Shin Seungjin, Li Na, Kobayashi Naoya, Yoon Ji-Won, Jun Hee-Sook
Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North, Chicago, Illinois, USA.
Mol Ther. 2008 May;16(5):854-61. doi: 10.1038/mt.2008.22. Epub 2008 Mar 18.
Type 1 diabetes results from destruction of the majority of the pancreatic beta cells by beta cell-specific autoimmune responses; therefore, expansion of the beta-cell mass in vivo is a possible approach to its treatment. Betacellulin (BTC) is known to promote beta-cell growth and differentiation. We investigated whether transient, constitutive expression, and secretion of BTC would regenerate sufficient numbers of pancreatic beta cells to restore normoglycemia in diabetic animals. We constructed a recombinant adenoviral vector (rAd-BTC) containing the cytomegalovirus promoter/enhancer, beta-globin chimeric intron, and albumin leader sequence to facilitate secretion, followed by BTC (1-80) complementary DNA (cDNA) encoding mature BTC. A single intravenous (i.v.) administration of rAd-BTC resulted in complete remission of streptozotocin (STZ)-induced diabetes within 2 weeks in mice. The mice remained normoglycemic for >100 days; glucose tolerance tests showed kinetics similar to normal, nondiabetic mice. Pancreatic insulin content, beta-cell mass, and serum insulin levels in rAd-BTC-treated mice were significantly higher than in the controls. Treatment of autoimmune diabetic mice with rAd-BTC in combination with an immune suppressor resulted in remission of diabetes. We conclude that transient expression of BTC by rAd-BTC administration results in prolonged remission of diabetes in mice, by the regeneration of sufficient numbers of beta cells in the pancreas.
1型糖尿病是由β细胞特异性自身免疫反应破坏大多数胰腺β细胞所致；因此，在体内扩大β细胞量是一种可能的治疗方法。已知β细胞ulin（BTC）可促进β细胞生长和分化。我们研究了BTC的瞬时、组成型表达和分泌是否能使足够数量的胰腺β细胞再生，从而使糖尿病动物恢复正常血糖水平。我们构建了一种重组腺病毒载体（rAd-BTC），其包含巨细胞病毒启动子/增强子、β-珠蛋白嵌合内含子和白蛋白前导序列以促进分泌，随后是编码成熟BTC的BTC（1-80）互补DNA（cDNA）。单次静脉注射（i.v.）rAd-BTC可使小鼠在2周内完全缓解链脲佐菌素（STZ）诱导的糖尿病。这些小鼠血糖正常超过100天；葡萄糖耐量试验显示其动力学与正常非糖尿病小鼠相似。rAd-BTC治疗的小鼠胰腺胰岛素含量、β细胞量和血清胰岛素水平显著高于对照组。用rAd-BTC联合免疫抑制剂治疗自身免疫性糖尿病小鼠可使糖尿病缓解。我们得出结论，通过给予rAd-BTC瞬时表达BTC可使胰腺中足够数量的β细胞再生，从而使小鼠糖尿病长期缓解。
