CRFR1 is expressed on pancreatic β cells, promotes β cell proliferation, and potentiates insulin secretion in a glucose-dependent manner

Mark O. Huising, Talitha Van Der Meulen, Joan M. Vaughan, Masahito Matsumotoa, Cynthia J. Donaldson, Hannah Park, Nils Billestrup, Wylie W. Vale

Research output: Contribution to journalArticlepeer-review

Abstract

Corticotropin-releasing factor (CRF), originally characterized as the principal neuroregulator of the hypothalamus-pituitary-adrenal axis, has broad central and peripheral distribution and actions. We demonstrate the presence of CRF receptor type 1 (CRFR1) on primary β cells and show that activation of pancreatic CRFR1 promotes insulin secretion, thus contributing to the restoration of normoglycemic equilibrium. Stimulation of pancreatic CRFR1 initiates a cAMP response that promotes insulin secretion in vitro and in vivo and leads to the phosphorylation of cAMP response element binding and the induction of the expression of several immediate-early genes. Thus, the insulinotropic actions of pancreatic CRFR1 oppose the activation of CRFR1 on anterior pituitary corticotropes, leading to the release of glucocorticoids that functionally antagonize the actions of insulin. Stimulation of the MIN6 insulinoma line and primary rat islets with CRF also activates the MAPK signaling cascade leading to rapid phosphorylation of Erk1/2 in response to CRFR1-selective ligands, which induce proliferation in primary rat neonatal β cells. Importantly, CRFR1 stimulates insulin secretion only during conditions of intermediate to high ambient glucose, and the CRFR1-dependent phosphorylation of Erk1/2 is greater with elevated glucose concentrations. This response is reminiscent of the actions of the incretins, which potentiate insulin secretion only during elevated glucose conditions. The presence of CRFR1 on β cells adds another layer of complexity to the intricate network of paracrine and autocrine factors and their cognate receptors whose coordinated efforts can dictate islet hormone output and regulate β cell proliferation.

Original languageEnglish (US)
Pages (from-to)912-917
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number2
DOIs
StatePublished - 2010
Externally publishedYes

Keywords

  • Corticotropin-releasing factor
  • Diabetes
  • Glucose homeostasis
  • Hypothalamus-pituitary- adrenal axis
  • Pancreas

ASJC Scopus subject areas

  • General

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