Cumulative autophagy insufficiency in mice leads to progression of β-cell failure
Cumulative autophagy insufficiency in mice leads to progression of β-cell failure
复制标题
小鼠的累积自噬不足导致 β 细胞衰竭的进展
DOI：
10.1016/j.bbrc.2022.04.040
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Watada H
中科院分区：
文献类型：
--
作者：
Suzuki L;Miyatsuka T;Himuro M;Wakabayashi Y;Osonoi S;Miura M;Katahira T;Fujitani Y;Iida H;Mizukami H;Nishida Y;Watada H
Autophagy is known to play a pivotal role in β-cell function. While the lifelong inhibition of autophagy throughAtg7deletion in β cells has been demonstrated to lead to impaired glucose tolerance together with β-cell dysfunction, the temporal association between autophagy inhibition and β-cell dysfunction remains unclear. To address such questions, inducible β-cell-specific Atg7-knockout (iβAtg7KO) mice were generated, and autophagy inhibition was induced for two different time durations. Whereas 2 weeks of Atg7 ablation was sufficient to induce autophagy deficiency, confirmed by the accumulation of p62,iβAtg7KOmice exhibited normal glucose tolerance. In contrast, prolonged autophagy deficiency for 6 weeks resulted in glucose intolerance together with impaired insulin secretion. Direct mRNA sequencing and pathway analysis revealed that the gene set associated with insulin secretion was downregulated only after the 6-week prolonged autophagy inhibition. Furthermore, we identified a novel gene,Sprr1a, which was expressed at more than 50-fold higher levels during both the 2-week and 6-week autophagy inhibition. These findings suggest that autophagy insufficiency cumulatively leads to β-cell failure after a certain interval, accompanied by stepwise alterations of gene expression patterns.
