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

通过诱导 β 细胞新生开发 1 型糖尿病再生疗法

• 批准号: 13671154
• 负责人: MIYAGAWA Jun-ichiro
• 金额: $ 2.24万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671154/
• 关键词: Diabetes mellitus; β cell; Regeneration; Differentiation; Betacellulin; Regeneration therapy; 1型糖尿病; 新生; HB-EGF; 膵β細胞

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

诱导β细胞新生，提高胰岛素缺乏型糖尿病内源性胰岛素分泌能力，将为糖尿病的治疗开辟新的途径。本研究探讨了成年糖尿病胰腺β细胞的新生或分化过程，并试图建立诱导或加速β细胞新生的方法，从而通过β细胞量的增加来改善个体的糖耐量。在导管结扎模型中，在结扎部分经常观察到导管的β细胞新生，我们检测了已知参与β细胞生长和/或分化过程的几种生长/分化因子，如IGF-1、TGF-β、β细胞素（BTC）、HB-EGF。此外，我们还检测到PDX-1、Pax 6、Islet 1和Nkx2.2等转录因子的诱导，表明它们与导管细胞向β细胞分化的过程密切相关， ...更多信息 我们还使用对照和糖尿病模型小鼠-包括NOD（非肥胖糖尿病）小鼠，检查了属于EGF致敏的生长因子的BTC和HB-EGF的体内作用，并且已经被认为是可能的β细胞分化因子。BTC和HB-EGF均显示出诱导导管细胞分化为β细胞的潜能，并显著增加新形成的胰岛样细胞簇（ICC），并显著改善对照小鼠中通过IPGTT（腹膜内葡萄糖耐量试验）评估的葡萄糖耐量。然而，尽管ICCs的出现，但四氧嘧啶和NOD小鼠部分灌注诱导的糖尿病小鼠的糖耐量没有观察到显著改善，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受不良。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新的再生疗法。少

项目成果

Yang Q., Yamagata K., Miyagawa J., Matsuzawa Y., et al.: "HNF-1α affects pancreatic β-cell growth by regulating IGF-1 expression in INS-1 cells"Diabetes. 51. 1785-1792 (2002)

Yang Q.、Yamagata K.、Miyakawa J.、Matsuzawa Y. 等人：“HNF-1α 通过调节 INS-1 细胞中的 IGF-1 表达影响胰腺 β 细胞生长”糖尿病。 2002）

Li M., Miyagawa J., Yamamoto K., Morikwaki M., Imagawa A., et al.: "β cell neogenesis from ducts and phenotypic conversion of the residual islet cells in the adult pancreas of glucose intolerant mice induced by selective alloxan perfusion"Endocrine J. 4-3

Li M.、Miyakawa J.、Yamamoto K.、Morikwaki M.、Imakawa A.等人：“选择性四氧嘧啶诱导的葡萄糖不耐症小鼠成年胰腺中的β细胞新生和残余胰岛细胞的表型转化灌注《内分泌杂志》4-3

Nammo T., Yamagata K, Miyagawa J, Matsuzawa Y., et al.: "Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas"Diabetologia. 45. 1142-1153 (2002)

Nammo T.、Yamagata K、Miyakawa J、Matsuzawa Y. 等人：“发育中小鼠胰腺中 MODY3/HNF-1α 蛋白的表达谱”Diabetologia。 45. 1142-1153 (2002)

Li M., Miyagawa J., Yamamoto K., Moriwaki M., Imagawa A., et al.: "β cell neogenesis from ducts and phenotypic conversion of the residual islet cells in the adult pancreas of glucose intolerant mice induced by selective alloxan perfusion"Endocrine J. 49・3

Li M.、Miyakawa J.、Yamamoto K.、Moriwaki M.、Imakawa A.等人：“选择性四氧嘧啶诱导的葡萄糖不耐症小鼠成年胰腺中的β细胞新生和残余胰岛细胞的表型转化灌注《内分泌杂志》49・3

Nammo T, Yamagata K, Miyagawa J, Matsuzawa Y. et al.: "Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas"Diabetologia. 45. 1142-1153 (2002)

Nammo T、Yamagata K、Miyakawa J、Matsuzawa Y. 等人：“MODY3/HNF-1α 蛋白在发育中的小鼠胰腺中的表达谱”Diabetologia。 45. 1142-1153 (2002)