<i>Plcb1</i><sup>f/f</sup>; <i>Pdx1-CreERt2</i> mice fed a high-fat diet developed more severe glucose intolerance because of a defect in insulin secretion.
We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance.
Adult Tshz1(+/-) mice display glucose intolerance due to defects in glucose-stimulated insulin secretion associated with reduced Pdx1 and Clec16a expression in Tshz1(+/-) islets.
Mice that are haploinsufficient for Pdx1 display impaired glucose tolerance and lack the ability to increase beta cell mass in response to decreased insulin signaling.
A 14.5-kb pdx1 genomic fragment corrected the glucose intolerance of pdx1(+/-) animals but, moreover, fully rescued the severe gut and pancreas defects in pdx1(-/-) embryos.
Heterozygous mutations in the gene result in impaired glucose tolerance and symptoms of diabetes as seen in MODY4 and late-onset Type II (non-insulin-dependent) diabetes mellitus.