Inada Akari
Clinical Research Department, Institute of Biomedical Research and Innovation (IBRI), Foundation for Biomedical Research and Innovation at Kobe (FBRI), 6-3-7 Minatojima Minami-machi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.
Diabetol Int. 2024 Nov 28;16(1):23-29. doi: 10.1007/s13340-024-00774-x. eCollection 2025 Jan.
The prevalence of diabetes has increased rapidly in recent years, and many types of therapeutic agents have been developed. However, the main purpose of these drugs is to lower blood glucose levels, and they are not fundamental solutions. In contrast, our research has been aimed at stimulating and inducing β-cell proliferation in vivo and replenishing β-cells. We demonstrated that pancreatic ductal cells are a source of β-cells both after birth and during regeneration after partial duct ligation: cell lineage tracing showed that 39% of growing islets and 50% of adult islets during tissue regeneration contained β-cells differentiated from duct cells. We also examined the factors contributing to β-cell depletion. Insulin and cyclin A genes are tightly regulated by transcriptional activators and repressors, and we found that imbalanced and excessive levels of repressors result in a drastic reduction of insulin and β-cell numbers, leading to severe diabetes. Thus, we searched for factors that induce β-cell proliferation in vivo. In our transgenic (Tg) mice, there was a sex difference in the progression of diabetes and sex steroid hormones were shown to contribute to this. Surprisingly, in diabetic male Tg mice, modulation of sex steroid hormones under certain conditions resulted in a marked increase of β-cells. We identified Greb1 as a factor inducing β-cell proliferation in response to a rapid elevation of E2 levels. This series of studies has demonstrated that islet cells exhibit plasticity and indicates that changes of islet cell mass and function are dynamic and recoverable.
近年来，糖尿病的患病率迅速上升，并且已经开发出多种治疗药物。然而，这些药物的主要目的是降低血糖水平，并非根本解决方案。相比之下，我们的研究旨在刺激和诱导体内β细胞增殖并补充β细胞。我们证明，胰腺导管细胞在出生后以及部分导管结扎后的再生过程中都是β细胞的来源：细胞谱系追踪显示，在组织再生过程中，39%的生长中的胰岛和50%的成年胰岛含有从导管细胞分化而来的β细胞。我们还研究了导致β细胞耗竭的因素。胰岛素和细胞周期蛋白A基因受到转录激活因子和抑制因子的严格调控，我们发现抑制因子水平失衡和过高会导致胰岛素和β细胞数量急剧减少，进而引发严重糖尿病。因此，我们寻找在体内诱导β细胞增殖的因素。在我们的转基因（Tg）小鼠中，糖尿病的进展存在性别差异，并且显示性类固醇激素对此有影响。令人惊讶的是，在糖尿病雄性Tg小鼠中，在某些条件下调节性类固醇激素会导致β细胞显著增加。我们确定Greb1是一种响应E2水平快速升高而诱导β细胞增殖的因子。这一系列研究表明胰岛细胞具有可塑性，并表明胰岛细胞质量和功能的变化是动态且可恢复的。
