Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice.
OBJECTIVE
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 (Deltapsi(m)) 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 Deltapsi(m) 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
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.
Department of Animal Science, Cornell University, 252 Morrison Hall, Ithaca, NY 14853, USA.
X D
XD
Wang
M Z
MZ
Vatamaniuk
S K
SK
Wang
C A
CA
Roneker
R A
RA
Simmons
X G
XG
Lei
D000818:Animals; D005979:Glutathione Peroxidase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006946:Hyperinsulinism / Q000201:enzymology*; D007333:Insulin Resistance; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology; D010179:Pancreas / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C116888:Gpx3 protein, mouse; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse