Maintenance of Hepatic Nuclear Factor 6 in Postnatal Islets Impairs Terminal Differentiation and Function of β-Cells
- Elizabeth Tweedie12,
- Isabella Artner2,
- Laura Crawford12,
- Greg Poffenberger1,
- Bernard Thorens3,
- Roland Stein2,
- Alvin C. Powers124 and
- Maureen Gannon12
- 1Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee
- 2Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee
- 3Institute of Physiology, University of Lausanne, Lausanne, Switzerland
- 4VA Tennessee Valley Healthcare System, Nashville, Tennessee
- Address correspondence and reprint requests to Maureen Gannon, Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, 2220 Pierce Ave., 746 PRB, Nashville, TN 37232-6303. E-mail: maureen.gannon{at}vanderbilt.edu
Abstract
The Onecut homeodomain transcription factor hepatic nuclear factor 6 (Hnf6) is necessary for proper development of islet β-cells. Hnf6 is initially expressed throughout the pancreatic epithelium but is downregulated in endocrine cells at late gestation and is not expressed in postnatal islets. Transgenic mice in which Hnf6 expression is maintained in postnatal islets (pdx1PBHnf6) show overt diabetes and impaired glucose-stimulated insulin secretion (GSIS) at weaning. We now define the mechanism whereby maintenance of Hnf6 expression postnatally leads to β-cell dysfunction. We provide evidence that continued expression of Hnf6 impairs GSIS by altering insulin granule biosynthesis, resulting in a reduced response to secretagogues. Sustained expression of Hnf6 also results in downregulation of the β-cell–specific transcription factor MafA and a decrease in total pancreatic insulin. These results suggest that downregulation of Hnf6 expression in β-cells during development is essential to achieve a mature, glucose-responsive β-cell.
- GSIS, glucose-stimulated insulin secretion
- HNF, hepatic nuclear factor
- IBMX, isobutylmethylxanthine
- IPGTT, intraperitoneal glucose tolerance test
- SCB, sodium cacodylate buffer
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted August 22, 2006.
- Received January 19, 2006.
- DIABETES
