Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France.
Nat Commun. 2019 Jul 25;10(1):3312. doi: 10.1038/s41467-019-11170-4.
Compromised function of insulin-secreting pancreatic β cells is central to the development and progression of Type 2 Diabetes (T2D). However, the mechanisms underlying β cell failure remain incompletely understood. Here, we report that metabolic stress markedly enhances macroautophagy-independent lysosomal degradation of nascent insulin granules. In different model systems of diabetes including of human origin, stress-induced nascent granule degradation (SINGD) contributes to loss of insulin along with mammalian/mechanistic Target of Rapamycin (mTOR)-dependent suppression of macroautophagy. Expression of Protein Kinase D (PKD), a negative regulator of SINGD, is reduced in diabetic β cells. Pharmacological activation of PKD counters SINGD and delays the onset of T2D. Conversely, inhibition of PKD exacerbates SINGD, mitigates insulin secretion and accelerates diabetes. Finally, reduced levels of lysosomal tetraspanin CD63 prevent SINGD, leading to increased insulin secretion. Overall, our findings implicate aberrant SINGD in the pathogenesis of diabetes and suggest new therapeutic strategies to prevent β cell failure.
胰岛素分泌胰腺β细胞功能受损是 2 型糖尿病（T2D）发生和发展的核心。然而，β细胞衰竭的机制仍不完全清楚。在这里，我们报告代谢应激显著增强了新生胰岛素颗粒的非自噬依赖性溶酶体降解。在包括源自人类的不同糖尿病模型系统中，应激诱导的新生颗粒降解（SINGD）导致胰岛素丢失，同时伴随着哺乳动物雷帕霉素靶蛋白（mTOR）依赖性自噬的抑制。在糖尿病β细胞中，蛋白激酶 D（PKD）的表达减少，PKD 是 SINGD 的负调节剂。PKD 的药理学激活可拮抗 SINGD，并延迟 T2D 的发生。相反，PKD 的抑制会加剧 SINGD，减轻胰岛素分泌，并加速糖尿病的发展。最后，溶酶体四跨膜蛋白 CD63 的水平降低可防止 SINGD，导致胰岛素分泌增加。总的来说，我们的研究结果表明，异常的 SINGD 参与了糖尿病的发病机制，并为预防β细胞衰竭提供了新的治疗策略。
