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World J Diabetes. 2011 Jul 15;2(7):114-8. doi: 10.4239/wjd.v2.i7.114.

Unravelling the story of protein misfolding in diabetes mellitus.

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Sally E Thomas, Lucy Dalton, Elke Malzer, Stefan J Marciniak, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB0 2XY, United Kingdom.


Both environmental and genetic factors contribute to the development of diabetes mellitus and although monogenic disorders are rare, they offer unique insights into the fundamental biology underlying the disease. Mutations of the insulin gene or genes involved in the response to protein misfolding cause early onset diabetes. These have revealed an important role for endoplasmic reticulum stress in β-cell survival. This form of cellular stress occurs when secretory proteins fail to fold efficiently. Of all the professional secretory cells we possess, β-cells are the most sensitive to endoplasmic reticulum stress because of the large fluctuations in protein synthesis they face daily. Studies of endoplasmic reticulum stress signaling therefore offer the potential to identify new drug targets to treat diabetes.


Diabetes; Endoplasmic reticulum stress; PKR-like ER kinase; Unfolded protein response

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