Impaired Glucose Tolerance in a Mouse Model of Sidt2 Deficiency

Jialin Gao,Xuefan Gu,Zhugang Wang,Don J Mahuran,Huiwen Zhang,Claudia Miele

doi:10.1371/journal.pone.0066139

Abstract

Sidt2 was identified as a novel integral lysosomal membrane protein recently. We generated global Sidt2 knockout mice by gene targeting. These mice have a comparatively higher random and fasting glucose concentration. Intraperitoneal and oral glucose tolerance tests in Sidt2 knockout mice indicated glucose intolerance and decreased serum insulin level. Notably, the Sidt2−/− mice had hypertrophic islets compared with control mice. By Western blot and immunofluorescence, Sidt2−/− mouse islets were shown to have increased insulin protein, which actually contained more insulin secretory granules than their controls, demonstrated by electromicroscopy. Consistent with the in vivo study, isolated islet culture from the Sidt2−/− mice produced less insulin when stimulated by a high concentration of glucose or a depolarizing concentration of KCl. Under electromicroscope less empty vesicles and more mature ones in Sidt2−/− mice islets were observed, supporting impaired insulin secretory granule release. In conclusion, Sidt2 may play a critical role in the regulation of mouse insulin secretory granule secretion.

Highlights

The lysosomal membrane has long been seen as a physical barrier that allows the acidification of the lumen in order to promote the turnover of both extra- and intra-cellular macromolecules
Statistical Analyses Results are expressed as means 6 standard errors of means (SEM)
By Transmission Electron Microscopy (TEM) analysis, we found that the b-cells of Sidt22/2 islets contained more insulin secretory granules (Figure 4G), which was consistent with the increased insulin expression level observed by Western blot analysis (Figure 4C)

Summary

Introduction

The lysosomal membrane has long been seen as a physical barrier that allows the acidification of the lumen in order to promote the turnover of both extra- and intra-cellular macromolecules. In recent years this membrane has been found to play more varied roles in the functions of the lysosomes. The lysosomal membrane is directly involved in micro-, macro-, and chaperone mediated autophagy[4]. Abnormalities in these pathways have been linked with several neurodegenerative diseases [5,6]

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Results

Conclusion