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

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 (fullfed) 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 (Δ= 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 Δ= 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/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.

Selenium biochemistry and its role for human health

“…GPx1 and GPxs reduce H 2 O 2 , so they are supposed to carry out an inhibitory action on the signalling cascade. Experimental evidence supports this hypothesis because transgenic mice over-expressing GPx1 exhibit insulin resistance, 218 whereas knockout of GPx1 improves insulin sensitivity. 219 Confirmation in humans raised from the observation that increased erythrocyte GPx1 activity associates with mild insulin resistance in pregnant women, 220 and systemic Se-proteins deficiency (by mutations into the SBP2 gene) enhances insulin sensitivity.…”

Selenoproteins: Molecular Pathways and Physiological Roles

“…It was proposed that these changes in GPx1-overexpressing mice might be explained by elevated pancreatic ␤-cell mass and ␤-cell insulin secretion caused by disrupted reactive oxygen species (ROS) signaling (250,285). By degrading H 2 O 2 , high GPx1 levels have been implicated in both promoting insulin secretion through activation of PDX1 transcription factor-dependent differentiation of pancreatic ␤-cells and increased insulin secretion due to lower levels of UCP2 protein (364). The development of type 2 diabetes-like phenotypes in GPx1-overexpressing mice might also be attributed to dysregulation of insulin signaling in insulin target tissues, which in turn reflects lower phosphorylation of insulin receptor and AKT following insulin stimulation as a result of decreased intracellular H 2 O 2 levels.…”

Selenium status and cardiometabolic health: State of the evidence

“…59 Moreover, it has been shown that highselenium diets may stimulate the release of glucagon, promoting hyperglycaemia, 60 or may induce over-expression of GPx-1 and other antioxidant selenoproteins in animal models resulting in the development of insulin resistance and obesity. [61][62][63] Likewise in humans, a strongly positive correlation between GPx activity and insulin resistance was found in a group of non-diabetic pregnant women. 64 In general, the toxic effects of selenium that might explain an etiologic role in diabetes are the capacity of some selenium compounds, notably selenite, to induce oxidative stress, [65][66][67] a mechanism that is likely to play a key role in the etiology of this disease.…”