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

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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Figure 1

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Growth curves and alterations in blood glucose and serum insulin levels....
Growth curves and alterations in blood glucose and serum insulin levels. (A) Body weights of male mice were determined between the ages of 4 and 20 weeks. Mice are divided into IR/IRS-1 (left panel) and PDX-1 (right panel) groups. P < 0.05, IRS-1 or IR/IRS-1 vs. WT at all time points; P < 0.05, IR vs. WT from 12 weeks onward; P < 0.05, IRS-1/PDX-1 or TKO vs. PDX-1 at all time points, IR/PDX-1 vs. PDX-1 from 12 weeks onward (n = 12_26). (B) Fasting blood glucose was measured after a 14-hour overnight fast in 2- and 4-month-old male mice. (C) Fed blood glucose was measured in random-fed 2- and 4-month-old male mice. (D) Fasting serum insulin was measured after a 14-hour overnight fast in 2- and 4-month-old male mice. (E) C-peptide levels were measured by RIA. *P < 0.05, IR/PDX-1, IRS-1/PDX-1, or TKO vs. PDX-1; P < 0.05, IR, IR/IRS-1, or PDX-1 vs. WT (n = 10_22).