β细胞去分化在2型糖尿病发生发展中起重要作用，其分子机制尚未完全阐明。课题组前期研究首次发现Ngn3等多潜能前体细胞标志物在ChREBP-/-小鼠胰岛β细胞中表达水平显著低于野生型小鼠，提示ChREBP参与了高糖诱导的β细胞去分化。进一步运用酵母双杂交技术筛查ChREBP在MIN6细胞cDNA文库中的相互作用蛋白谱，发现β-arrestin2是ChREBP的相互作用蛋白。细胞水平的研究发现ChREBP能够激活β-arrestin2，db/db糖尿病小鼠胰岛β细胞ChREBP表达增加，β-arrestin2活性增加，β-arrestin2调控的FoxO1泛素化降解途径被激活，导致胰岛β细胞去分化。课题组首次提出β细胞内存在高糖调控的“ChREBP-β-arrestin2- FoxO1”去分化通路，并将在细胞、糖尿病动物模型以及ChREBP基因敲除小鼠模型等层面进行验证。

Pancreatic β cell dedifferentiation play a pivotal role in the development of type 2 diabetes. We observed that Ngn3, Nanog, and L-Myc, the markers of β cell dedifferentiation, were significantly decreased in ChREBP-/- mice as compared with wild type mice, indicated that ChREBP involved in high glucose induced β cell dedifferentiation. Furthermore, we found that ChREBP interacted with β-arrestin2 by yeast two-hybrid system, and ChREBP could activate β-arrestin2 and induce FoxO1 ubiquitination degradation. Our study also demonstrated that FoxO1 ubiquitination degradation, induced by ChREBP-β-arrestin2 interaction, was increased in pancreatic β cells of db/db mice. We proposed that ChREBP-β-arrestin2-FoxO1 pathway involved in β cell dedifferentiation induced by high glucose. We will verify this hypothesis at cellular, diabetes animal models and ChREBP knockout mice levels.