Leibowitz G, Yuli M, Donath M Y, Nesher R, Melloul D, Cerasi E, Gross D J, Kaiser N
Department of Endocrinology and Metabolism, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
Diabetes. 2001 Feb;50 Suppl 1:S113-7. doi: 10.2337/diabetes.50.2007.s113.
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.
胰岛素分泌不足和相对高胰岛素原血症是2型糖尿病的特征性表现。沙鼠欧氏肥尾沙鼠似乎是人类该疾病的理想天然模型，因为它表现出因饮食诱导而患糖尿病的倾向增加，这与中度肥胖有关。该疾病的特征是最初出现高胰岛素血症，随后发展为低胰岛素血症，伴有胰腺胰岛素储备耗尽以及血液和胰岛中胰岛素前体分子比例增加。尽管在高血糖动物中发现胰岛素原翻译效率增加，但胰岛素mRNA水平并未升高，且随着疾病进展逐渐下降。高血糖的发展与β细胞增殖活性的短暂增加有关，与之相反的是β细胞死亡率的持续增加，最终导致胰岛结构破坏。在原代胰岛培养物中对体外实验进行了研究，以验证葡萄糖毒性在一定程度上导致这些体内变化的假说。在高葡萄糖浓度下培养的易患糖尿病的欧氏肥尾沙鼠的胰岛，其β细胞功能发生了变化，类似于在糖尿病动物中观察到的变化。这些变化包括胰岛素分泌不足、胰岛素含量减少、胰岛素前体分子比例增加、DNA片段化逐渐增加以及短暂的增殖反应。此外，体外短期将欧氏肥尾沙鼠的胰岛暴露于高葡萄糖环境中，胰岛素mRNA并未增加。有人提出，欧氏肥尾沙鼠的β细胞葡萄糖毒性是由于胰岛素原生物合成无法跟上慢性胰岛素分泌过多的步伐所致。胰岛素储备的耗尽可能与葡萄糖调节的胰岛素基因转录不足有关，这可能是由于成年欧氏肥尾沙鼠中胰腺十二指肠同源盒因子-1（PDX-1）表达缺陷所致。另一种葡萄糖毒性作用涉及高血糖的欧氏肥尾沙鼠中β细胞数量的减少，这是由于β细胞逐渐死亡而β细胞增殖率没有相应充分增加所致。
