β-cell glucotoxicity in the Psammomys obesus model of type 2 diabetes
β-cell glucotoxicity in the Psammomys obesus model of type 2 diabetes
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DOI：
10.2337/diabetes.50.2007.s113
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发表时间：
2001-02-01
期刊：
影响因子：
7.7
通讯作者：
Kaiser, N
中科院分区：
文献类型：
--
作者：
Leibowitz, G;Yuli, M;Kaiser, N
胰岛素分泌不足和相对高胰岛素原血症是2型糖尿病的特征。沙鼠Psammomys obesus似乎是一个理想的自然模型的人类疾病，因为它显示出增加的趋势，发展饮食诱导的糖尿病，这是与中度肥胖。该疾病的特征在于初始高胰岛素血症，进展为与耗尽的胰腺胰岛素储存和血液和胰岛中胰岛素前体分子比例增加相关的低胰岛素血症。尽管发现胰岛素原翻译效力在高血糖动物中增加，但胰岛素mRNA水平并未增加，并且随着疾病进展而逐渐降低。高血糖症的发展与β细胞增殖活性的短暂增加有关，而不是β细胞死亡率的长期增加，最终导致胰岛结构的破坏。在体外原代胰岛培养物中研究了葡萄糖毒性部分导致这些体内变化的假设。来自在高葡萄糖浓度下培养的糖尿病倾向的肥胖毕赤酵母的胰岛显示出与在糖尿病动物中观察到的那些相似的β细胞功能的变化。这些变化包括胰岛素分泌不足、胰岛素含量耗尽、胰岛素前体分子比例增加、DNA片段化进行性增加和短暂增殖反应。此外，短期暴露于体外高血糖的肥胖猪胰岛中胰岛素mRNA没有增加。提出肥胖毕赤酵母中的β-细胞葡萄糖毒性是由于胰岛素原生物合成不能跟上慢性胰岛素分泌过多的步伐而导致的。所导致的胰岛素储备的消耗可能与葡萄糖调节的胰岛素基因转录缺陷有关，可能是由于成年肥胖毕赤酵母中PDX-1（胰腺十二指肠同源框因子-1）表达缺陷。另一种葡萄糖毒性作用涉及高血糖肥胖毕赤酵母中β-细胞质量的损失，这是进行性β-细胞死亡的结果，而β-细胞增殖速率没有充分增加.
Deficient insulin secretion and relative hyperproinsulinemia are characteristic features of type 2 diabetes. The gerbil Psammomys obesus appears to be an ideal natural model of the human disease because it shows increased tendency to develop diet-induced diabetes, which is associated with moderate obesity. The disease is characterized by initial hyperinsulinemia, progressing to hypoinsulinemia associated with depleted pancreatic insulin stores and an increased proportion of insulin precursor molecules in the blood and islets. Although the proinsulin translational efficacy was found to be increased in hyperglycemic animals, insulin mRNA levels were not augmented and exhibited a gradual decrease with disease progression. The development of hyperglycemia was associated with a transient increase in beta -cell proliferative activity, as opposed to a prolonged increase in the rate of beta -cell death, culminating in disruption of islet architecture. The hypothesis that glucotoxicity is responsible in part for these in vivo changes was investigated in vitro in primary islet cultures. Islets from diabetes-prone P. obesus cultured at high glucose concentrations displayed changes in beta -cell function that mimic those observed in diabetic animals. These changes include deficient insulin secretion, depleted insulin content, an increased proportion of insulin precursor molecules, a progressive increase of DNA fragmentation, and a transient proliferative response. Furthermore, insulin mRNA was not increased by short-term exposure of P. obesus islets to elevated glucose in vitro. It is proposed that beta -cell glucotoxicity in P. obesus results from the inability of proinsulin biosynthesis to keep pace with chronic insulin hypersecretion, The resulting depletion of the insulin stores may be related to deficient glucose-regulated insulin gene transcription, possibly due to defective PDX-1 (pancreatic duodenal homeobox factor-1) expression in the adult P. obesus. An additional glucotoxic effect involves the loss of beta -cell mass in hyperglycemic P. obesus as a result of progressive beta -cell death without an adequate increase in the rate of beta -cell proliferation.