Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets

Barbara Ludwig, Christian G. Ziegler, Andrew V Schally, Claudius Richter, Anja Steffen, Normund Jabs, Richard H. Funk, Mathias D. Brendel, Norman L Block, Monika Ehrhart-Bornstein, Stefan R. Bornstein

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Abstract

Therapeutic strategies for transplantation of pancreatic islet cells are urgently needed to expand β-cell mass by stimulating islet cell proliferation and/or prolonging islet cell survival. Control of the islets by different growth factors provides a potential venue for augmenting β-cell mass. In the present study, we show the expression of the biologically active splice variant-1 (SV-1) of growth hormone-releasing hormone (GHRH) receptor in rat insulinoma (INS-1) cells as well as in rat and human pancreatic islets. In studies in vitro of INS-1 cells, the GHRH agonist JI-36 caused a significant increase in cell proliferation and a reduction of cell apoptosis. JI-36 increased islet size and glucose-stimulated insulin secretion in isolated rat islets after 48-72 h. At the ultrastructural level, INS-1 cells treated with agonist JI-36 revealed a metabolic active stimulation state with increased cytoplasm. Coincubation with the GHRH antagonist MIA-602 reversed the actions of the agonist JI-36, indicating the specificity of this agonist. In vivo, the function of pancreatic islets was assessed by transplantation of rat islets under the kidney capsule of streptozotocin-induced diabetic non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Islets treated withGHRHagonist JI-36 were able to achieve normoglycemia earlier and more consistently than untreated islets. Furthermore, in contrast to diabetic animals transplanted with untreated islets, insulin response to an i.p. glucose tolerance test (IPGTT) in animals receiving islets treated with agonist Jl-36 was comparable to that of normal healthy mice. In conclusion, our study provides evidence that agonists ofGHRHrepresent a promising pharmacological therapy aimed at promoting islet graft growth and proliferation in diabetic patients.

Original languageEnglish
Pages (from-to)12623-12628
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number28
DOIs
StatePublished - Jul 13 2010

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Keywords

  • Diabetes
  • Islet proliferation
  • Regenerative therapies

ASJC Scopus subject areas

  • General

Cite this

Ludwig, B., Ziegler, C. G., Schally, A. V., Richter, C., Steffen, A., Jabs, N., Funk, R. H., Brendel, M. D., Block, N. L., Ehrhart-Bornstein, M., & Bornstein, S. R. (2010). Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets. Proceedings of the National Academy of Sciences of the United States of America, 107(28), 12623-12628. https://doi.org/10.1073/pnas.1005098107