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.
Department of Surgery, Okayama University Graduate School of Medicine and Dentistry Shikata-cho, Okayama, Japan.
Mol Ther. 2008 May;16(5):854-861. doi: 10.1038/mt.2008.22. Epub 2016 Dec 8.
Type 1 diabetes results from destruction of the majority of the pancreatic β cells by β cell-specific autoimmune responses; therefore, expansion of the β-cell mass in vivo Is a possible approach to its treatment. Betacellulin (BTC) is known to promote β-cell growth and differentiation. We investigated whether transient, constitutive expression, and secretion of BTC would regenerate sufficient numbers of pancreatic β cells to restore normoglycemia in diabetic animals. We constructed a recombinant adenoviral vector (rAd-BTC) containing the cytomegalovirus promoter/enhancer, β-globin chimeric intron, and albumin leader sequence to facilitate secretion, followed by BTC (1-80) complementary DNA (cDNA) encoding mature BTC. A single intravenous (IV) 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, β-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 β 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（IV）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。这些小鼠在超过100天内保持正常血糖水平；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可通过胰腺中足够数量的β细胞再生使小鼠糖尿病长期缓解。
