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Diabetologia. 2013 May;56(5):1057-67. doi: 10.1007/s00125-013-2855-7. Epub 2013 Mar 9.

GRP78 overproduction in pancreatic beta cells protects against high-fat-diet-induced diabetes in mice.

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1
Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, 101 College Street, TMDT 10-706, Toronto, ON M5G 1L7, Canada.

Abstract

AIMS/HYPOTHESIS:

Endoplasmic reticulum (ER) stress has been detected in pancreatic beta cells and in insulin-sensitive tissues, such as adipose and liver, in obesity-linked rodent models of type 2 diabetes. The contribution of ER stress to pancreatic beta cell dysfunction in type 2 diabetes is unclear. We hypothesised that increased chaperone capacity protects beta cells from ER stress and dysfunction caused by obesity and improves overall glucose homeostasis.

METHODS:

We generated a mouse model that overproduces the resident ER chaperone GRP78 (glucose-regulated protein 78 kDa) in pancreatic beta cells under the control of a rat insulin promoter. These mice were subjected to high-fat diet (HFD) feeding for 20 weeks and metabolic variables and markers of ER stress in islets were measured.

RESULTS:

As expected, control mice on the HFD developed obesity, glucose intolerance and insulin resistance. In contrast, GRP78 transgenic mice tended to be leaner than their non-transgenic littermates and were protected against development of glucose intolerance, insulin resistance and ER stress in islets. Furthermore, islets from transgenic mice had a normal insulin content and normal levels of cell-surface GLUT2 (glucose transporter 2) and the transgenic mice were less hyperinsulinaemic than control mice on the HFD.

CONCLUSIONS/INTERPRETATION:

These data show that increased chaperone capacity in beta cells provides protection against the pathogenesis of obesity-induced type 2 diabetes by maintaining pancreatic beta cell function, which ultimately improves whole-body glucose homeostasis.

PMID:
23475366
DOI:
10.1007/s00125-013-2855-7
[Indexed for MEDLINE]
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