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Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis

Nature Medicine volume 11, pages 757–764 (2005)Cite this article

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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Figure 1: HFD produces obesity in Eif2s1+/tm1Rjk mice.
Figure 2: Eif2s1+/tm1Rjk mice show glucose intolerance and a defect in phase 1 insulin secretion.
Figure 3: HFD reduces insulin secretion from perifused islets of Eif2s1+/tm1Rjk mice.
Figure 4: Beta cells of HFD-fed Eif2s1+/tm1Rjk animals have distended ER.
Figure 5: Combination of high fat and Eif2s1tm1Rjk mutation causes accumulation of proinsulin in the ER in beta cells.

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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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Author notes

  1. Daisy Flamez

    Present address: Laboratory of Experimental Medicine, Université Libre de Bruxells, Route de Lennick 808, B-1070, Brussels, Belgium

Authors and Affiliations

  1. Howard Hughes Medical Institute, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Donalyn Scheuner, Benbo Song & Randal J Kaufman

  2. Department of Molecular Cell Biology, Gene Expression Unit, Katholieke Universiteit Leuven, Herestrat 49, Leuven, B-3000, Belgium

    Dirk Vander Mierde, Katsura Tsukamoto & Frans C Schuit

  3. Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, B-1090, Belgium

    Daisy Flamez

  4. Department Menselijke Erfelijkheid, Katholieke Universiteit Leuven, Leuven, and Vlaams Interuniversitiair Instituut voor Biotechnologie, Herestrat 49, Brussels, B-3000, Belgium

    John W M Creemers

  5. Department of Biological Chemistry, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Mark Ribick & Randal J Kaufman

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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)

Supplementary Methods (PDF 30 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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