Development of regeneration therapy for type 1 diabetes by induction of β cell neogenesis

诱导β细胞新生，提高胰岛素缺乏型糖尿病患者的内源性胰岛素分泌能力，将为糖尿病的再生治疗开辟新的治疗策略。本研究通过对成年糖尿病大鼠胰腺β细胞新生或分化过程的研究，试图建立诱导或加速β细胞新生的方法，从而通过增加β细胞质量来改善个体糖耐量。在β细胞结扎模型中，我们检测了几种已知参与β细胞生长和/或分化过程的生长/分化因子，如胰岛素样生长因子-1、转化生长因子-β、β-细胞生长因子、血红蛋白-表皮生长因子。此外，我们还检测到Pdx-1、Pax6、Islet 1和Nkx2.2等转录因子的诱导，提示它们与β细胞向导管细胞或…分化的过程密切相关。我们还检测了属于表皮生长因子肥胖生长因子的BTC和HB-EGF的体内效应，它们被认为是一种可能的β细胞分化因子，使用了对照组和糖尿病模型小鼠-包括NOD(非肥胖糖尿病)小鼠。BTC和HB-EGF均能诱导β细胞向导管细胞分化，显著增加新形成的胰岛样细胞团(ICCs)，并能显著改善对照组小鼠的糖耐量。然而，尽管有ICCs的出现，但部分灌流四氧嘧啶诱导的糖尿病小鼠和NOD小鼠的糖耐量并没有明显改善，这表明这些因素诱导的β细胞质量的增加不足以改善葡萄糖耐量。然而，这种诱导β细胞新生的方法可能为1型和/或胰岛素缺乏型糖尿病提供一种新的再生治疗方法。较少

Induction of β cell neogenesis which improve endogenous insulin secretory capacity in insulin-deficient type of diabetes will develop the new therapeutic strategy for diabetes as a regeneration therapy. In this research, we investigated the process of β cell neogenesis or differentiation in adult diabetic pancreas, and tried to develop the method for induction or acceleration of β cell neogenesis, thereby Individual glucose tolerance may be ameliorated by the increase of β cell mass.In the duct ligation model in which β cell neogenesis from ducts are frequently observed in the ligated portion, we detected several growth/differentiation factors such as IGF-1, TGF-β, betacellulin (BTC), HB-EGF that are known to be involved in the process of β cell growth and/or differentiation. In addition, we also detected induction of transcription factors including PDX-1, Pax6, Islet 1 and Nkx2.2, suggesting that they are closely associated with the process of β cell differentiation from duct cells or … More endocrine precursor cells in the duct lining.We also examined the in vivo effect of BTC and HB-EGF that belong to growth factor of EGF fatuity, and have been considered to be a possible β cell differentiation factor, using control and diabetic model mice-including NOD (non-obese diabetic) mice. Both BTC and HB-EGF showed a potency to induce β cell differentiation from duct cells and significantly increased newly formed Islet-like cell clusters (ICCs) , and significant improvement of glucose tolerance assessed by IPGTT (intra-peritoneal glucose tolerance test) in control mice. However, no significant improvement of glucose tolerance in diabetic mice induced by partial perfusion of alloxan and NOD mice were observed in spite of the appearance of ICCs, indicating that the increase of β cell mass induced by these factors was not enough to ameliorate glucose intolerance. Nevertheless, this approach to induce β cell neogenesis may provide a new regeneration therapy for type 1 and/or insulin-deficient type of diabetes mellitus. Less