We read with great interest the recent publication by Giuseppe Danilo Norata et al. highlighting the essential role of PCSK9/LDLR axis in the maintenance of pancreatic b-cell cholesterol homeostasis and its physiological function. Previously, the impaired insulin secretion caused by perturbation of b-cell cholesterol homeostasis was considered to be main reason for the systemic inflammation and the metabolic disturbance in adipose tissue and skeletal muscle. We indeed thought that more and longer experimental time points or suitable models should be involved in the extended study for the dynamically and comprehensively evaluating the impacts of pancreatic PCSK9/LDLR axis on the b-cell function and systemic metabolic reprogramming. Notably, the susceptibility of LDL aggregation caused by the great changes of its composition, such as the oxidation or glycosylation of lipoproteins and lipids in LDL particle, could predict future cardiovascular death in human study. Hence, we held the opinion that the adaptive response of LDL susceptibility might induce the b-cell dysfunction through irrelievable toxicity of lipids or proteins under the condition of PCSK9 deficiency or inhibition. In addition, one elegant study showed that adjustment of human diets, such as the reduction of dietary cholesterol and fat intake, could improve glucose tolerance by ameliorating b-cell function in non-diabetic subjects. We were wondering whether the administration of low cholesterol diet would be a potential preventative treatment for maintenance of b-cell normal function and reducing the risk of type 2 diabetes mellitus in the future studies focused on the long-term safety effects of targeting circulating PCSK9.

中文翻译：

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更多考虑β细胞功能和PCSK9/LDLR轴

我们饶有兴趣地阅读了 Giuseppe Danilo Norata 等人最近发表的文章。强调 PCSK9/LDLR 轴在维持胰腺 b 细胞胆固醇稳态及其生理功能中的重要作用。以前，b细胞胆固醇稳态紊乱引起的胰岛素分泌受损被认为是全身炎症和脂肪组织和骨骼肌代谢紊乱的主要原因。我们确实认为应该在扩展研究中加入更多更长的实验时间点或合适的模型，以动态、全面地评估胰腺 PCSK9/LDLR 轴对 b 细胞功能和全身代谢重编程的影响。值得注意的是，由于其组成的巨大变化而引起的低密度脂蛋白聚集的易感性，例如低密度脂蛋白颗粒中脂蛋白和脂质的氧化或糖基化，可以在人类研究中预测未来的心血管死亡。因此，我们认为，在 PCSK9 缺乏或抑制的情况下，LDL 易感性的适应性反应可能通过脂质或蛋白质的不可逆转的毒性诱导 b 细胞功能障碍。此外，一项优雅的研究表明，调整人类饮食，例如降低膳食胆固醇和脂肪摄入量，可以通过改善非糖尿病受试者的 b 细胞功能来改善葡萄糖耐量。