Patients with Huntington’s disease (HD) have an increased incidence of diabetes. However, the molecular mechanisms of pancreatic β-cell dysfunction have not been entirely clarified. Revealing the pathogenesis of diabetes can provide a novel understanding of the onset and progression of HD, as well as potential clues for the development of new therapeutics. Here, we demonstrated that the mouse pancreatic insulinoma cell line NIT-1 expressing N-terminal mutant huntingtin (mHTT) containing 160 polyglutamine (160Q cells) displayed lower cell proliferative ability than the cells expressing N-terminal wild-type HTT containing 20 polyglutamine (20Q cells). In addition, 160Q cells were more prone to apoptosis and exhibited deficient glucose-stimulated insulin expression and secretion. Furthermore, insulin signaling molecule insulin receptor substrate 2 (IRS-2) expression decreased and was recruited into mHTT aggregates. Consequently, glucose stimulation failed to activate the downstream molecule phosphatidylinositol-3 kinase (PI3K) in 160Q cells, leading to reduced phosphorylation levels of serine–threonine protein kinase AKT and forkhead box protein O1 (FoxO1). These data indicate that activation of the glucose-stimulated PI3K/AKT/FoxO1 signaling pathway is significantly blocked in pancreatic β-cells in HD. Importantly, insulin treatment inhibited the aggregation of mHTT and significantly improved the activation of PI3K/AKT/FoxO1 signaling in 160Q cells. These results suggest that the inhibition of the PI3K/AKT/FoxO1 pathway might be due to the recruitment of IRS-2 into mHTT aggregates in HD β-cells, ultimately contributing to the impairment of pancreatic β-cells. In conclusion, our work provides new insight into the underlying mechanisms of the high incidence of diabetes and abnormal glucose homeostasis in HD.

亨廷顿病 (HD) 患者的糖尿病发病率增加。然而，胰腺β细胞功能障碍的分子机制尚未完全阐明。揭示糖尿病的发病机制可以提供对 HD 发生和进展的新理解，以及开发新疗法的潜在线​​索。在这里，我们证明了小鼠胰腺胰岛素瘤细胞系 NIT-1 表达含有 160 聚谷氨酰胺（160Q 细胞）的 N 端突变亨廷顿蛋白 (mHTT) 的细胞增殖能力低于表达含有 20 聚谷氨酰胺的 N 端野生型 HTT 的细胞。 20Q 电池）。此外，160Q 细胞更容易发生细胞凋亡，并表现出葡萄糖刺激的胰岛素表达和分泌不足。此外，胰岛素信号分子胰岛素受体底物 2 (IRS-2) 表达降低并被募集到 mHTT 聚集体中。因此，葡萄糖刺激未能激活 160Q 细胞中的下游分子磷脂酰肌醇 3 激酶 (PI3K)，导致丝氨酸-苏氨酸蛋白激酶 AKT 和叉头盒蛋白 O1 (FoxO1) 的磷酸化水平降低。这些数据表明，葡萄糖刺激的 PI3K/AKT/FoxO1 信号通路的激活在 HD 的胰腺 β 细胞中被显着阻断。重要的是，胰岛素治疗抑制了 mHTT 的聚集并显着改善了 160Q 细胞中 PI3K/AKT/FoxO1 信号的激活。这些结果表明 PI3K/AKT/FoxO1 通路的抑制可能是由于将 IRS-2 募集到 HD β 细胞中的 mHTT 聚集体中，最终导致胰腺β细胞受损。总之，我们的工作为 HD 糖尿病高发病率和异常葡萄糖稳态的潜在机制提供了新的见解。