Aims/hypothesis
We previously observed hyperglycaemia, hyperinsulinaemia, insulin resistance and obesity in Gpx1-overexpressing mice (OE). Here we determined whether these phenotypes were eliminated by diet restriction, subsequently testing
whether hyperinsulinaemia was a primary effect of Gpx1 overexpression and caused by dysregulation of pancreatic duodenal homeobox 1 (PDX1) and uncoupling protein-2 (UCP2) in islets.
Methods
First, 24 male OE and wild-type (WT) mice (2 months old) were given 3 g (diet-restricted) or 5 g (full-fed) feed per day for
4 months to compare their glucose metabolism. Thereafter, several mechanistic experiments were conducted with pancreas and
islets of the two genotypes (2 or 6 months old) to assay for beta cell mass, reactive oxygen species (ROS) levels, mitochondrial
membrane potential (Δψm) and expression profiles of regulatory proteins. A functional assay of islets was also performed.
Results
Diet restriction eliminated obesity but not hyperinsulinaemia in OE mice. These mice had greater pancreatic beta cell mass
(more than twofold) and pancreatic insulin content (40%) than the WT, along with an enhanced Δψm and glucose-stimulated insulin secretion in islets. With diminished ROS production, the OE islets displayed hyperacetylation
of H3 and H4 histone in the Pdx1 promoter, elevated PDX1 and decreased UCP2.
Conclusions/interpretation
Overproduction of the major antioxidant enzyme, glutathione peroxidase 1, caused seemingly beneficial changes in pancreatic
PDX1 and UCP2, but eventually led to chronic hyperinsulinaemia by dysregulating islet insulin production and secretion.
Keywords Glutathione peroxidase - Histone acetylation - Hyperinsulinaemia - Insulin resistance - Insulin secretion - Islets - Oxidative stress - Selenium