TY - JOUR AU - Kulkarni, Rohit N. AU - Jhala, Ulupi S. AU - Winnay, Jonathon N. AU - Krajewski, Stan AU - Montminy, Marc AU - Kahn, C. Ronald T1 - PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance PY - 2004/09/15/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI21845 VL - 114 IS - 6 UR - https://doi.org/10.1172/JCI21845 SP - 828 EP - 836 PB - The American Society for Clinical Investigation ER -