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Des-Acyl Ghrelin Fragments and Analogues Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets and Prevent Diabetes in Streptozotocin-Treated Rats

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    Des-Acyl Ghrelin Fragments and Analogues Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets and Prevent Diabetes in Streptozotocin-Treated Rats
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    ‡ †Laboratory of Molecular and Cellular Endocrinology and ‡Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy
    § Alizé Pharma, Ecully, France
    ∥ Diabetes Research Institute (HSR-DRI) San Raffaele Scientific Institute, Milan, Italy.
    ⊥ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
    *Phone: (+39) 011 670 9558. Fax: (+39) 011 664 74 21. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2012, 55, 6, 2585–2596
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    https://doi.org/10.1021/jm201223m
    Published February 21, 2012
    Copyright © 2012 American Chemical Society
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    Abstract

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    Des-acyl ghrelin, although devoid of binding to ghrelin receptor (GRLN), exerts many biological effects, including regulation of glucose and lipid metabolism. Indeed, des-acyl ghrelin promotes pancreatic β-cell and human islet cell survival and prevents diabetes in streptozotocin (STZ) treated rats. We investigated whether des-acyl ghrelin fragments excluding serine3, which is essential for binding to GRLN, would display similar actions. Among the different compounds tested, des-acyl ghrelin(6–13) and des-acyl ghrelin(6–13) with alanine substitutions or cyclization, but not with d-amino acid substitutions, showed the best survival effect, similar to des-acyl ghrelin. Des-acyl ghrelin(6–13) even prevented diabetes in STZ-treated rats and protected human circulating angiogenic cells from oxidative stress and senescence, similar to des-acyl ghrelin. These results suggest that not only full-length des-acyl ghrelin but also short des-acyl ghrelin fragments have clear beneficial effects on several tissues in vitro and in vivo.

    Copyright © 2012 American Chemical Society

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    Table S1 listing chemical data for compounds 1–31. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 39 publications.

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    3. Xiao-Yan Liu, Dong-Guang Wei, Rong-Shan Li. Ghrelin attenuates inflammation in diabetic lung disease by TLR4 pathway in vivo and in vitro. BMJ Open Diabetes Research & Care 2023, 11 (2) , e003027. https://doi.org/10.1136/bmjdrc-2022-003027
    4. Danielle L. Overton, Teresa L. Mastracci. Exocrine-Endocrine Crosstalk: The Influence of Pancreatic Cellular Communications on Organ Growth, Function and Disease. Frontiers in Endocrinology 2022, 13 https://doi.org/10.3389/fendo.2022.904004
    5. Kiyoshi Chinen, Naoaki Sakata, Gumpei Yoshimatsu, Masafumi Nakamura, Shohta Kodama. Therapeutic effects of acylated ghrelin-specific receptor GHS-R1a antagonist in islet transplantation. Scientific Reports 2021, 11 (1) https://doi.org/10.1038/s41598-021-00740-6
    6. Nejmeddine Ouerghi, Moncef Feki, Nicola Luigi Bragazzi, Beat Knechtle, Lee Hill, Pantelis T. Nikolaidis, Anissa Bouassida. Ghrelin Response to Acute and Chronic Exercise: Insights and Implications from a Systematic Review of the Literature. Sports Medicine 2021, 51 (11) , 2389-2410. https://doi.org/10.1007/s40279-021-01518-6
    7. Y. Gu, A. Rampin, V. V. Alvino, G. Spinetti, P. Madeddu. Cell Therapy for Critical Limb Ischemia: Advantages, Limitations, and New Perspectives for Treatment of Patients with Critical Diabetic Vasculopathy. Current Diabetes Reports 2021, 21 (3) https://doi.org/10.1007/s11892-021-01378-4
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    14. Soraya Allas, Assumpta Caixàs, Christine Poitou, Muriel Coupaye, Denise Thuilleaux, Françoise Lorenzini, Gwenaëlle Diene, Antonino Crinò, Frédéric Illouz, Graziano Grugni, Diane Potvin, Sarah Bocchini, Thomas Delale, Thierry Abribat, Maithé Tauber, . AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial. PLOS ONE 2018, 13 (1) , e0190849. https://doi.org/10.1371/journal.pone.0190849
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    17. Gloria Baena‐Nieto, Isabel M. Lomas‐Romero, Rosa M. Mateos, Noelia Leal‐Cosme, Gonzalo Perez‐Arana, Manuel Aguilar‐Diosdado, Carmen Segundo, Alfonso M. Lechuga‐Sancho. Ghrelin mitigates β ‐cell mass loss during insulitis in an animal model of autoimmune diabetes mellitus, the BioBreeding/Worcester rat. Diabetes/Metabolism Research and Reviews 2017, 33 (1) https://doi.org/10.1002/dmrr.2813
    18. S. Allas, T. Delale, N. Ngo, M. Julien, P. Sahakian, J. Ritter, T. Abribat, A. J. van der Lely. Safety, tolerability, pharmacokinetics and pharmacodynamics of  AZP ‐531, a first‐in‐class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes. Diabetes, Obesity and Metabolism 2016, 18 (9) , 868-874. https://doi.org/10.1111/dom.12675
    19. Bjorn T. Tam, Xiao M. Pei, Benjamin Y. Yung, Shea P. Yip, Lawrence W. Chan, Cesar S. Wong, Parco M. Siu. Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice. Pflügers Archiv - European Journal of Physiology 2015, 467 (12) , 2555-2569. https://doi.org/10.1007/s00424-015-1721-5
    20. Rasha Mofeed Habeeb Mosa, Zhen Zhang, Renfu Shao, Chao Deng, Jiezhong Chen, Chen Chen. Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases. Endocrine 2015, 49 (2) , 307-323. https://doi.org/10.1007/s12020-015-0531-z
    21. T.D. Müller, R. Nogueiras, M.L. Andermann, Z.B. Andrews, S.D. Anker, J. Argente, R.L. Batterham, S.C. Benoit, C.Y. Bowers, F. Broglio, F.F. Casanueva, D. D'Alessio, I. Depoortere, A. Geliebter, E. Ghigo, P.A. Cole, M. Cowley, D.E. Cummings, A. Dagher, S. Diano, S.L. Dickson, C. Diéguez, R. Granata, H.J. Grill, K. Grove, K.M. Habegger, K. Heppner, M.L. Heiman, L. Holsen, B. Holst, A. Inui, J.O. Jansson, H. Kirchner, M. Korbonits, B. Laferrère, C.W. LeRoux, M. Lopez, S. Morin, M. Nakazato, R. Nass, D. Perez-Tilve, P.T. Pfluger, T.W. Schwartz, R.J. Seeley, M. Sleeman, Y. Sun, L. Sussel, J. Tong, M.O. Thorner, A.J. van der Lely, L.H.T. van der Ploeg, J.M. Zigman, M. Kojima, K. Kangawa, R.G. Smith, T. Horvath, M.H. Tschöp. Ghrelin. Molecular Metabolism 2015, 4 (6) , 437-460. https://doi.org/10.1016/j.molmet.2015.03.005
    22. Xiao M. Pei, Benjamin Y. Yung, Shea P. Yip, Lawrence W. Chan, Cesar S. Wong, Michael Ying, Parco M. Siu. Protective effects of desacyl ghrelin on diabetic cardiomyopathy. Acta Diabetologica 2015, 52 (2) , 293-306. https://doi.org/10.1007/s00592-014-0637-4
    23. Subrata Chakrabarti. Unacylated Ghrelin: A Gut-Limb Connection. Diabetes 2015, 64 (4) , 1097-1098. https://doi.org/10.2337/db14-1825
    24. Gabriele Togliatto, Antonella Trombetta, Patrizia Dentelli, Sara Gallo, Arturo Rosso, Paolo Cotogni, Riccarda Granata, Rita Falcioni, Thomas Delale, Ezio Ghigo, Maria Felice Brizzi. Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression. Diabetes 2015, 64 (4) , 1370-1382. https://doi.org/10.2337/db14-0991
    25. Antonia Diaz-Ganete, Gloria Baena-Nieto, Isabel M. Lomas-Romero, Jose Francisco Lopez-Acosta, Irene Cozar-Castellano, Francisco Medina, Carmen Segundo, Alfonso M. Lechuga-Sancho. Ghrelin’s Effects on Proinflammatory Cytokine Mediated Apoptosis and Their Impact on β -Cell Functionality. International Journal of Endocrinology 2015, 2015 , 1-11. https://doi.org/10.1155/2015/235727
    26. Motoyasu Satou, Yoshihiro Nishi, Akira Hishinuma, Hiroshi Hosoda, Kenji Kangawa, Hiroyuki Sugimoto. Identification of activated protein C as a ghrelin endopeptidase in bovine plasma. Journal of Endocrinology 2015, 224 (1) , 61-73. https://doi.org/10.1530/JOE-14-0529
    27. Brid Callaghan, John B. Furness, . Novel and Conventional Receptors for Ghrelin, Desacyl-Ghrelin, and Pharmacologically Related Compounds. Pharmacological Reviews 2014, 66 (4) , 984-1001. https://doi.org/10.1124/pr.113.008433
    28. Darko M. Stevanovic, Aldo Grefhorst, Axel P. N. Themmen, Vera Popovic, Joan Holstege, Elize Haasdijk, Vladimir Trajkovic, Aart-Jan van der Lely, Patric J. D. Delhanty, . Unacylated Ghrelin Suppresses Ghrelin-Induced Neuronal Activity in the Hypothalamus and Brainstem of Male Rats. PLoS ONE 2014, 9 (5) , e98180. https://doi.org/10.1371/journal.pone.0098180
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    31. Iacopo Gesmundo, Davide Gallo, Enrica Favaro, Ezio Ghigo, Riccarda Granata. Obestatin: A new metabolic player in the pancreas and white adipose tissue. IUBMB Life 2013, 65 (12) , 976-982. https://doi.org/10.1002/iub.1226
    32. Gabriele Togliatto, Antonella Trombetta, Patrizia Dentelli, Paolo Cotogni, Arturo Rosso, Matthias H. Tschöp, Riccarda Granata, Ezio Ghigo, Maria F. Brizzi. Unacylated Ghrelin Promotes Skeletal Muscle Regeneration Following Hindlimb Ischemia via SOD‐2–Mediated miR‐221/222 Expression. Journal of the American Heart Association 2013, 2 (6) https://doi.org/10.1161/JAHA.113.000376
    33. Patric J. D. Delhanty, Martin Huisman, Lucy Y. Baldeon‐Rojas, Iris Berge, Aldo Grefhorst, Thierry Abribat, Pieter J. M. Leenen, Axel P. N. Themmen, Aart‐Jan Lely. Des‐acyl ghrelin analogs prevent high‐fat‐diet‐induced dysregulation of glucose homeostasis. The FASEB Journal 2013, 27 (4) , 1690-1700. https://doi.org/10.1096/fj.12-221143
    34. Katherine A Banks, Kevin G Murphy. Role of ghrelin in glucose homeostasis and diabetes. Diabetes Management 2013, 3 (2) , 171-182. https://doi.org/10.2217/dmt.12.88
    35. Christine Delporte. Structure and Physiological Actions of Ghrelin. Scientifica 2013, 2013 , 1-25. https://doi.org/10.1155/2013/518909
    36. Akihiro Asakawa, Ikuo Kato, Akio Inui. Comment on Short-Term Effects of Sleeve Gastrectomy and Caloric Restriction on Blood Pressure in Diet-Induced Obese Rats. Obesity Surgery 2012, 22 (11) , 1788-1789. https://doi.org/10.1007/s11695-012-0758-1
    37. Michel Julien, Richard G. Kay, Patric J.D. Delhanty, Soraya Allas, Riccarda Granata, Chris Barton, Scott Constable, Ezio Ghigo, Aart J. van der Lely, Thierry Abribat. In vitro and in vivo stability and pharmacokinetic profile of unacylated ghrelin (UAG) analogues. European Journal of Pharmaceutical Sciences 2012, 47 (4) , 625-635. https://doi.org/10.1016/j.ejps.2012.07.014
    38. Patric J D Delhanty, Sebastian J Neggers, Aart J van der Lely. MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin. European Journal of Endocrinology 2012, 167 (5) , 601-608. https://doi.org/10.1530/EJE-12-0456
    39. Manuela Aragno, Raffaella Mastrocola, Corrado Ghé, Elisa Arnoletti, Eleonora Bassino, Giuseppe Alloatti, Giampiero Muccioli. Obestatin induced recovery of myocardial dysfunction in type 1 diabetic rats: underlying mechanisms. Cardiovascular Diabetology 2012, 11 (1) , 129. https://doi.org/10.1186/1475-2840-11-129
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2012, 55, 6, 2585–2596
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm201223m
    Published February 21, 2012
    Copyright © 2012 American Chemical Society
    Request reuse permissions

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