It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine—a natural polyamine exhibiting health-protective and anti-ageing effects—but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)—a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.

已经确定 N-乙酰转移酶 （鼠 NAT1 （mNAT1） 和人 NAT2 （hNAT2）） 介导 2 型糖尿病的胰岛素敏感性。在这里，我们表明 mNAT1 缺乏导致细胞亚精胺（一种具有健康和抗衰老作用的天然多胺）减少，但对其机制的了解有限。我们发现 mNAT1 和 hNAT2 调节一种涉及乙酰化亚精胺的翻译后修饰，我们将其命名为乙酰化亚精胺，对受体相互作用的丝氨酸/苏氨酸蛋白激酶 1 （RIPK1） （RIPK1） ——炎症和细胞死亡的关键调节因子。补充亚精胺可减少体内 NAT1 缺陷诱导的 RIPK1 介导的细胞死亡和糖尿病表型。此外，可以通过抑制 RIPK1 来阻断 NAT1 缺陷小鼠血管病理介导的胰岛素抵抗和糖尿病肾病。最后，我们证明了人类糖尿病患者血管组织中亚精胺的减少和 RIPK1 的激活。我们的研究表明血管病理学在糖尿病发病和进展中的作用，并确定 RIPK1 激酶的抑制是治疗 2 型糖尿病的潜在治疗方法。