| First Author | Suzuki L | Year | 2022 |
| Journal | Biochem Biophys Res Commun | Volume | 611 |
| Pages | 38-45 | PubMed ID | 35477091 |
| Mgi Jnum | J:324460 | Mgi Id | MGI:7278311 |
| Doi | 10.1016/j.bbrc.2022.04.040 | Citation | Suzuki L, et al. (2022) Cumulative autophagy insufficiency in mice leads to progression of beta-cell failure. Biochem Biophys Res Commun 611:38-45 |
| abstractText | Autophagy is known to play a pivotal role in beta-cell function. While the lifelong inhibition of autophagy through Atg7 deletion in beta cells has been demonstrated to lead to impaired glucose tolerance together with beta-cell dysfunction, the temporal association between autophagy inhibition and beta-cell dysfunction remains unclear. To address such questions, inducible beta-cell-specific Atg7-knockout (ibetaAtg7(KO)) 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, ibetaAtg7(KO) mice 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 beta-cell failure after a certain interval, accompanied by stepwise alterations of gene expression patterns. |
