Department of Chemical Biology, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya, 466-8555, Japan.
Sci Rep. 2022 Aug 26;12(1):14568. doi: 10.1038/s41598-022-18902-5.
Insulin secretion is regulated in multiple steps, and one of the main steps is in the endoplasmic reticulum (ER). Here, we show that UDP-glucose induces proinsulin ubiquitination by cereblon, and uridine binds and competes for proinsulin degradation and behaves as sustainable insulin secretagogue. Using insulin mutagenesis of neonatal diabetes variant-C43G and maturity-onset diabetes of the young 10 (MODY10) variant-R46Q, UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) protects cereblon-dependent proinsulin ubiquitination in the ER. Cereblon is a ligand-inducible E3 ubiquitin ligase, and we found that UDP-glucose is the first identified endogenous proinsulin protein degrader. Uridine-containing compounds, such as uridine, UMP, UTP, and UDP-galactose, inhibit cereblon-dependent proinsulin degradation and stimulate insulin secretion from 3 to 24 h after administration in β-cell lines as well as mice. This late and long-term insulin secretion stimulation is designated a day sustainable insulin secretion stimulation. Uridine-containing compounds are designated as proinsulin degradation regulators.
胰岛素分泌是在多个步骤中调节的，其中主要步骤之一是在内质网（ER）中。在这里，我们表明 UDP-葡萄糖通过 cereblon 诱导胰岛素原泛素化，尿苷结合并竞争胰岛素原降解，并作为可持续的胰岛素分泌激动剂。使用新生儿糖尿病变体-C43G 和年轻起病的 10 型糖尿病（MODY10）变体-R46Q 的胰岛素突变，UDP-葡萄糖：糖蛋白葡糖基转移酶 1（UGGT1）保护内质网中 cereblon 依赖性胰岛素原泛素化。Cereblon 是一种配体诱导型 E3 泛素连接酶，我们发现 UDP-葡萄糖是第一个被确定的内源性胰岛素原蛋白降解剂。含有尿苷的化合物，如尿苷、UMP、UTP 和 UDP-半乳糖，可抑制 cereblon 依赖性胰岛素原降解，并在给药后 3 至 24 小时刺激β细胞系和小鼠中的胰岛素分泌。这种晚期和长期的胰岛素分泌刺激被指定为可持续 1 天的胰岛素分泌刺激。含有尿苷的化合物被指定为胰岛素原降解调节剂。
