The diabetes gene Hhex maintains δ-cell differentiation and islet function
- 1Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 2Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510, USA
Abstract
The homeodomain transcription factor HHEX (hematopoietically expressed homeobox) has been repeatedly linked to type 2 diabetes mellitus (T2DM) using genome-wide association studies. We report here that within the adult endocrine pancreas, Hhex is selectively expressed in the somatostatin-secreting δ cell. Using two mouse models with Hhex deficiency in the endocrine pancreas, we show that Hhex is required for δ-cell differentiation. Decreased somatostatin levels in Hhex-deficient islets cause disrupted paracrine inhibition of insulin release from β cells. These findings identify Hhex as the first transcriptional regulator specifically required for islet δ cells and suggest compromised paracrine control as a contributor to T2DM.
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Footnotes
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↵3 Corresponding author
E-mail kaestner{at}mail.med.upenn.edu
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.235499.113.
- Received November 26, 2013.
- Accepted March 17, 2014.
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