Zhang Xuemei, Liang Wenbo, Mao Yiqing, Li Hui, Yang Yang, Tan Huanran
Department of Pharmacology, College of Medicine, Dalian University, Dalian 116622, PR China.
Biomed Pharmacother. 2009 Mar;63(3):180-6. doi: 10.1016/j.biopha.2007.07.006. Epub 2007 Aug 15.
Alloxan is a classical diabetogen which is used to achieve beta-cell destruction and type 1 diabetes due to its selective cytotoxic effect on pancreatic beta-cells. Although alloxan-induced diabetes is widely used in the laboratory to mimic diabetic pathology and for screening antidiabetic drugs, there has not been any comprehensive research in vivo on its diabetogenicity. In our study, alloxan-induced diabetic mice were generated by a single intravenous injection of alloxan (100 mg/kg). Our data show that these mice possess hyperglycemia, hypoinsulinism and morphological characteristics of impaired pancreas that are consistent with the accepted diabetogenic effects of alloxan. Alloxan is believed to confer its diabetogenic effect by inhibiting pancreatic glucokinase activity, leading to pancreatic beta-cell death. We examined the effects of alloxon on the other major site of glucokinase expression, the liver. Our results show that alloxan treatment led to an 81% reduction in glucokinase immunoreactivity and a greater than 90% reduction in glucokinase enzymatic activity in the liver, suggesting that alloxan's toxicity is not specific to the pancreas. Given the important role of glucokinase as a glucose sensor, and our findings on the effects of alloxon on liver glucokinase activity we propose that the effects on the liver are the primary contributor to pathogenesis in alloxan-induced diabetes. Alloxan-induced diabetes is thus a multifactor-promoted diabetes model which still could be used to examine the antidiabetic effects of compounds prompting insulin secretion and increasing liver-specific glucokinase activity. Despite alloxan-induced diabetes being inconsistent with the natural pathogenesis of human diabetes, further research on the causes of decreased glucokinase activity will help us to unravel the pathogenesis of diabetes and its complications.
四氧嘧啶是一种经典的致糖尿病物质，由于其对胰腺β细胞具有选择性细胞毒性作用，可导致β细胞破坏和1型糖尿病。尽管四氧嘧啶诱导的糖尿病在实验室中被广泛用于模拟糖尿病病理和筛选抗糖尿病药物，但尚未有关于其致糖尿病性的全面体内研究。在我们的研究中，通过单次静脉注射四氧嘧啶（100 mg/kg）制备了四氧嘧啶诱导的糖尿病小鼠。我们的数据表明，这些小鼠具有高血糖、低胰岛素血症以及胰腺受损的形态学特征，这与四氧嘧啶公认的致糖尿病作用一致。据信，四氧嘧啶通过抑制胰腺葡萄糖激酶活性发挥其致糖尿病作用，导致胰腺β细胞死亡。我们研究了四氧嘧啶对葡萄糖激酶表达的另一个主要部位——肝脏的影响。我们的结果表明，四氧嘧啶处理导致肝脏中葡萄糖激酶免疫反应性降低81%，葡萄糖激酶酶活性降低超过90%，这表明四氧嘧啶的毒性并非胰腺特异性的。鉴于葡萄糖激酶作为葡萄糖传感器的重要作用，以及我们关于四氧嘧啶对肝脏葡萄糖激酶活性影响的研究结果，我们提出对肝脏的影响是四氧嘧啶诱导糖尿病发病机制的主要因素。因此，四氧嘧啶诱导的糖尿病是一种多因素促进的糖尿病模型，仍可用于研究促使胰岛素分泌和增加肝脏特异性葡萄糖激酶活性的化合物的抗糖尿病作用。尽管四氧嘧啶诱导的糖尿病与人类糖尿病的自然发病机制不一致，但对葡萄糖激酶活性降低原因的进一步研究将有助于我们揭示糖尿病及其并发症的发病机制。
