{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:11:51Z","timestamp":1790802711503,"version":"4.1.0"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"33","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,8,16]]},"abstract":"<jats:p>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 (11\u03b2-HSD) isoforms; 11\u03b2-HSD\u2013type-1 and 11\u03b2-HSD\u2013type-2. We demonstrated expression of mRNA for 11\u03b2-HSD-1 and 11\u03b2-HSD-2 and protein for 11\u03b2-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 down-regulating 11\u03b2-HSD-1 and up-regulating 11\u03b2-HSD-2. The 11\u03b2-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 11\u03b2-HSD-1 enzyme activity or increased 11\u03b2-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.<\/jats:p>","DOI":"10.1073\/pnas.1110965108","type":"journal-article","created":{"date-parts":[[2011,8,9]],"date-time":"2011-08-09T02:20:00Z","timestamp":1312856400000},"page":"13722-13727","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":46,"title":["Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11\u03b2-hydroxysteroid dehydrogenase"],"prefix":"10.1073","volume":"108","author":[{"given":"Janine","family":"Schmid","sequence":"first","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, 01307 Dresden, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, 01307 Dresden, Germany;"},{"name":"The Paul Langerhans Institute, 01307 Dresden, Germany;"},{"name":"Center for Regenerative Therapies Dresden, Dresden University of Technology, 01307 Dresden, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew V.","family":"Schally","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Medicine, Divisions of Endocrinology and Hematology-Oncology, University of Miami Miller School of Medicine, Miami, FL 33136;"},{"name":"Veterans Administration Medical Center, Miami, FL 33125;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Steffen","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, 01307 Dresden, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian G.","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, 01307 Dresden, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman L.","family":"Block","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Medicine, Divisions of Endocrinology and Hematology-Oncology, University of Miami Miller School of Medicine, Miami, FL 33136;"},{"name":"Veterans Administration Medical Center, Miami, FL 33125;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yassemi","family":"Koutmani","sequence":"additional","affiliation":[{"name":"Developmental Biology Section, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias D.","family":"Brendel","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Carl Gustav Carus, 01307 Dresden, Germany;"},{"name":"The Paul Langerhans Institute, 01307 Dresden, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia P.","family":"Karalis","sequence":"additional","affiliation":[{"name":"Developmental Biology Section, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;"},{"name":"Division of Endocrinology, Children's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; 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