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The nucleotide exchange factor SIL1 is required for glucose-stimulated insulin secretion from mouse pancreatic beta cells in vivo

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Abstract

Aims/hypothesis

Regulation of insulin secretion along the secretory pathway is incompletely understood. We addressed the expression of SIL1, a nucleotide exchange factor for the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 kD (GRP78), in pancreatic beta cells and investigated whether or not SIL1 is involved in beta cell function.

Methods

SIL1 expression was analysed by immunoblotting and immunofluorescence. Metabolic and islet variables, including glucose tolerance, beta cell mass, insulin secretion, islet ultrastructure, insulin content and levels of ER stress marker proteins, were addressed in Sil1 knockout (Sil1 −/−) mice. Insulin, proinsulin and C-peptide release was addressed in Sil1 −/− islets, and SIL1 overexpression or knockdown was explored in MIN6 cells in vitro. Models of type 1 diabetes and insulin resistance were induced in Sil1 −/− mice by administration of streptozotocin (STZ) and a high-fat diet (HFD), respectively.

Results

We show that SIL1 is expressed in pancreatic beta cells and is required for islet insulin content, islet sizing, glucose tolerance and glucose-stimulated insulin secretion in vivo. Levels of pancreatic ER stress markers are increased in Sil1 −/− mice, and Sil1 −/− beta cell ER is ultrastructurally compromised. Isolated Sil1 −/− islets show lower proinsulin and insulin content and impaired glucose-stimulated insulin secretion. Modulation of SIL1 protein levels in MIN6 cells correlates with changes in insulin content and secreted insulin. Furthermore, Sil1 −/− mice are more susceptible to STZ-induced type 1 diabetes with increased apoptosis. Upon HFD feeding, Sil1 −/− mice show markedly lower insulin secretion and exacerbated glucose intolerance compared with control mice. Surprisingly, however, HFD-fed Sil1 −/− mice display pronounced islet hyperplasia with low amounts of insulin in total pancreas.

Conclusions/interpretation

These results reveal a novel role for the nucleotide exchange factor SIL1 in pancreatic beta cell function under physiological and disease conditions such as diabetes and the metabolic syndrome.

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Abbreviations

BiP:

Binding immunoglobulin protein

CHOP:

CCAAT-enhancer-binding protein homologous protein

ER:

Endoplasmic reticulum

GRP78:

Glucose-regulated protein 78 kDa

HFD:

High-fat diet

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

shRNA:

Short hairpin RNA

shSil1 :

Short hairpin Sil1

STZ:

Streptozotocin

TEM:

Transmission electron microscopy

XBP-1:

X-box binding protein 1

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Acknowledgements

The authors thank Dr J.-I. Miyazaki (Osaka University, Osaka, Japan) for providing the MIN6 cell line and S. Fraser (Electron Microscope Unit, University of New South Wales, Sydney, NSW, Australia) for technical assistance.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

AI designed experiments, analysed the data and wrote the manuscript. JB, BC and JvE performed experiments, analysed the data and drafted parts of manuscript. PP and LMI designed study and experiments and wrote the manuscript. All authors approved the final version. AI is responsible for the integrity of the work as a whole.

Funding

The research was supported by funding from the National Health and Medical Research Council (NHMRC), the Australian Research Council (ARC) and the University of New South Wales. LMI is a NHMRC Senior Research Fellow.

Author information

Authors and Affiliations

  1. School of Medical Sciences, University of New South Wales, Botany Street, Kensington, Sydney, 2052, NSW, Australia

    Arne A. Ittner, Josefine Bertz, Janet van Eersel, Patsie Polly & Lars M. Ittner

  2. Faculty of Medicine, University of Sydney, Sydney, NSW, Australia

    Arne A. Ittner, Josefine Bertz, Tse Yan Becky Chan, Janet van Eersel & Lars M. Ittner

  3. Neuroscience Research Australia, Sydney, NSW, Australia

    Lars M. Ittner

  4. Department of Pathology, University of New South Wales, Sydney, NSW, Australia

    Patsie Polly

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  1. Arne A. Ittner
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  2. Josefine Bertz
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Corresponding author

Correspondence to Arne A. Ittner.

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Ittner, A.A., Bertz, J., Chan, T.Y.B. et al. The nucleotide exchange factor SIL1 is required for glucose-stimulated insulin secretion from mouse pancreatic beta cells in vivo. Diabetologia 57, 1410–1419 (2014). https://doi.org/10.1007/s00125-014-3230-z

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  • DOI: https://doi.org/10.1007/s00125-014-3230-z

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