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PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance
Rohit N. Kulkarni, … , Marc Montminy, C. Ronald Kahn
Rohit N. Kulkarni, … , Marc Montminy, C. Ronald Kahn
Published September 15, 2004
Citation Information: J Clin Invest. 2004;114(6):828-836. https://doi.org/10.1172/JCI21845.
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Article Metabolism

PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance

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Abstract

Inadequate compensatory β cell hyperplasia in insulin-resistant states triggers the development of overt diabetes. The mechanisms that underlie this crucial adaptive response are not fully defined. Here we show that the compensatory islet-growth response to insulin resistance in 2 models — insulin receptor (IR)/IR substrate–1 (IRS-1) double heterozygous mice and liver-specific IR KO (LIRKO) mice — is severely restricted by PDX-1 heterozygosity. Six-month-old IR/IRS-1 and LIRKO mice both showed up to a 10-fold increase in β cell mass, which involved epithelial-to-mesenchymal transition. In both models, superimposition of PDX-1 haploinsufficiency upon the background of insulin resistance completely abrogated the adaptive islet hyperplastic response, and instead the β cells showed apoptosis resulting in premature death of the mice. This study shows that, in postdevelopmental states of β cell growth, PDX-1 is a critical regulator of β cell replication and is required for the compensatory response to insulin resistance.

Authors

Rohit N. Kulkarni, Ulupi S. Jhala, Jonathon N. Winnay, Stan Krajewski, Marc Montminy, C. Ronald Kahn

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