Abstract
Type 2 diabetes is a disorder of hyperglycemia resulting from failure of beta cells to produce adequate insulin to accommodate an increased metabolic demand. Here we show that regulation of mRNA translation through phosphorylation of eukaryotic initiation factor 2 (eIF2α) is essential to preserve the integrity of the endoplasmic reticulum (ER) and to increase insulin production to meet the demand imposed by a high-fat diet. Accumulation of unfolded proteins in the ER activates phosphorylation of eIF2α at Ser51 and inhibits translation. To elucidate the role of this pathway in beta-cell function we studied glucose homeostasis in Eif2s1tm1Rjk mutant mice, which have an alanine substitution at Ser51. Heterozygous (Eif2s1+/tm1Rjk) mice became obese and diabetic on a high-fat diet. Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distension of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells. We propose that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes.
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Acknowledgements
We thank A. Saltiel for scientific guidance and manuscript review. We thank O. MacDougald and K. Longo for their input in characterizing the obesity phenotype, including measurement of metabolic rates. We thank M. Pinter for technical assistance and her efforts in management of our mouse colony and diet studies. We also thank J. Mitchell for assistance with manuscript preparation. We thank D. Sorenson, S. Meshinchi and C. Edwards of the University of Michigan Microscopy and Image Analysis Lab and T. Pritchett of the Anatomical Pathology Department for technical and scientific contribution. This work was supported by US National Institutes of Health grant DK42394 (to R.J.K.) and grants from the Juvenile Diabetes Research Foundation (1-2002-801) and from the K.U. Leuven (grant GOA/2004/11) (to F.C.S.). J.C. is a postdoctoral fellow at the Flemish National Fund for Scientific Research (FWO-Vlaanderen). M.R. was supported by the US National Institute of General Medical Sciences (grant GM07767).
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Supplementary information
Supplementary Fig. 1
Heterozygous Eif2s1+/tm1Rjk HFD-fed animals exhibit macrovesicular liver steatosis. (PDF 800 kb)
Supplementary Fig. 2
Heterozygous Eif2s1+/tm1Rjk HFD-fed animals are obese, exhibit reduced metabolic rates and are diabetic. (PDF 175 kb)
Supplementary Fig. 3
Eif2s1+/tm1Rjk/Leprdb/db mice are more glucose intolerant than wild-type Eif2s1+/+/Leprdb/db mice. (PDF 45 kb)
Supplementary Fig. 4
Obesity does not correlate with glucose intolerance in heterozygous Eif2s1+/tm1Rjk HFD-fed animals. (PDF 39 kb)
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Scheuner, D., Mierde, D., Song, B. et al. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat Med 11, 757–764 (2005). https://doi.org/10.1038/nm1259
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DOI: https://doi.org/10.1038/nm1259
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