Wortham Matthew, Ramms Bastian, Zeng Chun, Benthuysen Jacqueline R, Sai Somesh, Pollow Dennis P, Liu Fenfen, Schlichting Michael, Harrington Austin R, Liu Bradley, Prakash Thazha P, Pirie Elaine C, Zhu Han, Baghdasarian Siyouneh, Lee Sean T, Ruthig Victor A, Wells Kristen L, Auwerx Johan, Shirihai Orian S, Sander Maike
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diab, UCSD, La Jolla, United States of America.
Institute of Chemistry and Biochemistry, Department of Biology, Chemistry a, Freie Universität Berlin, Berlin, Germany.
J Clin Invest. 2025 Jul 31. doi: 10.1172/JCI187020.
Selective and controlled expansion of endogenous β-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of β-cell proliferation to avoid excessive β-cell expansion. Here, we identified a regulator of β-cell proliferation whose inactivation results in controlled β-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in β-cells of mice increased β-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of β-cell mass. SIRT2 restrains proliferation of human islet β-cells, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on β-cells, with Sirt2 controlling how β-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves β-cell Sirt2 inactivation and stimulates β-cell proliferation during hyperglycemia. Overall, these studies identify a therapeutic strategy for increasing β-cell mass in diabetes without circumventing feedback control of β-cell proliferation. Future work should test the extent that these findings translate to human β-cells from individuals with and without diabetes.
内源性β细胞的选择性和可控性扩增已被视为糖尿病的一种潜在治疗方法。理想情况下，此类疗法应保留对β细胞增殖的反馈控制，以避免β细胞过度扩增。在此，我们鉴定出一种β细胞增殖调节因子，其失活会导致可控的β细胞扩增：蛋白脱乙酰酶沉默调节蛋白2（SIRT2）。小鼠β细胞中Sirt2基因缺失在高血糖期间增加了β细胞增殖，而在稳态条件下影响很小，这表明β细胞质量的反馈控制得以保留。SIRT2抑制人胰岛β细胞的增殖，证明了SIRT2功能的保守性。用SIRT2抑制剂处理的胰岛中乙酰化蛋白分析表明，SIRT2使参与氧化磷酸化的酶脱乙酰化，从而减弱高血糖期间耗氧量的适应性增加。在转录组水平上，Sirt2失活对β细胞具有背景依赖性影响，Sirt2控制着β细胞如何将高血糖视为一种应激。最后，我们提供了原理证明，即全身给予GLP1偶联的靶向Sirt2的反义寡核苷酸可实现β细胞Sirt2失活，并在高血糖期间刺激β细胞增殖。总体而言，这些研究确定了一种在不规避β细胞增殖反馈控制的情况下增加糖尿病患者β细胞质量的治疗策略。未来的工作应测试这些发现对有糖尿病和无糖尿病个体的人类β细胞的适用程度。
