The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells

Jonathan C. Schisler, Per Bo Jensen, David G. Taylor, Thomas C. Becker, Filip Krag Knop, Shiro Takekawa, Michael German, Gordon C. Weir, Danhong Lu, Raghavendra G. Mirmira, Christopher B. Newgard

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

We have previously described rat insulinoma INS-1 derived cell lines with robust or poor glucose-stimulated insulin secretion (GSIS). In the current study, we have further resolved these lines into three classes: class 1, glucose-unresponsive glucagon-expressing; class 2, glucose-unresponsive glucagon-negative; and class 3, glucose-responsive glucagon-negative. The transcription factor Nkx2.2 was expressed with relative abundance of 3.3, 1.0, and 1.0 in class 1, class 2, and class 3 cells, respectively, whereas Nkx6.1 expression had the opposite trend: 1.0, 2.6, and 6.4 in class 1, class 2, and class 3 cells, respectively. In class 1 cells, overexpressed Nkx6.1 suppressed glucagon expression but did not affect the levels of several other prominent beta cell transcription factors. RNA interference (RNAi)-mediated suppression of Nkx6.1 in class 3 cells resulted in a doubling of glucagon mRNA, with no effect on Pdx1 levels, whereas suppression of Pdx1 in class 3 cells caused a 12-fold increase in glucagon transcript levels, demonstrating independent effects of Nkx6.1 and Pdx1 on glucagon expression in beta cell lines. RNAi-mediated suppression of Nkx6.1 expression in class 3 cells also caused a decrease in GSIS from 13.9- to 3.7-fold, whereas suppression of Pdx1 reduced absolute amounts of insulin secretion without affecting fold response. Finally, RNAi-mediated suppression of Nkx6.1 mRNA in primary rat islets was accompanied by a significant decrease in GSIS relative to control cells. In sum, our studies have revealed roles for Nkx6.1 in suppression of glucagon expression and control of GSIS in islet beta cells.

Original languageEnglish (US)
Pages (from-to)7297-7302
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number20
DOIs
StatePublished - May 17 2005
Externally publishedYes

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