Molecular mechanisms for hyperinsulinaemia... : Diabetologia (original) (raw)

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

X. D. Wang
M. Z. Vatamaniuk
S. K. Wang
C. A. Roneker
R. A. Simmons
X. G. Lei

Diabetologia

(

)

1515

1524

August 2008

| DOI: 10.1007/s00125-008-1055-3

Abstract

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.