Investigation of insulin resistance-induced endoplasmic reticulum stress in the pancreatic β-cell and development of diabetes mellitus

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There are accumulating evidences that decrease in β-cell mass play roles in the development and progression of type 2 diabetes mellitus. Endoplasmic reticulum stress has recently emerged as a candidate mechanism of β-cell loss. We investigated this mechanism using Wfs1 knock-out mouse as a model. The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein, homozygous mutations of which cause selective β-cell loss in humans. The WFS1 protein is involved in ER stress responses, but the mechanism of β-cell death in WFS1-deficient β-cells is still not fully understood. Interestingly, the phenotype of Wfs1^<-/-> mice depends mainly on their genetic backgrounds. Wfs1^<-/-> mice with the C57BL/6J background do not develop overt diabetes. However, we found that when these mice become mildly obese and insulin resistant due to the agouti lethal yellow mutation (Wfs1^<-/-> A^y/a), they develop selective β-cell loss and severe insulin-deficient diabetes as early as 16 weeks of ag … More e. This β-cell loss appeared to be due to apoptosis. In A^y/a murine islets, ER chaperone Bip/GRP78 expression and EIF2□ phosphorylation increased, suggesting that obesity induced ER stress in β-cells. Expression of the Bip/GRP78 protein was further increased in Wfs1^<-/-> A^y/a mice as compared to Wfs1^<-/-> or A^y/a mice. Electron micrography revealed markedly dilated ERs and decreased insulin granules in β-cells, suggesting that insulin resistance causes ER stress, and that pancreatic β-cells lacking Wfs1 are more susceptible to ER stress-induced apoptosis. Interestingly, pioglitazone treatment almost completely prevented diabetes, and protected β-cells form apoptosis. In islets, despite no difference in ER chaperone expression, CHOP expression was reduced. Although Wolfram syndrome is a distinct disease, there may be common processes involving slow, but progressive β-cell loss in patients with type 2 diabetes mellitus, in whom insulin demands rise continuously due to insulin resistance. Investigation of this model is anticipated to provide insights into the mechanism and prevention of β-cell loss. Less