Publications by authors named "Maria Stathopoulos"

2 Publications

  • Page 1 of 1

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice.

J Endocrinol 2016 Jan 22;228(1):61-73. Epub 2015 Oct 22.

Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.

Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with β-cell dysfunction. A genome-wide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a ∼211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucose-mediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving β-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to β-cell dysfunction in T2D.
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January 2016

High-fat-fed obese glutathione peroxidase 1-deficient mice exhibit defective insulin secretion but protection from hepatic steatosis and liver damage.

Antioxid Redox Signal 2014 May 11;20(14):2114-29. Epub 2014 Mar 11.

1 Department of Biochemistry and Molecular Biology, Monash University , Victoria, Australia .

Aims: Reactive oxygen species (ROS) such as H2O2 can promote signaling through the inactivation of protein tyrosine phosphatases (PTPs). However, in obesity, the generation of ROS exceeds the antioxidant reserve and can contribute to the promotion of insulin resistance. Glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme that eliminates H2O2. Here, we have used Gpx1(-/-) mice to assess the impact of oxidative stress on glucose homeostasis in the context of obesity.

Results: Gpx1(-/-) mice fed an obesogenic high-fat diet for 12 weeks exhibited systemic oxidative stress and hyperglycemia, but had unaltered whole-body insulin sensitivity, improved hepatic insulin signaling, and decreased whole-body glucose production. High-fat-fed Gpx1(-/-) mice also exhibited decreased hepatic steatosis and liver damage accompanied by decreased plasma insulin and decreased glucose-induced insulin secretion. The decreased insulin secretion was associated with reduced islet β cell pancreatic and duodenal homeobox-1 (Pdx1) and insulin content, elevated pancreatic PTP oxidation (including PTPN2 oxidation), and elevated signal transducer and activator of transcription 1 (STAT1) Y701 phosphorylation.

Innovation And Conclusion: Taken together, these results are consistent with H2O2 inactivating pancreatic PTPs (such as the STAT1 phosphatase PTPN2) for the promotion of STAT-1 signaling to suppress Pdx1 expression and differentiation and, consequently, reduce β cell insulin secretion. We propose that the decreased insulin secretion, in turn, results in decreased hepatic lipogenesis and steatosis, attenuates liver damage, and improves hepatic insulin signaling to suppress hepatic glucose production. Limiting insulin secretion may help combat the development of hepatic steatosis and liver damage in diet-induced obesity.
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May 2014