Impaired Glucose Tolerance in a Mouse Model of Sidt2 Deficiency

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.

Movement of regulatory RNA between animal cells

“…In planaria, silencing in response to ingested dsRNA can occur in most tissues (Rouhana et al, 2013) and weak homologs of SID-1 are present (Zayas et al, 2005) but the roles of these homologs in the uptake of dsRNA are yet to be evaluated. Finally, a mammalian homolog of SID-1, SidT2, is a lysosomal membrane protein (Jialin et al, 2010), which is in contrast to the reported plasma membrane localization of C. elegans SID-1 (Winston et al, 2002), and mouse knockouts of SidT2 have impaired glucose tolerance (Gao et al, 2013), which is in contrast to the lack of obvious defects in C. elegans that lack SID-1 (Winston et al, 2002), suggesting that SID-1 and its mammalian homologs also have alternative function(s). An intriguing clue to such alternative functions comes from a close inspection of sequence similarity, which suggests that both SID-1 and CHUP-1 have a domain with weak similarity to hydrolases (Pei et al, 2011).…”

Sidt2 regulates hepatocellular lipid metabolism through autophagy

“…−/− mice were generated as previously described (21). All mice were housed with standard temperature and humidity and were maintained on a 12 h light/dark cycle.…”

SIDT2 is involved in the NAADP-mediated release of calcium from insulin secretory granules

“…Generation of the Sidt2 −/− mice was described previously (Gao et al 2013). All mice were housed in Animal Laboratory Center at Xinhua hospital, Shanghai, China.…”

“…Five-micrometer paraffin-embedded pancreas sections were stained as described previously (Gao et al 2013). Isolated primary β-cells were fixed with 4% paraformaldehyde for 20 min, permeabilized for 20 min in 0.2% Triton X-100 buffer, blocked with PBS containing 5% BSA, and subjected to double immunofluorescence staining.…”

“…To explore its pathophysiological function, we generated a global knockout Sidt2 −/− mouse model, which exhibited age-dependent increased plasma glucose levels and impaired glucose tolerance (Gao et al 2013). Islets from Sidt2 −/− mice cultured in vitro produced less insulin when stimulated with a high concentration of glucose or a depolarizing concentration of KCl.…”