Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11β-hydroxysteroid dehydrogenase

Janine Schmid, Barbara Ludwig, Andrew Schally, Anja Steffen, Christian Ziegler, Norman Block, Yassemi Koutmani, Mathias Brendel, Katia Karalis, Charmaine Simeonovic, Julio Licinio, Monika Ehrhart-Bornstein, Stefan Bornstein

    Research output: Contribution to journalArticlepeer-review

    31 Citations (Scopus)

    Abstract

    Corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GHRH), primarily characterized as neuroregulators of the hypothalamic- pituitary-adrenal axis, directly influence tissue-specific receptor-Systems for CRH and GHRH in the endocrine pancreas. Here, we demonstrate the expression of mRNA for CRH and CRH-receptor type 1 (CRHR1) and of protein for CRHR1 in rat and human pancreatic islets and rat insulinoma cells. Activation of CRHR1 and GHRH-receptor significantly increased cell proliferation and reduced cell apoptosis. CRH stimulated both cellular content and release of insulin in rat islet and insulinoma cells. At the ultrastructural level, CRHR1 stimulation revealed a more active metabolic state with enlarged mitochondria. Moreover, glucocorticoids that promote glucose production are balanced by both 11b-hydroxysteroid dehydrogenase (11β-HSD) isoforms; 11β-HSD-type-1 and 11β-HSD-type-2. We demonstrated expression of mRNA for 11β-HSD-1 and 11β-HSD-2 and protein for 11β-HSD-1 in rat and human pancreatic islets and insulinoma cells. Quantitative real-time PCR revealed that stimulation of CRHR1 and GHRH-receptor affects the metabolism of insulinoma cells by downregulating 11β-HSD-1 and up-regulating 11β-HSD-2. The 11β-HSD enzyme activity was analyzed by measuring the production of cortisol from cortisone. Similarly, activation of CRHR1 resulted in reduced cortisol levels, indicating either decreased 11β-HSD-1 enzyme activity or increased 11β-HSD-2 enzyme activity; thus, activation of CRHR1 alters the glucocorticoid balance toward the inactive form. These data indicate that functional receptor systems for hypothalamic-releasing hormone agonists exist within the endocrine pancreas and influence synthesis of insulin and the pancreatic glucocorticoid shuttle. Agonists of CRHR1 and GHRH-receptor, therefore, may play an important role as novel therapeutic tools in the treatment of diabetes mellitus.

    Original languageEnglish
    Pages (from-to)13722-13727
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume108
    Issue number33
    DOIs
    Publication statusPublished - 16 Aug 2011

    Keywords

    • Islet proliferation
    • Metabolic syndrome
    • Regenerative therapy

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