, M., Torlone, E., Krinelke, L. G., 205-Nations Study Group, Conget, I., Storms, F., Rodriguez, J., Leperlier, C., Davies, M., At Lantus, Study Group, Peter, R., Luzio, S. D., Dunseath, G., Miles, A., Hare, B., Backx, K., Pauvaday, V., Owens, D. R., Caselli, A., Marfia, G. A., Battista, C., Veves, A., Spallone, V., Uccioli, L., Gonzalez, J. S., Peyrot, M. F., Rubin, R. R., Leventhal, H., Scheffler, N., Ulbrecht, J. S., Cavanagh, P. R., Boulton, A. J., Perrin, N. A., Oglesby, A., Bastyr, E. J., Ziegler, D., Siekierka-Kleiser, E., Meyer, B., Schweers, M., Selvarajah, D., Wilkinson, I. D., Emery, C. J., Shaw, P. J., Griffiths, P. D., Tesfaye, S., Obrosova, I. G., Arezzo, J., Phillips, K., Fidarestat Study Group, Gribble, F. M., Williams, L., Reimann, F., Iakoubov, R., Whiteside, C., Brubaker, P. L., Acitores, A., Gonzalez, N., Sancho, V., Valverde, I., Villanueva-Penacarrillo, M. L., Martin-Duce, A., Trigo, M. V., Arnes, L., Burkart, V., Ichino, N., Ohashi, A., Klein, B. S., Paxian, S., Schmid, R., Karlsen, A. E., Heding, P. E., Frobose, H., Ronn, S. G., Kruhoffer, M., Orntoft, T. F., Nerup, J., Mandrup-Poulsen, T., Billestrup, N., Cardozo, A. K., Ortis, F., Feng, Y-M, Rasschaert, J., Eylen, F., Storling, J., Herchuelz, A., Eizirik, D. L., Wang, H., Kouri, G., Wollheim, C. B., Ribaux, P., Hammar, E., Parnaud, G., Rouiller, D., Bosco, D., Halban, P., Midthjell, K., Carlsson, S., Grill, V., Lau, C., Farch, K., Glumer, C., Tetens, I., Jorgensen, T., Tillin, T., Forouhi, N., Mckeigue, P., Chaturvedi, N., Zethelius, B., Hales, C. N., Berne, C., Coleman, R. L., Stevens, R. J., Holman, R. R., Christensen, J. O., Sandbak, A., Lauritzen, T., Irwin, N., Gault, V. A., Green, B. D., Harriott, P., O Harte, F. P. M., Bouman, S. D., Urso, B., Brand, C. L., Rolin, B., Ribel, U., Schaffer, L., Maggs, D. G., Ceriello, A., Frias, J. P., Wang, Y., Ruggles, J. A., Kolterman, O. G., Piconi, L., Weyer, C., Want, L. L., Ratner, R. E., Uwaifo, G. I., Thornberry, N. A., Eiermann, G., Kim, D., Lankas, G., Leiting, B., Li, Z., Lyons, K., Petrov, A., Sinha Roy, R., Woods, A., Woods, J., Zhang, B. B., Fisher, M., Moller, D. E., Weber, A. E., Dreyer, M., Bellin, C., Schmitz, V., Roesen, R., Nescheret, A. P., Bose, A. K., Mocanu, M. M., Carr, R. D., Yellon, D. M., Manolopoulos, K., Born, S., Wagner, A., Jeziorska, M., Ben Drief, A., Bashir, M., Tomlinson, D., Malik, R. A., Zeymer, U., Schwarzmaier-D Assie, A., Petzinna, D., Chiasson, J-L, Stratton, I. M., Af Bjorkesten, C-G, Fagerudd, J., Rosengard-Barlund, M., Forsblom, C., Pettersson-Fernholm, K., Waden, J., Saraheimo, M., Ronnback, M., Thorn, L., Groop, P-H, Mollsten, A., Svensson, M., Kockum, I., Rudberg, S., Brismar, K., Dahlquist, G., Hovind, P., Hansen, T. K., Tarnow, L., Thiel, S., Jensen, B. R., Flyvbjerg, A., Kankova, K., Hertlova, M., Krusova, D., Schwenke, S., Ott, J., Thom, S. A. M., Mistry, P., Sjolie, A., Larsen, B., Witt, N., Hughes, A. D., Samira, H. H., Lahiry, S., Howlader, S. R., Parveen, S., Azad Khan, A. K., Clarke, P. M., Gray, A., Stevens, R., Holman, R., Phillips, L., Phillips, P. J., Chittleborough, C., Baldock, K., Taylor, A., North West Adelaide Health Study Team, Davis, W. A., Davis, T. M. E., Knuiman, M. W., Hendrie, D., Worthley, D., Nicolucci, A., Pellegrini, F., Berardis, G., Franciosi, M., Belfiglio, M., Rossi, M. C. E., Sacco, M., Valentini, M., Richardson, C. C., Jones, P., Persaud, S., Hussain, K., Clark, A., Christie, M. R., Gniuli, D., Hribal, M. L., Accili, D., Khan, M., Zervou, S., Cheung, L., Abouna, S., Ifandi, V., Pelengaris, S., Luco, R. F., Ferrer, J., Ma, D., Shield, J. P. H., Dean, W., Leclerc, I., Knauf, C., Burcelin, R., Kelsey, G., Powers, A. C., Shostak, A., Ferrara, N., Poffenberger, G., Jerome, W. G., Brissova, M., Geloneze, S. R., Tambascia, M. A., Pareja, J. C., Chaim, E., Silveira, H. V., Geloneze, B., Ravikumar, B., Carey, P. E., Snaar, J. E., Dheelchand, D., Cook, D. B., Neely, D., Taylor, G., Morris, P. G., Taylor, R., Stears, A. J., Masding, M. G., Wootton, S. A., Sandeman, D. D., Klimes, I., Wein, S., Gasperikova, D., Ukropec, J., Wiernsperger, N., Sebokova, E., Manco, M., Mingrone, G., Granato, L., Greco, A. 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B., Fujita, A., Doi, A., Matsuno, S., Okamoto, K., Matsumoto, E., Furuta, H., Nishi, M., Tsuno, T., Taniguchi, H., Bessho, H., Wasen, E., Isoaho, R., Mattila, K., Vahlberg, T., Kivela, S-L, Irjala, K., Rigalleau, V., Lasseur, C., Perlemoine, C., Barthes, N., Raffaitin, C., Chauveau, P., Combe, C., Baillet-Blanco, L., Beauvieux, M-C, Gin, H., Heinrich, S., Steiner, T., Ott, U., Holdass, H., Fellstrom, B., Jardine, A., Staffler, B., Logan, J. O., Gimpelewicz, C., Stanciu, C. C., Pena, C. M., Serafinceanu, C. C., Gonzalez-Posada, J. M., Hernandez, D., Perez-Tamajo, L., Lo, A. J., Herna Alarco, M., Meneses, M., Barsotti, M., Rizzo, G., Schmauss, S., Havrdova, T., Saudek, F., Boucek, P., Adamec, M., Invitti, C., Gilardini, L., Parati, G., Mazzilli, G., Pontiggia, B., Sartorio, A., Lutgers, H. L., Groenier, K. H., Zasadzinska, G., Saryusz-Wolska, M., Temelkova-Kurktschiev, T. S., Kurktschiev, D. P., Majdrakova, I., Varbanova, T., Todorova, B., Bajo-Martinez, A., Bernal, E., Sanchez, O., Ugalde-Canitrot, A., Sanchez-Largo, E., Coca-Robinot, D., Fabregate, R., Calbacho, M., Marquez, J., Saban-Ruiz, J., Penesova, A., Cizmarova, E., Blazicek, P., Jongh, R. T., Serne, E. H., Ijzerman, R. G., Vries, G., Stehouwer, C. D. A., Poulsen, P. L., Andersen, N. H., Knudsen, S. T., Helleberg, K., Mogensen, C. E., Walus, M., Idzior-Walus, B., Sztefko, K., Cieslik, G., Fedak, D., Wozniakiewicz, E., Lin, S. D., Guo, M. Y., Lin, C. J., Liu, X. C., Francisco, M-M J., Rodriguez-Rosas, H., Peiro-Martinez, I., Macias-Batista, A., Harte, A. L., Rodriguez-Cuenca, S., Valsamakis, G., Chetty, R., Anderson, L. A., Roca, P., Matyka, K., Lasalle, J., Hershon, K., Berman, L., Gibson, E., Gillen, D., Maroni, J., Simmons, D., Hiukka, A., Forder, P., Leinonen, E., Hilden, H., Fruchart, J., Fruchart, J-C, Keech, A., Farnier, M., Freeman, M., Macdonell, G., Perevozskaya, I., Mitchel, Y., Gumbiner, B., Didangelos, T. P., Athyros, V. G., Mikhailidis, D. P., Papageorgiou, A. A., Bouloukos, V. I., Pehlivanidis, A. N., Symeonidis, A. N., Elisaf, M., Mckenney, J., Insull, W. Jr, Lewin, A., Maccubbin, D., Lee, M., Kush, D., Schuster, H., Barter, P. J., Stender, S., Cheung, R. C., Bonnet, J., Morrell, J. M., Watkins, C., Kallend, D., Stalenhoef, A. F. H., Ballantyne, C. M., Murin, J., Tonstad, S., Rose, H., Wilpshaar, W., Jenkins, A., Karschimkus, C., Dragicevic, G., Rowley, K., Wolthers, T., Best, J. D., Voet, B., Murdoch, S. J., Marcovina, S. M., Chen, H. C., Brunzell, J. D., Caparevic, Z. V., Kostic, N. D., Ilic, S. M., Sartore, G., Piarulli, F., Cantaro, S., Reitano, R., Fiore, C., Marin, R., Bassan, S., Manzato, E., Fedele, D., Solini, A., Santini, E., Thornalley, P. J., Babaei-Jadidi, R., Karachalias, N., Kupich, C., Ahmed, N., Fowler, A. E., Baker, A. R., Starczynski, J., O Hare, P., Szepietowska, B., Szelachowska, M., Puch, U., Glebocka, A., Quinn, D. W., Da Silva, N. F., Mcternan, C. L., Bonser, R. S., Mcternan, P., Dimitriou, K., Apostolou, O., Kontela, E., Devangelio, E., Gould, E. M., Serri, O., Roussin, A., Buithieu, J., Mamputu, J-C, Renier, G., Giordanetti, S., Amici, E., Poggi, G., Turpini, C., Fratino, P., Garzaniti, A., Yin, D., Banu, I., Roman, G., Negrean, M., Bala, C. G., Nita, C., Kistorp, C., Gustafsson, F., Chong, A., Lip, G., Galatius, S., Shearer, A. T., Ari, N., Sahilli, M., Ceylan-Isik, A., Ozansoy, G., Karasu-Yilmaz, C., Matteucci, E., Rosada, J., Pallini, M., Evangelista, I., Cassetti, G., Giusti, C., Giampietro, O., Capaldo, B., Galderisi, M., Cicala, S., Turco, A., Imbroinise, A., Nosso, G., D Errico, A., Divitiis, O., Klimontov, V. V., Korolyova, E. A., Jeltova, L. I., Bondar, I. A., Tarkun, I., Arslan, B., Canturk, Z., Tarkun, P., Agacdiken, A., Komsuoglu, B., Meneveau, N., Pierre-Justin, E., Alsayed, M., Sabbah, R., Paulin, S., Marcu, S., Tauveron, I., Zimmermann, C., Schiele, F., Seronde, M-E, Vautrin, P., Lusson, J-R, Thieblot, P., Bernard, Y., Mistry, A., Pye, M. P., Peovska, I., Maksimovic Pavlovic, J., Vavlukis, M., Pop Gorceva, D., Bosevski, M., Scognamiglio, R., Negut, C., Kreutzenberg, S., Madonna, R., Caterina, R., Willerson, J. T., Geng, Y-J, Vahsen, S., Ledwig, D., Ramrath, S., Frantz, S., Schmidt, I., Calvillo, L., Dienesch, C., Elbing, I., Bischoff, H., Ertl, G., Bauersachs, J., Davydov, A. L., Mkrtum Yan, A. M., Baranova, L. Y., Ikeda, Y., Suehiro, T., Osaki, F., Ota, K., Arii, K., Kumon, Y., Hashimoto, K., Doney, A. S. F., Fischer, B., Morris, A. D., Palmer, C. N. A., Ahn, Y-M, Lee, B-C, Kim, S-I, Byun, S-H, Ahn, S-Y, Doo, H-K, Pagnin, E., Calo, L. A., Fadini, G., Kubaszek, A., Chai, S., Chai, Q., Rasmussen, L., Ledet, T., Wogensen, L., Lengyel, C., Varro, A., Virag, L., Magyar, J., Biro, T., Jost, N., Skoumal, R., Nanasi, P., Toth, M., Horkay, F., Papp, J. G., Zacharopoulou, O., Athanaselis, S., Tsokos, N., Doupis, J., Psallas, M., Cokkinos, D., Pavlatos, S., Liatis, S., Akhobadze, T., Dzneladze, L., Samarguliani, I., Taskiran, M., Rasmussen, V., Rasmussen, B., Jensen, G. B., Fisher, A. A., Petrovsky, N., Davis, M. W., Srikusalanukul, W., Budge, M. M., Trifunovic-Zamaklar, D. D., Zivkovic, M., Jelic, V., Vukomanovic, G., Ristic, A. D., Seferovic, P. M., Costa, J. V., Duarte, S., Manley, S. E., Sailesh, S., Venkataraman, A., Haider, Y., Groza, I., Oprean, M., Ardelean, A., Morosanu, A., Darkow, T., Vanderplas, A., Mamas, M. A., Mcelduff, P., Burns, J., Edwards, R., Fitchet, A., Young, R. J., Gibson, J. M., New, J. P., Lichiardopol, R., Niculescu, N., Totora, A., Pencea, C., Tomescu, I., Cinteza, M., Manicardi, V., Coscelli, C., Navazio, A., Catellani, E., Michelini, M., Dall Asta, D., Guberti, A., Piazza, A., Gasparini, E., Pantaleoni, M., Guiducci, U., Manari, A., Sejil, S., Janand-Delenne, B., Avierinos, J-F, Habib, G., Labastie, N., Vague, P., Lassmann-Vague, V., Luzniak, P., Wojciechowska Luzniak, A., Zairis, M., Lyras, A., Patsourakos, N., Tsirimbis, V., Foussas, S., Lupon, J., Urrutia, A., Herreros, J., Gonzalez, B., Coll, R., Altimir, S., Prats, M., Valle, V., Abreu-Padi, C., Rabago, G., Ivanova, L. A., Brasacchio, D., Calkin, A., Jandeleit-Dahm, K. A., Harno, E., Keenan, A. K., Li, H. L., Yu, Y. R., Lu, Z. M., Zhang, X. E., Ke, L., Liu, H., Zhang, X. X., Jeong, I-K, Chae, M-K, Choi, M-H, Yoo, H-J, Kim, C. D., Yun, M. R., Na, M. A., Kang, Y. H., Kong, O. N., Son, S. M., Kim, I. J., Kim, Y. K., Tanaka, N., Hosoi, M., Matsuyama, Y., Fukumoto, M., Yamakita, T., Yoshioka, K., Ishii, T., Sato, T., Fujii, S., Aoki, T., Shibata, T., Mizutani, N., Suzuki, J-Y, Fowelin, J. H. R., Samuelsson, P., Brandrup-Wogsen, G., Okumura, K., Tokmakova, A. Y., Staroverova, D. N., Antcieferov, M. B., Shutichina, I. V., Kuntchevich, G. I., Vriesendorp, T. M., Morelis, Q. J., Legemate, D. A., Schaper, F., Mainas, E. I., Gkioulmpasanis, I., Panagiotou, I., Vassilikos, G., Skorda, L., Sidira, M., Christoforidou, M., Alaveras, A., Artikis, V., Evdemon, E., Lechleitner, M., Koch, T., Ebenbichler, C., Sturm, W., Moretti, L., Moruzzo, D., Boldrini, E., Pandolfo, C., Kameyama, M., Iwasa, R., Cho, M-H, Nam, J-Y, Kim, C-S, Kim, D-M, Ahn, C-W, Cha, B-S, Lim, S-K, Kim, K-R, Lee, H-C, Huh, K-B, Kaplar, M., Paragh, G., Erdei, A., Csongradi, E., Garai, I., Varga, J., Galuska, L., Udvardy, M., Higa, M., Kaneko, Y., Hiroi, N., Koziarska, D., Nowacki, P., Majkowska, L., Wojciechowska-Luzniak, A., Tushuizen, M. E., Nieuwland, R., Snoeck, D. P., Sturk, A., Diamant, M., Aguiar, L. G. K., Bahia, L., Villela, N., Laflor, C., Conde, C., Bottino, D., Dorigo, D., Bouskela, E., Pu, S., Yu, H. L., Luo, Z. T., Lam, K. S. L., Dan, Q., Xu, A., Shen, J., Cheng, K., Xu, J. Y. U., Thamer, C., Stefan, N., Haap, M., Heller, E., Tschritter, O., Prado, A., Ortiz, A., Ybarra, J., Gich, I., Pou, J. M., Ehren, M., Meyer, M. F., Roggenland, D., Reinsen, B., Klein, H. H., Rittig, K., Stock, J., Kocher, B., Balletshofer, B., Lee, J., Shon, H. S., Chung, D. S., Nakatani, Y., Matsuhisa, M., Kaneto, H., Hatazaki, M., Yoshiuchi, K., Katakami, N., Kawamori, D., Ohtoshi, K., Sakamoto, K., Matsuoka, T-A, Ozawa, K., Ogawa, S., Hori, M., Yamasaki, Y., Zitouni, K., Harry, D., Nourooz-Zadeh, J., Betteridge, J. D., Earle, K. A., Rasmussen, L. M., Olesen, P., Franco, L., Corvaja, C., Semplicini, A., Rosen, P., Lee, I-K, Kim, M-J, Park, K-G, Jung, E-D, Shin, D-W, Jo, S-R, Obuobie, K., Prakash, P. K., Hanna, F. W., Evans, M., Lazarus, J., Varadhan, L., Gurushankar, J., James, D., Sheikh, S., Gaede, P., Li, H., Zou, D., Lee, S. J., Choi, M. G., Kim, D. S., Kim, T. W., Vilarrasa, N., Perez-Maraver, M., Mena, E., Perez, D., Setti, G., Buckingham, R., Urbancic, V., Stefanovska, A., Bernjak, A., Azman-Juvan, K., Kocijancic, A., Glowania, A., Filters, T. S., Fosmark, D. S., Torjesen, P. A., Kilhovd, B., Berg, T. 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M., Krusinova, E., Wohl, P., Klementova, M., Lanska, V., Mcdougall, C., Thomas, S. J., Kelly, I., Abbas, Z. G., Lutale, J. K., Archibald, L. K., Karunajeewa, H., Stingemore, N., Stuccio, G., Mcgechie, D., Muller, L. M. A., Hak, E., Goudzwaard, W. L., Montorsi, F., Homering, M., Sprenger, K., Goldstein, I., Asnaghi, V., Ferrari, G., Rastaldi, M., Gabellini, D., Antonio, G., Maestroni, A., Ruggieri, D., Luzi, L., Piemonti, L., Zerbini, G., Anafaroglu, I., Tutuncu, N. B., Sultana, M., Siddiqua, N., Iwasaki, T., Nakajima, A., Yoneda, M., Mukasa, K., Tanaka, S., and Sekihara, H.
22. 40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004
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S. Artigas, A V Dreval, Mark I. McCarthy, C Watson, Peter H. Bennett, M Quint, Y Ikeda, E Alpert, F Schiele, H Sekihara, Erik Gylfe, P Lowe, J Kuhlmann, Alain Golay, V Longo, Shahidul Alam Khan Akm., L G Mantovani, M Zawodniak-Szalapska, G Winkler, T Harrity, L Virág, U Johne, Kuo S-W., Linda C Tapsell, J Rodriguez, Michel Komajda, K Kankova, Carole A. Cull, M Sporna, E Estilles, U Ribel, M C Spruce, E Buzzigoli, T Prazak, J K McLaughlin, M K Lingohr, M Lim, F Calara, A Siebenhofer, G Meregalli, Roberto Anichini, A D Baron, R Kurashvili, P C Butler, G I Fantus, T. E. De Gooyer, Park Y-M., R. Walther, S Heinrich, Agnieszka Zawiejska, S Mukherjee, Nikolaos Papanas, G Wong, Ian D. Caterson, David M. Maahs, Shuichi Kaneko, Alexandra E. Butler, Francisco Javier Ampudia-Blasco, O N Kong, Attali J-R., C A Hedman, K Oshinyemi, Nicolle Müller, I C Cranston, N Okumus, M V Vlaiculescu, Balasubramanian Ravikumar, W W Cheatham, K Mukasa, K B Biswas, Annunziata Lapolla, Phil McEwan, G Mader, Gilles Chassot, Dragi Anevski, Werner A. Scherbaum, M Donath, C Hesselmann, R A Gandhi, David E. Moller, Ezio Bonifacio, C Garcia, V Ifandi, P Hornnes, Nieuwenhoven Fav., C Puech, S Pérez-Del-Pulgar, Kim S-R., G Hines, C Rubio Terrés, Michael Gaster, N. Hosszufalusi, A Scholze, Andrew A. Young, Stavros Liatis, F Hariri, S Tan, Paul Valensi, Allan E. Karlsen, J Kim, E. Moberg, J Kaiser, L Berman, G Nelson, A Altkrüger, P Kothare, D B Cook, S Doran, G. van Dijk, Shahnaz Shahinfar, Kim C-S., P Stahl, M Manousaki, S Sigrist, S K Lim, M. P. Stern, A Guberti, C Rezzani, J McKenney, Karl Thomaseth, Sofia Carlsson, M Julia, R Brillante, I Rubesova, T Darkow, E Matsumoto, Wendy M. Macfarlane, M Di Martino, G Bardini, Rossella Menghini, D Duhot, E Farcasiu, Annalisa Natalicchio, I Lindner, J Buvat, Christian L. Brand, Harry Dorchy, Iwona Pietrzak, Z T Luo, P Home, M Ekelund, Jesper Gromada, Kristine Færch, F Piarulli, H Kim, R Mentel, Zsuzsanna K. Zsengellér, Dullaart Rpf., Anton Luger, Thomas A. Pearson, V Manicardi, P Rösen, Feng Y-M., R Morganti, Lars Hansen, Demuth H-U., Haruo Kasai, A Shostak, Rudi Steffensen, G Taylor, Markolf Hanefeld, C Santini, E Hamaguchi, Roberto Miccoli, F Storms, M Cooper, Y Lee, Allison E. Aiello, P Smith, T Suehiro, K Treece, M Waluś, Timothy A Welborn, Simone Baltrusch, E Kontela, S Chai, J Crean, H Yokoyama, Johan G. Eriksson, Rafael Hernández Hernández, J Rodríguez-Saldaña, M P Tornero, G Formoso, D. Lovell, E Bingham, A Mylonakis, M Manteghetti, D Fedele, Antonio Martín-Duce, Ralph A. DeFronzo, D Salcedo, Kurt Højlund, Antonio Petrone, Sheu Whh., C Gutierrez, Flavia Pricci, S Kurita, Z G Abbas, M M Benedetti, Philippe A. Halban, Daniel J. Cox, O Ljungkvist, Justine Davies, J Palsgaard, Lars Sjöström, E Bosi, L Janin-Manificat, W. F. Kelly, M. Fernandez, E Colak, O V Mulyarchik, B Kronshage, F Lang, M Erfurth, Takashi Kadowaki, N Jendrike, U Walter, J Wishart, Y. Neye, D Kim, N Furuhashi, M Barsotti, D Florow, L Ke, L Borgquist, N C Jackson, Ffolliott M. Fisher, V Baskar, K Yoshioka, Bryan A. Wolf, G Chabrier, R Skoumal, Livio Luzi, H Kose, I Pharisien, B. Klein, H Winiarska, M C Johnson, L Griffiths, Nonna Kravchun, C Combe, Baptist Gallwitz, J Zdychova, L Skorda, Jorma Ilonen, W Gao, I N Steen, A Terrinoni, P D Ambery, W Kern, C M Kusminski, Cho M-H., Paolo Pozzilli, Louise G. Grunnet, E Schönle, David R Matthews, Robert W. Taylor, Y Cohen, Kim H-S., M P Eccles, N B Tutuncu, D McDowell, Richard M. Bergenstal, K Takamatsu, T Steiner, Jaan Palgi, Valdemar Grill, N Niculescu, G Federici, S Lehto, P. M. McKeigue, M Barone, Michael E. Trautmann, S Smirnov, J Mannion, M Eto, C Rousseau, M Conti, C S Ernest, Antonio Ceriello, D H Schweitzer, Jung E-D., Andreas Festa, Avijit Lahiri, A Shepelkevich, A Murro, A Kollmann, Jonathan R.S. Arch, R Landgraf, Son H-Y., I Engelsberger, E Agardh, S Rodríguez-Mulero, P J Kraml, K Lee, D. F. Du Toit, E Kim, G Fadini, Williams Ajk., Philip Home, M B Antcieferov, C Perlemoine, D Perrea, Song X-L., D Ruggieri, Krister Bokvist, Heidi Sørensen, Bilbao, G Yoshino, J P Taylor, Shen H-M., S M Furier, R Urquhart, J Wohlgelernter, Jianping Weng, T. Baba, Q Hong, C Silva, Castaigne J-P., M Felaco, X X Zhang, M Jaroň, Milla Rosengård-Bärlund, J G Papp, Toshio Miyata, Lervang H-H., Park M-K., I Kinalska, A Long, Oomen Phn., N Kogawa, Ippolita Patrizia Patera, S. Karadeniz, Dinesh Selvarajah, D S Chung, A Wensaas, Richard Imrich, M Recasens, J Ruxer, O Buchea, E Wilpart, S P Stepanenko, Le Ttd., H Ohgawara, Mariaconsuelo Valentini, A Mondok, M Peltonen, Marianne O. Larsen, K Chatzianagnostou, Agneta Ståhle, A L Ferrari, L Bordier, F Maingrette, A Matsuda, G Vukomanovic, Jakob D. Wikstrom, T Yamakita, E Gorostiaga, J Jin, B Gopalan, Heinz Drexel, S Hewitt, Rury R. Holman, C Dieterle, T L Ruchti, N Asatiani, M Sidira, A Iezzi, A J Sommerfield, D Châtenet, M L Olsen, R Bergemann, C Koehler, T L Kuraeva, B Balas, Christian Berne, E Santos-Mazo, G Smith, A Siejka, R Kožnarová, A Mattina, S Sheikh, A Adomeit, M Rasmussen, J. Fagerudd, N Busciantella Ricci, Nuria Vilarrasa, E Hammar, T L Thoms, L Aydın, Ron G. Rosenfeld, A Nikolajuk, R Gos, C L Morgan, H L Yu, D Dheelchand, S Ramrath, N Boudriga, Jerome I. Rotter, C Jahannault, W M Weston, Folke Lindgärde, M Hertlova, D Knight, A Monroy-Mayorga, E Pardini, A Chamson-Reig, B Franke, Janie McCluskey, Joseph Bryan, C Nikolopoulou, Christie M. Ballantyne, Fausto Santeusanio, L Pegoraro, M Lee, A Klimenko, S Jaiveer, K. Pettersson-Fernholm, Michael A. Nauck, A Ekbom-Schnell, G Deferrari, Riccardo Schiaffini, S. Pampanelli, Khan Aka., David Hopkins, Maija Wessman, M Kamarinos, Noh J-H., O Ebisui, K McCarroll, Jeppe Sturis, Peter Nowotny, N Gorbenko, Åke Sjöholm, David G. Maggs, A E Halseth, B Cresci, A A Ortiz-Gress, A Korakovouni, O Matejkova, C E Mogensen, C J Lin, Ramon Gomis, H Seaman, C Granier, Yang C-H., F Assah, O Sanchez, Fausto Machicao, Peter G. Morris, Alberto Ortiz, A Giardinelli, D Bracaglia, A Gonzalo, S Pavlatos, Andreas Lechner, F Canovic, L Sjolind, Allan Vaag, Birgitte Bruun Nielsen, David A. Ziegler, Vito Lampasona, R Gershoni-Baruch, A. Dei Cas, H Renz, E Mena, Matthew Waltham, Kim D-M., H Levanen, D D Mick, Valentina Alexandrovna Peterkova, E Meskhishvili, Sarah Nutland, R Bustani, John R. Lindsay, M Christoforidou, A Abicht, E Harno, K Cyganek, A Fitchet, S Neelotpol, P Nikishin, P Serradas, J Hinrichsen, M Halvorson, M Chovatia, B Voet, Jinny Willis, E Parretti, M Haslbeck, M Wellard, L Teng, Julio Wainstein, J S Fischer, K. Lalic, D Roggenland, I Gich, R Anwar, Maurizio Cassader, D Serota, X J Li, R J Schotzinger, Vilmundur Gudnason, Björn Zethelius, S A Wootton, W Andrzejewski, R Rezsohazy, R Gao, T Klimentova, T Mazurek, I Bruckner, C Dohrmann, R E James, G daSilva Xavier, Kim S-Y., A Dorca, Stuart J. Pocock, Terri J. Allen, I Giovos, P B Parab, N H Andersen, P Fotinakis, Miriam Cnop, H Lee, Norbert Tennagels, Omorodola I. Abatan, F Ailett, I. Lager, D Manzella, H Hut, Larry A. Distiller, G Lip, Lim S-K., Rong Zhang, T Tsuno, Steen Knudsen, M. Bajardi, Manuel Benito, Dai Sugimoto, Melvin J. Prince, D W Dunstan, D Rankins, K A Majali, G Ozansoy, Isabella Russo, S Uçak, G Annuzzi, R Talar-Wojnarowska, K Lange, S Neugebauer-Baba, Campbell H. Thompson, Eric Renard, P. D. Mountjoy, Z Morrison, Elizabeth A. Davis, Franco Cavallo, C Corvaja, R Antuña, Craig John Currie, H Linnebjerg, He Y-L., A J Palmer, Mariola R. Chacón, H Malinska, M. Jones, R Lichnovská, K Mandes, Paolo Tessari, T Mokhort, A Laina, H. L. Y. Chan, I Schmidt, R Banks, Richard G. IJzerman, L Ksinantova, G Setti, H Vaudry, A Gallo, V Spallone, Chen J-W., Thomas Danne, A Chong, M Hallschmid, S Aczel, S Hulme, N Islam, M Hosoi, P M Ternan, P Di Bartolo, N Bishara, T Shibasaki, Martin A. Osterhoff, Im S-S., M Jecht, T Hamaguchi, S Mattera, K Ways, Elizabeth Northam, U Rajala, Reinhard W. Holl, L Yang, S Panaiotopoulos, K Horvath, R Kluge, Thora B. Bodvarsdottir, Y Dong, Irene Alemanno, C McDougall, Reimar W. Thomsen, M Campbell, W Rabl, John Öhrvik, Yuichiro Yamada, Paola Ungaro, W Benzer, Mike Sampson, Roberto Trevisan, R G Radu, Aas A-M., P E Lobo, Ricardo Scott, S M Son, Josephine M. Forbes, T A Hillier, K L Wyne, Louis L. Nguyen, J Farmer, M H Tan, Kwon H-S., J Yang, L Sandvik, Franco Folli, A K Jenum, M Nguyen, W Pratipanawatr, A L Frederiksen, Rebecca Smith, Lee H-J., A Schäfer, C Manuelli, G S Denver, T Vukovich, B Maceira, K Matsumoto, K. Chokkalingam, Nurcan Üçeyler, P Modi, Timothy M. Morgan, S Mertens, B M Singh, Michaela Riedl, K Iso, C Cucurullo, G. F. Bottazzo, M Calvani, K Hur, J Wetzels, Kazuhiro Takahashi, Y Aso, H Stammer, M G Masding, Fitsum Guebre-Egziabher, J L González-Sánchez, L Armstrong, Alberto Maran, Peter G.F. Swift, S S Popovic, J Starczynski, E Vitacolonna, Luigi Laviola, R W Gelling, Marina Cardellini, D Barilla, Rosa de Diego Martínez, W H Landschulz, Anne Mette Rosenfalck, R K Wong, Kevin E. Schneider, K Peros, Giuseppe Nanni, F Zhang, I Rákóczi, T Iburi, M Nakhjavani, X Q Zhang, S Tournis, Per Lav Madsen, Graham A. Hitman, A. Tura, K Laubner, N D Kostic, Lawrence M. Dolan, R. Sinha Roy, J A Wagner, J. Tuomilehto, J Hauptman, M Abdel-Ghany, D Lacombe, Toralph Ruge, Johannes A Maassen, Triantafyllos Didangelos, K Sasaki, I Argüelles, Klaus Levin, C Popow, Emanuel Christ, R Chetty, L Baillet-Blanco, Jo-Ann Salmon, T Mine, James L. Trevaskis, I Franke, J Gorski, E A Andrianova, A Dayan, A Caballero, Aleksandra Gilis-Januszewska, M Yasujima, Z Kasalová, C.D.A. Stehouwer, F. K. Gorus, G A Nichols, A Glowania, David P. Strachan, P Fredlund, N. F. da Silva, P Reboldi, M Sausbier, K H Groenier, G Stuccio, N Guttman, K R Ahmed, A D Ristic, T Kapellen, J Coutcher, Aldo V. Greco, Oswald Wagner, A Zagayko, Maria Alevizaki, B B Zhang, W F Ferris, Jenny Fredriksson, Lois Jovanovic, J Hänninen, R De Giglio, Kazuo Yagui, O Potterat, P Hamliton, R E Scranton, B Mankovsky, A Stylianou, B Fellström, Abdel-Wahab Yha., M Kitagawa, Katherine L. Baldock, F R Johnson, F Baigts, S D'Addato, F J Sanz, A Mistry, S D Wise, T Pratipanawatr, U R Fölsch, James R.C. Parkinson, Claudia Sommer, C Park, F E Griffiths, M L Martí, R Demirtunc, S Taniguchi, J Lundkvist, T Siegmund, Juan Sztajzel, C Dienesch, F Baumgartner, L Scalone, T M Mckolanis, K Otake, Ullrik Pedersen-Bjergaard, T M Vriesendorp, Michael B. Wheeler, Henry Schmitt, Peter Hovind, S Lange, Stephane Roze, L. Van Gaal, B Klaproth, Anthony E. Civitarese, D Eckland, A Dagar, D F Hopkins, Kari Stefansson, C Gonzalez-Yanes, B Meyboom-de Jong, D. J. Betteridge, K Buhling, M Crepaldi, Ana M. Wägner, L Renna, L Volpe, R McBride, V Corbo, E O Brennesvik, R P Hayes, R Abdollahnia, G Viviani, C F Liew, Francisco Pérez-Bravo, Jeffrey Baron, Brian M. Frier, H H Samira, D Szentendrei, K. J. Schjoedt, W K Waldhäusl, D Gniuli, D Zou, G Tschank, V Urbančič, A L Nolan, Albertini J-P., J Malcomson, M Larbig, C Cheyssac, K Aurich, C M Kesson, S Heller, Maija E. Miettinen, R F Luco, Adrian J. Cameron, Luigi Mattiello, Z. Metelko, X E Zhang, M Parramón, I. G. Obrosova, J Fruchart, M Ilic, Björn Eliasson, Gilles Chatellier, M A Martín, D M Kendall, Holger Luthman, V F Varillas, D Maccubbin, Jang S-A., Amalia Gastaldelli, E Salzsieder, P. de Mol, A Yoshida, H D Lindner, D Gostiljac, M Just, Pan C-Y., J M Fujitaki, G Eiermann, K Bergenheim, A D Frick, A Agacdiken, K Varytimiadis, K Cseh, D A Jackson, S Calderari, Dena G. Hernandez, H M Liebich, K Min, F. de Zegher, Bernd Kulzer, K Han, Ulrich A. Müller, D Marrero, H Hatakeyama, René Koopman, Doo H-K., Petr Wohl, P. Sharp, P Forder, Thor Aspelund, N Meneveau, R M Schmülling, R Aubert, Thom Sam., H Youshikawa, M Ankelo, D Bowden, I Kelly, Frédéric Fumeron, M Sartini, Robert S. Sherwin, L Varadhan, A Criscimanna, John Betteridge, V Jelic, M Bartnik, N Lemke, B Ursø, A Bertoldo, A M Owona, H Okochi, L Pérez-Tamajó, S L Monfre, Daniel Brandhorst, K T Legg, Andries J. Smit, Veronica Sancho, Masashi Hirai, C Klein, Paul J. Thornalley, A Chaidaroglou, K Miura, B Zinman, O M Dvoynishnikova, J Plank, Jan Bolinder, C Lush, B Rubi, R Pozzilli, M Bashir, S A Shtandel, F Mosca, A Naskalska, Josef Vcelak, U Sausbier, P Cavaiani, T U Baehring, Michele Solimena, P Formisano, M Rastaldi, Bernard Thorens, J Ruzzin, E Arbit, M. Hori, Torkel B. Brismar, E Soltes Rak, A Filo, P Heinke, Matthew P. Coghlan, M Masotti, I Perevozskaya, K Ahn, I Moules, K Van Dyck, I Goldstein, Z Mathe, G Z Zhao, S Fajardo, J Taylor, S Chrul, J C Pareja, D Hadjidakis, A J Scheen, N Siddiqua, D C Cavan, R Grella, Krabbe S, H J Rochlitz, A E Hinkkanen, W Wilpshaar, Richard Stevens, M Dreyer, S Hara, X Wang, Melania Manco, D Gillen, Magalie A. Ravier, Olli Simell, John C. Lawrence, Kohnert K-D., Agardh C-D., A Berghold, L Kristensen, Grant Sfa., N Gursoy, Leif Groop, N Freemantle, Anja Schweizer, L Pala, Legros J-J., C. Di Pietro, N. Yamamoto, J Magyar, B Nikolovski, H Ikeda, D Lee, Bruce A. Buckingham, A O Wollitzer, I Kennedy, C Ernest, Neville H. McClenaghan, S Tanaka, Asimina Mitrakou, T Heinze, W Kerner, Moeenaldeen Al-Sayed, Charles Thivolet, L Klaff, A Miconi, Cristina Valeri, J. O. Christensen, K. Ekberg, A Jardine, T Endo, X Zhang, D F Child, A Kienitz, D K Seidel, H. Tada, Sylvie Abouna, Cyrus Cooper, Catherine R Chittleborough, Roberta Assaloni, S Corbi, A K Bose, K Ozawa, C Ahn, K A Deans, G Jackowski, Martin Gibson, Patrick McElduff, O A Mojiminiyi, Manuel Serrano-Ríos, O Dupuy, A L Davydov, Iwar Klimes, Sten-Anders Ivarsson, N Ichino, R Matsutomo, E R Smith, A Stefanovska, B Dehmel, K Koniavitou, E Agascioglu, M Hatazaki, J. M. Gibson, T Yada, P Ribaux, M Rupnik, K Fridell, G Scutaru, L Chugunova, Henrietta Mulnier, A Kendereski, H Lehnert, C Billi, M Sobczak, Francisco M-Mj., L K Archibald, S Sukumvanich, David B. Dunger, I. Benke, G Yillar, N Stingemore, J. M. Boavida, Y Shi, Jimmy D. Bell, L Bozzetto, Andrew J. Ahmann, E Jebens, J Keiding, Elena Henkel, Mark Fineman, J F McRae, Carol Forsblom, S Martemucci, Lourdes Ibáñez, P G Prieto, L Ringholm Nielsen, S Pratas, B von Stritzky, Julio Rosenstock, Lee K-W., J Stocks, L J Strow, I Samarguliani, L Wennekes, R Cheung, Abhishek Nag, Roberto Gambino, Y Suleymanoglu, E Murphy, T T Durck, M F Peyrot, Y Unno, Alexander Mayorov, Eleuterio Ferrannini, D. C. Rao, D Neely, H Karunajeewa, J Palmisano, Julia B. Lewis, M Ravid, G Pons, E Junca, P Vexiau, S Sailesh, D K Miloslavskiy, O N Bondarenko, U Smith, S Torri, Constantine Tsigos, Cesario Bianchi, Mattia Locatelli, D Jaquet, Virpi Lindi, M Moroi, M E Tushuizen, P Pelicci, R Scognamiglio, Pal Pacher, S M Thyssen, A Péterfalvi, Y Ho, S Guntram, L Romics, T Nakagami, Clive S. Cockram, Irina Kowalska, K Brodbeck, Gojka Roglic, J. Dörig, Lise Tarnow, Therese Tillin, A López-Alba, Martin Krššák, Moses Elisaf, S Hata, D P Snoeck, D Schmoll, O V Udovichenko, A Scaramuzza, J Paul, John H. Fuller, Nicholas Katsilambros, Michele Muggeo, Pia Ekbom, Piero Marchetti, V Melki, C Bailleau, H Stavrianos, A D'Errico, Geremia B. Bolli, Amabile Maier, Kelter A-R., Anders Green, Q J Morélis, Steffen Thiel, C Watkins, R C Cheung, A Clark, Elvira Fioriti, N Ari, Nam J-Y., Y Cottin, L G Krinelke, H Al Mohammedi, Simon C. Fleming, C Jones, Z Kerényi, Ahn Y-H., Meile M-J., P Nánási, M Graner, V Canonico, Gangnerau M-N., Hugh R. Taylor, Giovanni Sartore, A. Dejgaard, Carol Kelley, S. Ali, Stéphane Dalle, Jeffrey S. Gonzalez, Elena Šeböková, Alexander Beck, Ingo B. Leibiger, M Rosu, C Pencea, Werner Waldhäusl, Kaltenbacher M-C., R Butzer, S Thore, Adam G. Tabak, Angelo Avogaro, E Standi, Boris Kovatchev, O Bradescu, Patrizia Dentelli, A Fujita, C Verri, R Chlup, Prasad Ydm., S V Hörsten, van der Merwe M-T., D Hilliard, W Klein, D Worthley, M Udvardy, Berit R. Jensen, A D'Avanzo, J Monaghan, K P Yeo, Guivarch P-H., B Bauduceau, D Weghuber, P Tatti, J Ybarra, S Gwozdziewiczová, E Gasparini, B Saltin, Charlotte Granhall, Howard Leventhal, R Marin, M Tumiati, Cicero Afg., L Csémy, B Berger, S Mikros, D Dall'Asta, M Shahmanesh, Y G Vasiljev, F Potthoff, H S Randeva, G De Berardis, J O Logan, K Warncke, P Uitterlinden, E Rehring, K Gilmore, K Shankhdhar, V V Bojko, M Vahatalo, E A Korolyova, D Wiemann, P G Lankisch, D Hendrie, F Galtier, M Rybarczyk, Gisela Dahlquist, N N Rudovich, G Stein, A Liebl, F Tan, A Westerlund, S Gronemann, I Franklin, Jonathan A. Prince, Peter Arner, E Skliros, T. Sparre, M Vigas, Maddalena Trombetta, L. Bjerre Knudsen, A C Sima, I Dubroca, Alastair Gray, I Weets, R Ferraresi, Schauer Ujw., E. Leinonen, S Corazza, Jonathan Levy, P K Prakash, R Guzder, S. Barnhill, John Blangero, J Herreros, G. de Vries, Cheng Ptw., A Macías-Batista, K. Capito, R Thomas, G Thomas, G Boemi, Lotte Pietraszek, Pierre Fontaine, I Holme, J Smedegaard, C A Harrop, U Helwig, B Levy, A P Gribben, Hiroto Furuta, P Beckett, S Giannini, Ruth L. Coleman, Eva Fernqvist-Forbes, N Cugnardey, A Dumas, Jane Pinaire, S E Hofer, D Shimono, Erik H. Serné, Alain D. Baron, C Battista, M Tanen, M Klementova, V Adams, J Komorowski, Antonio Nicolucci, E. C. Burns, H Sydall, M G Fanara, M G Giovannitti, N Okabayashi, Magdalena Szurkowska, I A Eroshkin, M. I. J. Uusitupa, D Ma, C C Dieguez, J Sutcliffe-Goulden, A V Gaddi, Michał Arabski, Serge Halimi, Wendy C. Burns, S Seclén, H Sugano, A Vinterby, K Backx, L F Diaconu, Fernando Gomez-Peralta, O'Harte Fpm., G Lepeniotis, D Laune, H Kvasničková, N H Wallén, G Boner, G Cieślik, Robert Hermann, Paul Q. Thomas, Y Kumon, Maria Maiello, M Atkins, Kenneth A. Earle, Guowang Xu, H Y Bae, I Reynisdottir, D Perez, D E Cannon, P Fabietti, I Geronooz, J Østergaard, K J Jeitler, S Skourtis, A Zambanini, A Saemann, K Kuboki, Helen L. Lutgers, A C Thai, Arne Melander, D Pinkowski, S G Straub, S A Wolfe-Coote, A Totora, Hayley Dickinson, A Lindenmair, A Ginis, I Faturos, F Van Eylen, C Huard, F Fu, N Wang, B M Rasmussen, Angela Napoli, L Granato, Markus M. Lerch, M. Frandsen, A Lyras, Lawrence S. Phillips, J Mabley, R Goldschmeding, B K Kilhovd, W Liu, Greg Poffenberger, P Cipriano, Anna Maria Charlotte K Lindqvist, A Matsuzawa, J Wang, T Yu, M S Pepper, Lena M. Thorn, Y Sakamoto, Blanche Schwappach, Anna L. Gloyn, P Dupraz, A. M. Schmidt, M Psallas, V Tsirimbis, Carl D. Langefeld, D Sass, H E Scholtz, M. Cailleau, Lauren Julia Brown, K Phillips, M. Iezzi, C Jayawarna, Eleni Anastasiou, R Lobmann, R Lundershausen, H Fujiwara, H R Nan, I C Smith, I A Karpova, A Navazio, S Kang, T. Hansen, T Watanabe, Gang Hu, Malik Rja., T Kennedy-Martin, Ulla M Smidt, J.M. Dekker, A A Fisher, H Liu, R E Pratley, B Sun, C Fledelius, J F Raposo, R Langham, Ahn S-Y., B R Waterhouse, Shaoping Deng, W Ricart, S V Melnichenko, Henrike Sell, M. Tomalino, N Takeda, Paola Massucco, A Harlan, W Henrich, C D Byrne, R Junik, Khalid Hussain, D Pop Gorceva, Torben Hansen, C Ritterath, K Ogawa, D V Phan, Bradley S Metcalf, Robb E. Moses, Juan P. Frias, Hitoshi Ishii, C Brisard, P Wolkow, H H Maurer, Ingo Rustenbeck, Juris J. Meier, Octavian Savu, S D Lin, V B Bregovski, A Fox, S Cicala, M. Koenen, L Vignati, O de Divitiis, Constantin Ionescu-Tirgoviste, Kilian Rittig, J Song, Riccardo Candido, F Cohen-Boulakia, U Shankhdhar, P Jahan, Antonio Tiengo, E Liepinsh, C Álvarez, Sigurd Lenzen, James E. Foley, A. del Arco, M A Maitan, U Mollenhauer, M A Na, A Beha, B Aicher, Gabriele Meyer, E Sommariva, J Åman, B Gmeinhart, Theede A-M., Bjorn Bolinder, Giulio Ceolotto, S Sbrana, F Biarnes, Damini Dey, Barbara Thorand, H H Klein, Juliana C.N. Chan, L Piconi, S Gudbjornsdottir, E Bobbioni-Harsch, Joanna Polanska, Cristian Serafinceanu, S Gambardella, Olivier Huber, J D Brunzell, T Nagasawa, Loretta Vileikyte, A Szocs, H Löwel, Z Lin, Anders Juul, H Tsuneki, L Sauriol, G Siebert, Marit E. Jørgensen, K Matthies, Brian D. Green, P Jurowski, Z Gao, M Furuya, Silvia Manfrini, Efthymios Motakis, E Souvatzoglou, Qian Y-Z., Byun S-H., T Nguyen, M R Anwar, Geltrude Mingrone, B. Idzior-Walus, Mamas A. Mamas, G Scholl-Schilling, C Bittner, A E Raptis, L Laghi, Murray Stewart, M Orel, Janet M. 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Dell'Antonio, G, Maestroni, A, Ruggieri, D, Luzi, L, Piemonti, L, Zerbini, G, Anafaroglu, I, Tutuncu, N, Sultana, M, Siddiqua, N, Iwasaki, T, Nakajima, A, Yoneda, M, Mukasa, K, Tanaka, S, and Sekihara, H
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0303 health sciences ,medicine.medical_specialty ,business.industry ,EASD ,Endocrinology, Diabetes and Metabolism ,Human physiology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Family medicine ,Internal Medicine ,Medicine ,business ,030217 neurology & neurosurgery ,030304 developmental biology - Published
- 2004
23. Molecular basis for inhibiting human glucose transporters by exofacial inhibitors.
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Wang N, Zhang S, Yuan Y, Xu H, Defossa E, Matter H, Besenius M, Derdau V, Dreyer M, Halland N, He KH, Petry S, Podeschwa M, Tennagels N, Jiang X, and Yan N
- Subjects
- Glucose metabolism, Glucose Transporter Type 1 genetics, Glucose Transporter Type 3 genetics, Humans, Glucose Transport Proteins, Facilitative metabolism, Insulin metabolism
- Abstract
Human glucose transporters (GLUTs) are responsible for cellular uptake of hexoses. Elevated expression of GLUTs, particularly GLUT1 and GLUT3, is required to fuel the hyperproliferation of cancer cells, making GLUT inhibitors potential anticancer therapeutics. Meanwhile, GLUT inhibitor-conjugated insulin is being explored to mitigate the hypoglycemia side effect of insulin therapy in type 1 diabetes. Reasoning that exofacial inhibitors of GLUT1/3 may be favored for therapeutic applications, we report here the engineering of a GLUT3 variant, designated GLUT3exo, that can be probed for screening and validating exofacial inhibitors. We identify an exofacial GLUT3 inhibitor SA47 and elucidate its mode of action by a 2.3 Å resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development., (© 2022. The Author(s).)
- Published
- 2022
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24. Insulin Fused to Apolipoprotein A-I Reduces Body Weight and Steatosis in DB/DB Mice.
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Ardaiz N, Gomar C, Vasquez M, Tenesaca S, Fernandez-Sendin M, Di Trani CA, Belsué V, Escalada J, Werner U, Tennagels N, and Berraondo P
- Abstract
Background: Targeting long-lasting insulins to the liver may improve metabolic alterations that are not corrected with current insulin replacement therapies. However, insulin is only able to promote lipogenesis but not to block gluconeogenesis in the insulin-resistant liver, exacerbating liver steatosis associated with diabetes. Methods: In order to overcome this limitation, we fused a single-chain insulin to apolipoprotein A-I, and we evaluated the pharmacokinetics and pharmacodynamics of this novel fusion protein in wild type mice and in db/db mice using both recombinant proteins and recombinant adenoassociated virus (AAV). Results: Here, we report that the fusion protein between single-chain insulin and apolipoprotein A-I prolonged the insulin half-life in circulation, and accumulated in the liver. We analyzed the long-term effect of these insulin fused to apolipoprotein A-I or insulin fused to albumin using AAVs in the db/db mouse model of diabetes, obesity, and liver steatosis. While AAV encoding insulin fused to albumin exacerbated liver steatosis in several mice, AAV encoding insulin fused to apolipoprotein A-I reduced liver steatosis. These results were confirmed upon daily subcutaneous administration of the recombinant insulin-apolipoprotein A-I fusion protein for six weeks. The reduced liver steatosis was associated with reduced body weight in mice treated with insulin fused to apolipoprotein A-I. Recombinant apolipoprotein A-I alone significantly reduces body weight and liver weight, indicating that the apolipoprotein A-I moiety is the main driver of these effects. Conclusion: The fusion protein of insulin and apolipoprotein A-I could be a promising insulin derivative for the treatment of diabetic patients with associated fatty liver disease., Competing Interests: UW and NT are employees of Sanofi-Aventis Deutschland GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ardaiz, Gomar, Vasquez, Tenesaca, Fernandez-Sendin, Di Trani, Belsué, Escalada, Werner, Tennagels and Berraondo.)
- Published
- 2021
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25. Equipotency of insulin glargine 300 and 100 U/mL with intravenous dosing but differential bioavailability with subcutaneous dosing in dogs.
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Werner U, Tennagels N, Fanelli CG, and Bolli GB
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- Animals, Biological Availability, Blood Glucose, Dogs, Insulin Glargine, Insulin, Long-Acting, Diabetes Mellitus, Type 2, Hypoglycemic Agents
- Abstract
Aims: Insulin glargine 300 U/mL (Gla-300) contains the same units versus glargine 100 U/mL (Gla-100) in three-fold lower volume, and higher subcutaneous (SC) doses are required in people with diabetes. To investigate blood glucose (BG) lowering potency, Gla-300 and Gla-100 were compared after intravenous (IV, for 4 h) and SC (for 24 h) injection in healthy Beagle dogs., Materials and Methods: The dose of 0.15 U/kg Gla-300 and Gla-100 was injected IV in 12 dogs. BG, C-peptide, glucagon and the active metabolite 21A-Gly-human insulin (M1; liquid chromatography-tandem mass spectrometry method) were measured. Twelve other dogs were studied after SC injection of 0.3 U/kg Gla-300 and Gla-100., Results: After IV injection, Gla-300 and Gla-100 were equally potent [BG_AUC
0-4 h ratio 1.01 (95% confidence interval, 0.94; 1.09)]. After SC injection, BG decreased slower and less with Gla-300. Similar metabolism of Gla-300 and Gla-100 to M1 occurred with IV dosing [M1_AUC0-1 h ratio 0.99 (95% confidence interval, 0.82; 1.22)], but with SC dosing M1_Cmax and AUC0-24h were 44% and 17% lower; mean residency time and bioavailability were 32% longer and 50% lower, with Gla-300., Conclusions: IV Gla-300 and Gla-100 have the equivalent of BG-lowering potency and M1 metabolism. SC Gla-300 has lower M1 bioavailability with a reduced BG-lowering effect and need for greater doses versus Gla-100., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)- Published
- 2021
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26. Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice.
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Ziegler N, Raichur S, Brunner B, Hemmann U, Stolte M, Schwahn U, Prochnow HP, Metz-Weidmann C, Tennagels N, Margerie D, Wohlfart P, and Bielohuby M
- Subjects
- Acetylation, Animals, Blood Glucose metabolism, Gene Knockdown Techniques, Hepatocytes metabolism, Histone Deacetylases metabolism, Mice, RNA, Small Interfering, Gluconeogenesis genetics, Glucose metabolism, Histone Deacetylases genetics, Lipid Metabolism genetics, Liver metabolism
- Abstract
Histone deacetylases (HDACs) are important regulators of epigenetic gene modification that are involved in the transcriptional control of metabolism. In particular class IIa HDACs have been shown to affect hepatic gluconeogenesis and previous approaches revealed that their inhibition reduces blood glucose in type 2 diabetic mice. In the present study, we aimed to evaluate the potential of class IIa HDAC inhibition as a therapeutic opportunity for the treatment +of metabolic diseases. For that, siRNAs selectively targeting HDAC4, 5 and 7 were selected and used to achieve a combinatorial knockdown of these three class IIa HDAC isoforms. Subsequently, the hepatocellular effects as well as the impact on glucose and lipid metabolism were analyzed in vitro and in vivo . The triple knockdown resulted in a statistically significant decrease of gluconeogenic gene expression in murine and human hepatocyte cell models. A similar HDAC-induced downregulation of hepatic gluconeogenesis genes could be achieved in mice using a liver-specific lipid nanoparticle siRNA formulation. However, the efficacy on whole body glucose metabolism assessed by pyruvate-tolerance tests were only limited and did not outweigh the safety findings observed by histopathological analysis in spleen and kidney. Mechanistically, Affymetrix gene expression studies provide evidence that class IIa HDACs directly target other key factors beyond the described forkhead box (FOXP) transcription regulators, such as hepatocyte nuclear factor 4 alpha (HNF4a). Downstream of these factors several additional pathways were regulated not merely including glucose and lipid metabolism and transport. In conclusion, the liver-directed combinatorial knockdown of HDAC4, 5 and 7 by therapeutic siRNAs affected multiple pathways in vitro , leading in vivo to the downregulation of genes involved in gluconeogenesis. However, the effects on gene expression level were not paralleled by a significant reduction of gluconeogenesis in mice. Combined knockdown of HDAC isoforms was associated with severe adverse effects in vivo , challenging this approach as a treatment option for chronic metabolic disorders like type 2 diabetes., (Copyright © 2020 Ziegler, Raichur, Brunner, Hemmann, Stolte, Schwahn, Prochnow, Metz-Weidmann, Tennagels, Margerie, Wohlfart and Bielohuby.)
- Published
- 2020
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27. High-throughput screening assay for the quantification of Cer d18:1/16:0, d18:1/24:0, d18:1/24:1, d18:1/18:0, d18:1/14:0, d18:1/20:0, and d18:1/22:0 in HepG2 cells using RapidFire mass spectrometry.
- Author
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Dittakavi S, Mahadevan L, Chandrashekar DV, Bhamidipati RK, Suresh J, Dhakshinamoorthy S, Li Z, Baerenz F, Tennagels N, and Mullangi R
- Subjects
- Ceramides isolation & purification, Hep G2 Cells, Humans, Solid Phase Extraction, Ceramides chemistry, High-Throughput Screening Assays methods, Tandem Mass Spectrometry methods
- Abstract
Ceramides are known to be involved in various biological processes with their physiological levels elevated in various disease conditions such as diabetes, Alzheimer's, atherosclerosis. To facilitate the rapid screening of Cer d18:1/16:0, d18:1/24:0, d18:1/24:1, d18:1/18:0, d18:1/14:0, d18:1/20:0, and d18:1/22:0 inhibition in HepG2 cells, a RapidFire coupled to tandem mass spectrometry (RF-MS/MS) method has been developed. The RF platform provides an automated solid-phase extraction system that gave a throughput of 12.6 s per sample to an MS/MS system using electrospray ionization under the positive ion mode. Chromatographic separation of Cer d18:1/16:0, d18:1/24:0, d18:1/24:1, d18:1/18:0, d18:1/14:0, d18:1/20:0, and d18:1/22:0 was achieved using a ternary gradient on C
8 type E cartridge. The MS/MS ion transitions monitored were 538.2 → 264.2, 650.7 → 264.2, 648.6 → 264.2, 566.4 → 264.2, 510.4 → 264.2, 594.4 → 264.2, 622.5 → 264.2, and 552.3 → 250.2 for Cer d18:1/16:0, d18:1/24:0, d18:1/24:1, d18:1/18:0, d18:1/14:0, d18:1/20:0, d18:1/22:0, and the internal standard (Cer d17:1/18:0), respectively. The RF-MS/MS methodology showed an excellent performance with an average Z' value of 0.5-0.7. This is the first report of an RF-MS/MS assay for screening of ceramides which is amenable for high-throughput screening., (© 2019 John Wiley & Sons, Ltd.)- Published
- 2020
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28. Insulin-induced vascular redox dysregulation in human atherosclerosis is ameliorated by dipeptidyl peptidase 4 inhibition.
- Author
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Akoumianakis I, Badi I, Douglas G, Chuaiphichai S, Herdman L, Akawi N, Margaritis M, Antonopoulos AS, Oikonomou EK, Psarros C, Galiatsatos N, Tousoulis D, Kardos A, Sayeed R, Krasopoulos G, Petrou M, Schwahn U, Wohlfart P, Tennagels N, Channon KM, and Antoniades C
- Subjects
- Animals, Coronary Artery Bypass, Humans, Insulin therapeutic use, Mice, Oxidation-Reduction, Atherosclerosis, Dipeptidyl Peptidase 4
- Abstract
Recent clinical trials have revealed that aggressive insulin treatment has a neutral effect on cardiovascular risk in patients with diabetes despite improved glycemic control, which may suggest confounding direct effects of insulin on the human vasculature. We studied 580 patients with coronary atherosclerosis undergoing coronary artery bypass surgery (CABG), finding that high endogenous insulin was associated with reduced nitric oxide (NO) bioavailability ex vivo in vessels obtained during surgery. Ex vivo experiments with human internal mammary arteries and saphenous veins obtained from 94 patients undergoing CABG revealed that both long-acting insulin analogs and human insulin triggered abnormal responses of post-insulin receptor substrate 1 downstream signaling ex vivo, independently of systemic insulin resistance status. These abnormal responses led to reduced NO bioavailability, activation of NADPH oxidases, and uncoupling of endothelial NO synthase. Treatment with an oral dipeptidyl peptidase 4 inhibitor (DPP4i) in vivo or DPP4i administered to vessels ex vivo restored physiological insulin signaling, reversed vascular insulin responses, reduced vascular oxidative stress, and improved endothelial function in humans. The detrimental effects of insulin on vascular redox state and endothelial function as well as the insulin-sensitizing effect of DPP4i were also validated in high-fat diet-fed ApoE
-/- mice treated with DPP4i. High plasma DPP4 activity and high insulin were additively related with higher cardiac mortality in patients with coronary atherosclerosis undergoing CABG. These findings may explain the inability of aggressive insulin treatment to improve cardiovascular outcomes, raising the question whether vascular insulin sensitization with DPP4i should precede initiation of insulin treatment and continue as part of a long-term combination therapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2020
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29. Nearly a Century of Insulin at Sanofi: Looking Back Over the Decades of Production and Development.
- Author
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Bosnyak Z, Korn M, Bielohuby M, Wohlfart P, and Tennagels N
- Subjects
- Diabetes Mellitus drug therapy, Humans, Hypoglycemic Agents, Insulin supply & distribution
- Abstract
Almost a century ago, the first insulin was produced by Banting, Best, MacLeod and Collip in Toronto, thereby enabling life-saving treatment for people with diabetes. Since then, there have been many advancements in insulin production and development of new insulin analogues. In this article, we reflect on the rich heritage of Sanofi and its predecessor, Hoechst, in insulin production and development, from being one of the first companies to produce insulin in Europe in 1923, to modern-day insulin analogues and integrated care solutions at present-day Sanofi., (Copyright© of YS Medical Media ltd.)
- Published
- 2020
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30. Comparison of metabolic and mitogenic response in vitro of the rapid-acting insulin lispro product SAR342434, and US- and EU-approved Humalog®.
- Author
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Korn M, Wohlfart P, Gossas T, Kullman-Magnusson M, Niederhaus B, Dedio J, and Tennagels N
- Subjects
- Adipocytes, Animals, Antigens, CD metabolism, CHO Cells, Cell Line, Cricetulus, Drug Evaluation, Preclinical, Humans, Insulin metabolism, Lipolysis drug effects, Mitosis drug effects, Receptor, Insulin metabolism, Recombinant Proteins metabolism, Biosimilar Pharmaceuticals pharmacology, Hypoglycemic Agents pharmacology, Insulin Lispro pharmacology
- Abstract
SAR342434 is a biosimilar of insulin lispro (Humalog® U-100). Batches of SAR342434 were compared with Humalog® batches of either EU or US origin in a panel of in vitro biological assays that included insulin binding to insulin receptor (IR) isoforms A (IR-A) and B (IR-B) and IR-A/IR-B autophosphorylation. A surface plasmon resonance biosensor-based assay was developed to characterize the kinetics of insulin binding to solubilized full-length IR-A or IR-B. Insulin-dependent metabolic activity assays included inhibition of lipolysis in in vitro differentiated human adipocytes, glucose uptake in L6-myocytes, and repression of glucose-6-phosphatase gene expression in human hepatocytes. Mitogenic activity assays included insulin binding to insulin-like growth factor-1 receptor (IGF1R), IGF1R autophosphorylation, and cell proliferation in MCF-7 cells. Weighted geometric means and their respective 95% confidence intervals (CI) were calculated for all 50% inhibitory or effective concentration values and kinetic binding constants for IR-A and IR-B. Statistical evaluation of the data demonstrated that the 90% CIs of the ratio of geometric means between SAR342434 and Humalog® EU or Humalog® US were within the predefined acceptance limits for each assay. Insulin lispro as SAR342434 solution demonstrated similarity to both US- and EU-approved Humalog® based on a side-by-side biological similarity assessment., (Copyright © 2019. Published by Elsevier Inc.)
- Published
- 2019
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31. The role of C16:0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach.
- Author
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Raichur S, Brunner B, Bielohuby M, Hansen G, Pfenninger A, Wang B, Bruning JC, Larsen PJ, and Tennagels N
- Subjects
- Adipose Tissue, Brown metabolism, Animals, Blood Glucose metabolism, Diet, High-Fat adverse effects, Disease Models, Animal, Gene Knockdown Techniques, Hep G2 Cells, Humans, Insulin Resistance, Leptin deficiency, Liver metabolism, Male, Membrane Proteins antagonists & inhibitors, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Obese, Obesity etiology, Oligonucleotides, Antisense pharmacology, Sphingosine N-Acyltransferase antagonists & inhibitors, Sphingosine N-Acyltransferase genetics, Thionucleotides, Weight Gain, Ceramides metabolism, Diabetes Mellitus, Type 2 metabolism, Obesity metabolism, Oligonucleotides, Antisense metabolism, Sphingosine N-Acyltransferase metabolism
- Abstract
Objective: Ectopic fat deposition is associated with increased tissue production of ceramides. Recent genetic mouse studies suggest that specific sphingolipid C16:0 ceramide produced by ceramide synthase 6 (CerS6) plays an important role in the development of insulin resistance. However, the therapeutic potential of CerS6 inhibition not been demonstrated. Therefore, we pharmacologically investigated the selective ablation of CerS6 using antisense oligonucleotides (ASO) in obese insulin resistance animal models., Methods: We utilized ASO as therapeutic modality, CerS6 ASO molecules designed and synthesized were initially screened for in-vitro knock-down (KD) potency and cytotoxicity. ASOs with >85% inhibition of CerS6 mRNA were selected for further investigations. Most promising ASOs verified for in-vivo KD efficacy in healthy mice. CerS6 ASO (AAGATGAGCCGCACC) was found most active with hepatic reduction of CerS6 mRNA expression. Prior to longitudinal metabolic studies, we performed a dose titration target engagement analysis with CerS6 ASO in healthy mice to select the optimal dose. Next, we utilized leptin deficiency ob/ob and high fat diet (HFD) induced obese mouse models for pharmacological efficacy study., Results: CerS6 expression were significantly elevated in the liver and brown adipose, this was correlated with significantly elevated C16:0 ceramide concentrations in plasma and liver. Treatment with CerS6 ASO selectively reduced CerS6 expression by ∼90% predominantly in the liver and this CerS6 KD resulted in a significant reduction of C16:0 ceramide by about 50% in both liver and plasma. CerS6 KD resulted in lower body weight gain and accompanied by a significant reduction in whole body fat and fed/fasted blood glucose levels (1% reduction in HbA1c). Moreover, ASO-mediated CerS6 KD significantly improved oral glucose tolerance (during oGTT) and mice displayed improved insulin sensitivity. Thus, CerS6 appear to play an important role in the development of obesity and insulin resistance., Conclusions: Our investigations identified specific and selective therapeutic valid ASO for CerS6 ablation in in-vivo. CerS6 should specifically be targeted for the reduction of C16:0 ceramides, that results in amelioration of insulin resistance, hyperglycemia and obesity. CerS6 mediated C16:0 ceramide reduction could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2019
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32. The signalling conformation of the insulin receptor ectodomain.
- Author
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Weis F, Menting JG, Margetts MB, Chan SJ, Xu Y, Tennagels N, Wohlfart P, Langer T, Müller CW, Dreyer MK, and Lawrence MC
- Subjects
- Cryoelectron Microscopy, Crystallography, X-Ray, Humans, Protein Binding, Protein Conformation, Protein Structure, Secondary, Receptor, Insulin metabolism, Signal Transduction physiology, Receptor, Insulin chemistry, Receptor, Insulin ultrastructure
- Abstract
Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin's negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design.
- Published
- 2018
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33. Facile folding of insulin variants bearing a prosthetic C-peptide prepared by α-ketoacid-hydroxylamine (KAHA) ligation.
- Author
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Boross GN, Shimura S, Besenius M, Tennagels N, Rossen K, Wagner M, and Bode JW
- Abstract
The chemical synthesis of insulin is an enduring challenge due to the hydrophobic peptide chains and construction of the correct intermolecular disulfide pattern. We report a new approach to the chemical synthesis of insulin using a short, traceless, prosthetic C-peptide that facilitates the formation of the correct disulfide pattern during folding and its removal by basic treatment. The linear precursor is assembled by an ester forming α-ketoacid-hydroxylamine (KAHA) ligation that provides access to the linear insulin precursors in good yield from two readily prepared segments. This convergent and flexible route provides access to various human, mouse, and guinea pig insulins containing a single homoserine mutation that shows no detrimental effect on the biological activities.
- Published
- 2018
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34. Acute and Repeated Treatment with 5-PAHSA or 9-PAHSA Isomers Does Not Improve Glucose Control in Mice.
- Author
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Pflimlin E, Bielohuby M, Korn M, Breitschopf K, Löhn M, Wohlfart P, Konkar A, Podeschwa M, Bärenz F, Pfenninger A, Schwahn U, Opatz T, Reimann M, Petry S, and Tennagels N
- Subjects
- Animals, Diet, Fat-Restricted, Diet, High-Fat, Glucagon-Like Peptide 1 metabolism, Glucose metabolism, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Models, Animal, Rats, Rats, Sprague-Dawley, Hyperglycemia drug therapy, Insulin Resistance, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Obesity drug therapy, Obesity metabolism, Palmitic Acid administration & dosage, Palmitic Acid pharmacology, Stearic Acids administration & dosage, Stearic Acids pharmacology
- Abstract
Fatty acid esters of hydroxylated fatty acids (FAHFAs) were discovered as a novel class of endogenous mammalian lipids whose profound effects on metabolism have been shown. In the current study, in vitro and in vivo the metabolic effects of two of these FAHFAs, namely palmitic acid-5- (or -9) -hydroxy-stearic acid (5- or 9-PAHSA, respectively) were profiled. In DIO mice fed with differentially composed low- or high-fat diets, acute and subchronic treatment with 5-PAHSA and 9-PAHSA alone, or in combination, did not significantly improve the deranged metabolic status. Neither racemic 5- or 9-PAHSA, nor the enantiomers were able to: (1) increase basal or insulin-stimulated glucose uptake in vitro, (2) stimulate GLP-1 release from GLUTag cells, or (3) induce GSIS in rat, mouse, or human islets or in a human pancreatic β cell line. Therefore, our data do not support the further development of PAHSAs or their derivatives for the control of insulin resistance and hyperglycemia., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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35. Evaluation of the innate immunostimulatory potential of originator and non-originator copies of insulin glargine in an in vitro human immune model.
- Author
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Luna E, Agrawal P, Mehta R, Boone ME, Vernhes C, Denys C, Small R, Mukherjee B, Tennagels N, Maerten S, and Drake DR 3rd
- Subjects
- Antigens, CD immunology, Dendritic Cells immunology, Humans, Immunity, Innate drug effects, Immunity, Innate immunology, Insulin analogs & derivatives, Insulin chemistry, Insulin immunology, Insulin Glargine chemistry, Insulin, Long-Acting immunology, Insulin, Long-Acting pharmacology, Interleukin-6 immunology, Interleukin-8 immunology, Receptor, Insulin immunology, Dendritic Cells drug effects, Endothelial Cells drug effects, Insulin pharmacology, Insulin Glargine immunology
- Abstract
Background: The manufacture of insulin analogs requires sophisticated production procedures which can lead to differences in the structure, purity, and/or other physiochemical properties of resultant products that can affect their biologic activity. Here, we sought to compare originator and non-originator copies of insulin glargine for innate immune activity and mechanisms leading to differences in these response profiles in an in vitro model of human immunity., Methods: An endothelial/dendritic cell-based innate immune model was used to study antigen-presenting cell activation, cytokine secretion, and insulin receptor signalling pathways induced by originator and non-originator insulin glargine products. Mechanistic studies included signalling pathway blockade with specific inhibitors, analysis of the products in a Toll-like receptor reporter cell line assay, and natural insulin removal from the products by immunopurification., Findings: All insulin glargine products elicited at least a minor innate immune response comparable to natural human insulin, but some lots of a non-originator copy product induced the elevated secretion of the cytokines, IL-8 and IL-6. In studies aimed at addressing the mechanisms leading to differential cytokine production by these products, we found (1) the inflammatory response was not mediated by bacterial contaminants, (2) the innate response was driven by the native insulin receptor through the MAPK pathway, and (3) the removal of insulin glargine significantly reduced their capacity to induce innate activity. No evidence of product aggregates was detected, though the presence of some high molecular weight proteins argues for the presence of insulin glargine dimers or others contaminants in these products., Conclusion: The data presented here suggests some non-originator insulin glargine product lots drive heightened in vitro human innate activity and provides preliminary evidence that changes in the biochemical composition of non-originator insulin glargine products (dimers, impurities) might be responsible for their greater immunostimulatory potential., Competing Interests: The authors confirm they are all employees of Sanofi, which manufactures insulin glargine for the treatment of diabetes. EL, PA, CD, RS, BM, NT, SM, and DRD hold shares in Sanofi. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2018
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36. Erratum to: Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes.
- Author
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Gallagher EJ, Zelenko Z, Tobin-Hess A, Werner U, Tennagels N, and LeRoith D
- Published
- 2017
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37. Progress towards the replacement of the rabbit blood sugar bioidentity assay by an in vitro test for batch release of insulins in quality control.
- Author
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Hack R, Rueggeberg S, Schneider L, Mayert D, Tennagels N, Welte S, Niederhaus B, Arz W, Usener D, Troschau G, Meiwes J, and Maas J
- Subjects
- Animal Testing Alternatives standards, Humans, Insulins therapeutic use, Pharmaceutical Preparations standards, Reproducibility of Results, Biological Assay, Blood Glucose biosynthesis, Insulins analysis, Quality Control
- Published
- 2017
- Full Text
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38. Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes.
- Author
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Gallagher EJ, Zelenko Z, Tobin-Hess A, Werner U, Tennagels N, and LeRoith D
- Subjects
- Animals, Cell Line, Tumor, Diabetes Mellitus, Type 2 blood, Disease Models, Animal, Female, Humans, Hypoglycemic Agents adverse effects, Hypoglycemic Agents chemistry, Hypoglycemic Agents therapeutic use, Insulin chemistry, Insulin therapeutic use, Insulin Glargine chemistry, Insulin Glargine therapeutic use, Mice, Phosphorylation drug effects, Receptor, Insulin metabolism, Receptors, Somatomedin metabolism, Diabetes Mellitus, Type 2 drug therapy, Insulin Glargine adverse effects, Mammary Neoplasms, Animal chemically induced, Mammary Neoplasms, Animal pathology
- Abstract
Aims/hypothesis: Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present. In this study, we aimed to determine whether a non-metabolisable form of insulin glargine induced murine breast cancer growth., Methods: A mouse model of type 2 diabetes (MKR) was used for these studies. MKR mice were injected with two murine mammary cancer cell lines: Mvt-1 cells (derived from MMTV-c-Myc/Vegf tumours) and Met1 cells (derived from MMTV-polyoma virus middle T antigen tumours). Mice were treated with 25 U/kg per day of the long-acting insulin analogues, insulin glargine, insulin detemir, insulin degludec or non-metabolisable glargine, or vehicle., Results: No difference in tumour growth was seen in terms of tumour size after insulin glargine, detemir, degludec or vehicle injections. Non-metabolisable glargine did not increase tumour growth compared with insulin glargine or vehicle. Insulin glargine and non-metabolisable glargine led to insulin receptor phosphorylation in vivo rather than IGF-1 receptor phosphorylation., Conclusions/interpretation: These results demonstrate that in a mouse model of type 2 diabetes, at high concentrations, basal insulin analogues and a non-metabolisable glargine analogue do not promote the progression of breast tumours.
- Published
- 2016
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39. Effect of the long-acting insulin analogues glargine and degludec on cardiomyocyte cell signalling and function.
- Author
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Hartmann T, Overhagen S, Ouwens DM, Raschke S, Wohlfart P, Tennagels N, Wronkowitz N, and Eckel J
- Subjects
- Animals, Diabetes Mellitus, Type 1 metabolism, Hypoglycemia metabolism, Mice, Myocytes, Cardiac metabolism, Rats, Receptor, Insulin metabolism, Blood Glucose drug effects, Hypoglycemic Agents pharmacology, Insulin Glargine pharmacology, Insulin, Long-Acting pharmacology, Myocytes, Cardiac drug effects, Signal Transduction drug effects
- Abstract
Background: The effects of insulin on cardiomyocytes, such as positive inotropic action and glucose uptake are well described. However, in vitro studies comparing long-acting insulin analogues with regard to cardiomyocyte signalling and function have not been systematically conducted., Methods: Insulin receptor (IR) binding was assessed using membrane embedded and solubilised IR preparations. Insulin signalling was analysed in adult rat ventricular myocytes (ARVM) and HL-1 cardiac cells. Inotropic effects were examined in ARVM and the contribution of Akt to this effect was assessed by specific inhibition with triciribine. Furthermore, beating-rate in Cor.4U(®) human cardiomyocytes, glucose uptake in HL-1 cells, and prevention from H2O2 induced caspase 3/7 activation in cardiac cells overexpressing the human insulin receptor (H9c2-E2) were analysed. One-way ANOVA was performed to determine significance between conditions., Results: Insulin degludec showed significant lower IR affinity in membrane embedded IR preparations. In HL-1 cardiomyocytes, stimulation with insulin degludec resulted in a lower Akt(Ser(473)) and Akt(Thr(308)) phosphorylation compared to insulin, insulin glargine and its active metabolite M1 after 5- and 10-min incubation. After 60-min treatment, phosphorylation of Akt was comparable for all insulin analogues. Stimulation of glucose uptake in HL-1 cells was increased by 40-60 %, with a similar result for all analogues. Incubation of electrically paced ARVM resulted for all insulins in a significantly increased sarcomere shortening, contractility- and relaxation-velocity. This positive inotropic effect of all insulins was Akt dependent. Additionally, in Cor.4U(®) cardiomyocytes a 10-20 % increased beating-rate was detected for all insulins, with slower onset of action in cells treated with insulin degludec. H9c2-E2 cells challenged with H2O2 showed a fivefold increase in caspase 3/7 activation, which could be abrogated by all insulins used., Conclusions: In conclusion, we compared for the first time the signalling and functional impact of the long-acting insulin analogues insulin glargine and insulin degludec in cardiomyocyte cell models. We demonstrated similar efficacy under steady-state conditions relative to regular insulin in functional endpoint experiments. However, it remains to be shown how these results translate to the in vivo situation.
- Published
- 2016
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40. Effect of insulin analogues on phosphatidyl inositol-3 kinase/Akt signalling in INS-1 rat pancreatic derived β-cells.
- Author
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Pagesy P, Fardini Y, Nguyen TT, Lohmann M, Pierre-Eugene C, Tennagels N, and Issad T
- Subjects
- Animals, Cell Line, Insulin Glargine metabolism, Insulin-Secreting Cells drug effects, Phosphatidylinositol Phosphates biosynthesis, Rats, Insulin analogs & derivatives, Insulin pharmacology, Insulin-Secreting Cells cytology, Insulin-Secreting Cells metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects
- Abstract
Context: Insulin analogues are largely used for the treatment of diabetic patients, but concerns have been raised about their mitogenic/anti-apoptotic potential. It is therefore important to evaluate these analogues in different cell systems., Objective: The aim of this work was to establish the pharmacological profiles of insulin analogues towards PI-3 kinase/Akt pathway in INS-1 β-pancreatic cells., Methods: Bioluminescence Resonance Energy Transfer (BRET), in cell western and caspase 3/7 assays, was used to study the effects of ligands., Results: Among the five analogues evaluated, only glargine stimulated PI-3 kinase/Akt pathway with higher efficiency than insulin, whereas glargine's metabolite M1 was less efficient. However, glargine did not show higher anti-apoptotic efficiency than insulin., Conclusion: Glargine was more efficient than insulin for the activation of PI-3 kinase/Akt pathway, but not for the inhibition of caspase 3/7 activity. Moreover, glargine's metabolite M1 displayed lower efficiency than insulin towards PI-3 kinase/Akt activation and caspase 3/7 inhibition.
- Published
- 2016
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41. Metabolic effect and receptor signalling profile of a non-metabolisable insulin glargine analogue.
- Author
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Werner U, Korn M, Schmidt R, Wendrich TM, and Tennagels N
- Subjects
- Animals, Humans, Insulin Glargine, Male, Phosphorylation drug effects, Rats, Rats, Wistar, Signal Transduction drug effects, Tandem Mass Spectrometry, Blood Glucose drug effects, Hypoglycemic Agents pharmacology, Insulin, Long-Acting pharmacology, Proto-Oncogene Proteins c-akt metabolism, Receptor, IGF Type 1 metabolism, Receptor, Insulin metabolism
- Abstract
Context: Insulin glargine (GLA) is rapidly metabolized in vivo to metabolite M1, which has in vitro metabolic and mitogenic profiles comparable with human insulin (HI)., Objective: To investigate the pharmacologic and signalling profiles of a non-metabolizable analogue (A21Gly,DiD-Arg) insulin (D-GLA)., Methods: Rats were injected s.c. with 1, 12.5 or 200 U/kg of GLA or D-GLA; blood glucose and phosphorylation status of the insulin receptor (IR), Akt and IGF-1 receptor (IGF1R) in tissue samples were investigated after 1 h. Plasma samples were analysed for insulin by LC-MS/MS., Results: Blood glucose lowering was prolonged with D-GLA. D-GLA comprised ≥98% of insulin after D-GLA injection; M1 comprised 76-92% after GLA injection. IR and Akt phosphorylation were comparable with GLA and D-GLA. Neither analogue stimulated IGF1R phosphorylation., Conclusions: Suprapharmacological doses of D-GLA did not activate IGF1R in vivo. Mitogenic effects of insulin and insulin analogues might be solely based on IR growth-promoting activity.
- Published
- 2014
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42. Chitinase-3-like protein 1 protects skeletal muscle from TNFα-induced inflammation and insulin resistance.
- Author
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Görgens SW, Eckardt K, Elsen M, Tennagels N, and Eckel J
- Subjects
- Adipokines genetics, Adolescent, Adult, Cell Differentiation, Cells, Cultured, Chemokine CCL2 metabolism, Chitinase-3-Like Protein 1, Cytokines genetics, Female, Humans, Interleukin-6 metabolism, Interleukin-8 metabolism, Lectins genetics, Male, Muscle Fibers, Skeletal cytology, Muscle Fibers, Skeletal immunology, Muscle Fibers, Skeletal metabolism, Muscle, Skeletal cytology, Muscle, Skeletal immunology, NF-kappa B antagonists & inhibitors, NF-kappa B metabolism, Receptor, PAR-2 antagonists & inhibitors, Receptor, PAR-2 genetics, Receptor, PAR-2 metabolism, Recombinant Proteins metabolism, Signal Transduction, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha genetics, Young Adult, Adipokines metabolism, Cytokines metabolism, Insulin Resistance, Lectins metabolism, Muscle, Skeletal metabolism, Tumor Necrosis Factor-alpha metabolism, Up-Regulation
- Abstract
CHI3L1 (chitinase-3-like protein 1) is a glycoprotein consisting of 383 amino acids with a molecular mass of 40 kDa, and its serum level is elevated in inflammatory diseases. Although CHI3L1 is described as a biomarker of inflammation, the function of this protein is not completely understood. In the present study, we examined the regulation of CHI3L1 in primary human skeletal muscle cells. Moreover, we analysed potential autocrine effects of CHI3L1. We show that myotubes express CHI3L1 in a differentiation-dependent manner. Furthermore, pro-inflammatory cytokines up-regulate CHI3L1 expression (6-fold) and release (3-fold). Importantly, CHI3L1 treatment blocked TNFα (tumour necrosis factor α)-induced inflammation by inhibiting NF-κB (nuclear factor κB) activation in skeletal muscle cells. We show that this effect is mediated via PAR2 (protease-activated receptor 2). In addition, CHI3L1 treatment diminished the TNFα-induced expression and secretion of IL (interleukin)-8, MCP1 (monocyte chemoattractant protein 1) and IL-6. In addition, impaired insulin action at the level of Akt and GSK3α/β (glycogen synthase kinase 3α/β) phosphoryl-ation and insulin-stimulated glucose uptake was normalized by CHI3L1. In conclusion, the novel myokine CHI3L1, which is induced by pro-inflammatory cytokines, can counteract TNFα-mediated inflammation and insulin resistance in human skeletal muscle cells, potentially involving an auto- and/or para-crine mechanism.
- Published
- 2014
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43. BMP4 and BMP7 induce the white-to-brown transition of primary human adipose stem cells.
- Author
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Elsen M, Raschke S, Tennagels N, Schwahn U, Jelenik T, Roden M, Romacho T, and Eckel J
- Subjects
- Adipose Tissue, Brown cytology, Adipose Tissue, White cytology, Adult, Cells, Cultured, Female, Gene Expression Regulation, Humans, Ion Channels genetics, Ion Channels metabolism, Lipid Metabolism, Mitochondria metabolism, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Oxygen Consumption, PPAR gamma genetics, PPAR gamma metabolism, Primary Cell Culture, RNA, Messenger metabolism, Recombinant Proteins metabolism, Signal Transduction, Time Factors, Tumor Necrosis Factor Receptor Superfamily, Member 9 metabolism, Uncoupling Protein 1, Adipocytes, Brown metabolism, Adipocytes, White metabolism, Adipogenesis, Adipose Tissue, Brown metabolism, Adipose Tissue, White metabolism, Bone Morphogenetic Protein 4 metabolism, Bone Morphogenetic Protein 7 metabolism, Cell Transdifferentiation, Stem Cells metabolism
- Abstract
While white adipose tissue (AT) is an energy storage depot, brown AT is specialized in energy dissipation. Uncoupling protein 1 (UCP1)-expressing adipocytes with a different origin than classical brown adipocytes have been found in white AT. These "brite" (brown-in-white) adipocytes may represent a therapeutic target to counteract obesity. Bone morphogenetic proteins (BMPs) play a role in the regulation of adipogenesis. Based on studies with murine cells, BMP4 is assumed to induce stem cell commitment to the white adipocyte lineage, whereas BMP7 promotes brown adipogenesis. There is evidence for discrepancies between mouse and human AT. Therefore, we compared the effect of BMP4 and BMP7 on white-to-brown transition in primary human adipose stem cells (hASCs) from subcutaneous AT. Long-term exposure of hASCs to recombinant BMP4 or BMP7 during differentiation increased adipogenesis, as determined by lipid accumulation and peroxisome proliferator-activated receptor-γ (PPARγ) expression. Not only BMP7, but also BMP4, increased UCP1 expression in hASCs and decreased expression of the white-specific marker TCF21. The ability of hASCs to induce UCP1 in response to BMP4 and BMP7 markedly differed between donors and could be related to the expression of the brite marker CD137. However, mitochondrial content and oxygen consumption were not increased in hASCs challenged with BMP4 and BMP7. In conclusion, we showed for the first time that BMP4 has similar effects on white-to-brown transition as BMP7 in our human cell model. Thus the roles of BMP4 and BMP7 in adipogenesis cannot always be extrapolated from murine to human cell models.
- Published
- 2014
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44. On ceramides, other sphingolipids and impaired glucose homeostasis.
- Author
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Larsen PJ and Tennagels N
- Abstract
In most people with type 2 diabetes, progression from obesity to diabetes is accompanied by elevated tissue exposures to a variety of lipids. Among these lipid species, ceramides and more complex sphingolipids have gained recent attention as being pathophysiologically relevant for the development of insulin resistance and impaired glycemic control. Upon excess intake of saturated fat, ceramides accumulate in insulin sensitive tissues either as a consequence of de novo synthesis or through mobilization from complex sphingolipids. Clinical studies have confirmed positive correlation between plasma and tissue levels of several ceramide species and insulin resistance. At the cellular level, it has been demonstrated that ceramides impair insulin signaling and intracellular handling of glucose and lipids with resulting deleterious effects on cellular metabolism. Hence, we are reviewing whether therapeutic interventions aiming at reducing tissue exposure to ceramides or other sphingolipids represent viable therapeutic approaches to improve glucose metabolism in people with diabetes.
- Published
- 2014
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45. Insulin receptor phosphorylation by endogenous insulin or the insulin analog AspB10 promotes mammary tumor growth independent of the IGF-I receptor.
- Author
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Gallagher EJ, Alikhani N, Tobin-Hess A, Blank J, Buffin NJ, Zelenko Z, Tennagels N, Werner U, and LeRoith D
- Subjects
- Animals, Breast Neoplasms etiology, Breast Neoplasms pathology, Cell Line, Tumor, Female, Humans, Hypoglycemic Agents administration & dosage, Insulin administration & dosage, Insulin adverse effects, Mammary Neoplasms, Experimental, Mice, Mice, Transgenic, Phosphorylation, Prognosis, Signal Transduction, Tumor Cells, Cultured, Breast Neoplasms metabolism, Diabetes Mellitus, Experimental drug therapy, Hyperinsulinism complications, Hypoglycemic Agents adverse effects, Insulin analogs & derivatives, Insulin-Like Growth Factor I drug effects, Metabolic Syndrome complications, Molecular Targeted Therapy trends, Obesity complications, Receptor, IGF Type 1 drug effects
- Abstract
Endogenous hyperinsulinemia and insulin receptor (IR)/IGF-I receptor (IGF-IR) phosphorylation in tumors are associated with a worse prognosis in women with breast cancer. In vitro, insulin stimulation of the IR increases proliferation of breast cancer cells. However, in vivo studies demonstrating that IR activation increases tumor growth, independently of IGF-IR activation, are lacking. We hypothesized that endogenous hyperinsulinemia increases mammary tumor growth by directly activating the IR rather than the IGF-IR or hybrid receptors. We aimed to determine whether stimulating the IR with the insulin analog AspB10 could increase tumor growth independently of IGF-IR signaling. We induced orthotopic mammary tumors in control FVB/n and hyperinsulinemic MKR mice, and treated them with the insulin analog AspB10, recombinant human IGF-I, or vehicle. Tumors from mice with endogenous hyperinsulinemia were larger and had greater IR phosphorylation, but not IGF-IR phosphorylation, than those from control mice. Chronic AspB10 administration also increased tumor growth and IR (but not IGF-IR) phosphorylation in tumors. IGF-I led to activation of both the IGF-IR and IR and probably hybrid receptors. Our results demonstrate that IR phosphorylation increases tumor growth, independently of IGF-IR/hybrid receptor phosphorylation, and warrant consideration when developing therapeutics targeting the IGF-IR, but not the IR.
- Published
- 2013
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46. Concentrations of insulin glargine and its metabolites during long-term insulin therapy in type 2 diabetic patients and comparison of effects of insulin glargine, its metabolites, IGF-I, and human insulin on insulin and igf-I receptor signaling.
- Author
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Varewijck AJ, Yki-Järvinen H, Schmidt R, Tennagels N, and Janssen JA
- Subjects
- Chromatography, Liquid, Diabetes Mellitus, Type 2 blood, Dose-Response Relationship, Drug, Female, Humans, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Insulin Glargine, Insulin, Isophane metabolism, Insulin, Isophane pharmacology, Insulin, Isophane therapeutic use, Insulin, Long-Acting pharmacology, Male, Middle Aged, Signal Transduction drug effects, Signal Transduction physiology, Tandem Mass Spectrometry, Diabetes Mellitus, Type 2 drug therapy, Insulin, Long-Acting metabolism, Insulin, Long-Acting therapeutic use, Insulin-Like Growth Factor I metabolism, Receptor, IGF Type 1 metabolism, Receptor, Insulin metabolism
- Abstract
We investigated 1) the ability of purified glargine (GLA), metabolites 1 (M1) and 2 (M2), IGF-I, and NPH insulin to activate the insulin receptor (IR)-A and IR-B and IGF-I receptor (IGF-IR) in vitro; 2) plasma concentrations of GLA, M1, and M2 during long-term insulin therapy in type 2 diabetic patients; and 3) IR-A and IR-B activation in vitro induced by serum from patients treated with GLA or NPH insulin. A total of 104 patients (age 56.3 ± 0.8 years, BMI 31.4 ± 0.5 kg/m(2), and A1C 9.1 ± 0.1% [mean ± SE]) were randomized to GLA or NPH insulin therapy for 36 weeks. Plasma concentrations of GLA, M1, and M2 were determined by liquid chromatography-tandem mass spectrometry assay. IR-A, IR-B, and IGF-IR autophosphorylation was induced by purified hormones or serum by kinase receptor activation assays. In vitro, M1 induced comparable IR-A, IR-B, and IGF-IR autophosphorylation (activation) as NPH insulin. After 36 weeks, M1 increased from undetectable (<0.2 ng/mL) to 1.5 ng/mL (0.9-2.1), while GLA and M2 remained undetectable. GLA dose correlated with M1 (r = 0.84; P < 0.001). Serum from patients treated with GLA or NPH insulin induced similar IR-A and IR-B activation. These data suggest that M1 rather than GLA mediates GLA effects and that compared with NPH insulin, GLA does not increase IGF-IR signaling during long-term insulin therapy in type 2 diabetes.
- Published
- 2013
- Full Text
- View/download PDF
47. The metabolic and mitogenic properties of basal insulin analogues.
- Author
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Tennagels N and Werner U
- Subjects
- Cell Proliferation, Databases, Factual, Diabetes Complications physiopathology, Diabetes Mellitus physiopathology, Humans, Hypoglycemic Agents administration & dosage, Hypoglycemic Agents pharmacology, Insulin Glargine, Insulin, Long-Acting administration & dosage, Insulin, Long-Acting adverse effects, Mitogens analysis, Phosphorylation, Protein Binding, Receptor, IGF Type 1 metabolism, Receptor, Insulin metabolism, Signal Transduction, Diabetes Complications chemically induced, Diabetes Mellitus drug therapy, Hypoglycemic Agents adverse effects, Insulin, Long-Acting pharmacology, Neoplasms chemically induced
- Abstract
Context: Retrospective, observational studies have reported an association between diabetes treatment with insulin and a higher incidence of cancer., Objective: Overview the literature for in vitro and in vivo studies of the metabolic and mitogenic properties of basal insulin analogues and assess the implications for clinical use., Methods: Relevant studies were identified through PubMed and congress abstract database searches; data on metabolic and mitogenic signalling in relation to insulin treatment of diabetes are included in this review., Results: The balance of evidence shows that although some analogues have demonstrated mitogenic potency in some in vitro studies in cancer cell lines, these findings do not translate to the in vivo setting in animals or to the clinical setting in humans., Conclusions: The current consensus is that there is no clinical or in vivo evidence to indicate that any commercially available insulin analogue has carcinogenic effects. Large-scale, prospective clinical and observational studies will further establish any potential link.
- Published
- 2013
- Full Text
- View/download PDF
48. Functional annotation of the human fat cell secretome.
- Author
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Dahlman I, Elsen M, Tennagels N, Korn M, Brockmann B, Sell H, Eckel J, and Arner P
- Subjects
- Adipocytes cytology, Adipokines, CCN Intercellular Signaling Proteins genetics, CCN Intercellular Signaling Proteins metabolism, Complement C4a genetics, Complement C4a metabolism, Gene Expression, Gene Expression Profiling, Humans, Intra-Abdominal Fat cytology, Metabolome, Metabolomics, Obesity metabolism, Obesity pathology, Oligonucleotide Array Sequence Analysis, Proteinase Inhibitory Proteins, Secretory genetics, Proteinase Inhibitory Proteins, Secretory metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Subcutaneous Fat cytology, Adipocytes metabolism, Gene Expression Regulation, Intra-Abdominal Fat metabolism, Obesity genetics, Subcutaneous Fat metabolism
- Abstract
Context: Recent secretome analyses suggest that human fat cells secrete hundreds of proteins (adipokines)., Objective: We made an overall analysis of their potential functional importance., Materials and Methods: A secretome of 347 adipokines was evaluated by in silico analysis of their expression during adipocyte differentiation, regulation by obesity and adipose region. The gene expression in human adipose tissue was investigated in microarray studies using samples from different adipose depots from lean or obese patients., Results: 60% of the adipokines were regulated by obesity and 50% between visceral and subcutaneous adipose region. Eight adipokines, all novel, scored particularly high in the in silico analysis. Among those, four were both regulated by obesity and adipose region, namely WNT1-inducible-signaling pathway protein 2, transmembrane glycoprotein NMB, inter-alpha-trypsin inhibitor heavy chain H5, and complement C4-A. Furthermore, many adipokines were extracellular matrix proteins., Conclusion: Several novel adipokines have potential important functional features warranting in depth analysis.
- Published
- 2012
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49. Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2.
- Author
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Pierre-Eugene C, Pagesy P, Nguyen TT, Neuillé M, Tschank G, Tennagels N, Hampe C, and Issad T
- Subjects
- HEK293 Cells, Humans, Insulin Glargine, MCF-7 Cells, Phosphatidylinositol Phosphates biosynthesis, Signal Transduction drug effects, Insulin, Long-Acting metabolism, Insulin, Long-Acting pharmacology, Receptor, IGF Type 1 metabolism, Receptor, Insulin metabolism, Recombinant Fusion Proteins metabolism
- Abstract
Background: In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R), present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids., Methodology: To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET) assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP(3)) production in living cells. Using this assay, we performed a detailed pharmacological analysis of PIP(3) production induced by IGF1, insulin and insulin analogues in living breast cancer-derived MCF-7 and MDA-MB231 cells., Results: Among the five insulin analogues tested, only glargine stimulated IR/IGF1R hybrids with an EC50 that was significantly lower than insulin and close to that of IGF1. Glargine more efficiently stimulated PIP(3) production in MCF-7 cells but not in MDA-MB231 cells as compared to insulin. In contrast, glargine metabolites M1 and M2 showed lower potency for hybrid receptors stimulation, PIP(3) production, Akt and Erk1/2 phosphorylation and DNA synthesis in MCF-7 cells, compared to insulin., Conclusion: Glargine, possibly acting through IR/IGF1R hybrids, displays higher potency, whereas its metabolites M1 and M2 display lower potency than insulin for the stimulation of proliferative/anti-apoptotic pathways in MCF-7 cells.
- Published
- 2012
- Full Text
- View/download PDF
50. In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites.
- Author
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Sommerfeld MR, Müller G, Tschank G, Seipke G, Habermann P, Kurrle R, and Tennagels N
- Subjects
- Adipocytes cytology, Animals, CHO Cells, Cricetinae, Cricetulus, Fibroblasts metabolism, Humans, In Vitro Techniques, Insulin Glargine, Insulin, Long-Acting, Mice, Phosphorylation, Rats, Receptor, IGF Type 1 metabolism, Receptor, Insulin metabolism, Insulin analogs & derivatives, Insulin metabolism, Signal Transduction
- Abstract
Background: Insulin glargine (Lantus) is a long-acting basal insulin analog that demonstrates effective day-long glycemic control and a lower incidence of hypoglycemia than NPH insulin. After subcutaneous injection insulin glargine is partly converted into the two main metabolites M1 ([Gly(A21)]insulin) and M2 ([Gly(A21),des-Thr(B30)]insulin). The aim of this study was to characterize the glargine metabolites in vitro with regard to their insulin receptor (IR) and IGF-1 receptor (IGF1R) binding and signaling properties as well as their metabolic and mitogenic activities., Methods: The affinity of human insulin, insulin glargine and its metabolites to the IR isoforms A and B or IGF1R was analyzed in a competitive binding assay using SPA technology. Receptor autophosphorylation activities were studied via In-Cell Western in CHO and MEF cells overexpressing human IR-A and IR-B or IGF1R, respectively. The metabolic response of the insulins was studied as stimulation of lipid synthesis using primary rat adipocytes. Thymidine incorporation in Saos-2 cells was used to characterize the mitogenic activity., Conclusions: The binding of insulin glargine and its metabolites M1 and M2 to the IR were similar and correlated well with their corresponding autophosphorylation and metabolic activities in vitro. No differences were found towards the two IR isoforms A or B. Insulin glargine showed a higher affinity for IGF1R than insulin, resulting in a lower EC(50) value for autophosphorylation of the receptor and a more potent stimulation of thymidine incorporation in Saos-2 cells. In contrast, the metabolites M1 and M2 were significantly less active in binding to and activation of the IGF1R and their mitogenicity in Saos-2 cells was equal to human insulin. These findings strongly support the idea that insulin glargine metabolites contribute with the same potency as insulin glargine to blood glucose control but lead to significantly reduced growth-promoting activity.
- Published
- 2010
- Full Text
- View/download PDF
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