Prevention of diabetes due to growth retardation

描述(由申请人提供)：流行病学研究表明，在出生时发育迟缓的人中，2型糖尿病的发病率增加。宫内环境异常导致成年后糖尿病的发生机制尚不清楚。我们建立了一种双侧子宫动脉结扎所致的啮齿动物胎儿生长迟缓模型，命名为IUGR(宫内生长迟缓)。IUGR啮齿动物发生糖尿病的表型与人类2型糖尿病患者相似：胰岛素分泌和胰岛素作用的进行性功能障碍。最重要的是，IUGR啮齿动物表现出与b细胞增殖减少相关的β细胞质量的进行性下降，以及早期PDX表达的减少，PDX是一种胰腺同源框转录因子，起着胰腺发育和β细胞分化的主要调节作用。在这个模型中，在新生儿期给予胰腺β细胞营养因子Exendin-4(Ex-4)完全可以防止成人发病糖尿病的发生，这表明在新生期接触Exendin-4可以逆转胎儿程序化的不良后果。在IUGR大鼠中，Ex-4刺激β细胞增殖，将PDX的表达恢复到正常水平，并阻止β细胞质量的下降。我们假设PDX-1转录减少是受损的β细胞新生和增殖的主要原因，从而导致IUGR大鼠β细胞质量的进行性丧失和随后的糖尿病发展。此外，我们假设Ex-4预防糖尿病的发展在很大程度上是因为它能够使PDX-1的表达正常化。这些假说的实验验证具体目的如下：(1)确定PDX-1表达减少导致IUGR动物β细胞质量进行性丧失；(2)确定Ex-4是否通过促进b细胞新生和增殖，和/或减少细胞死亡来防止IUGR啮齿动物β细胞质量的恶化；(3)确定Ex-4治疗是否使IUGR PDX-1 LacZ报告小鼠的PDX-1启动子活性正常化；以及(4)确定Ex-4治疗是否通过直接作用b细胞来改善IUGR啮齿动物的糖耐量。这些目标可以通过这里建议的研究来实现，对于为未来关于β细胞在糖尿病中的作用的假说开发和测试奠定基础是至关重要的。

DESCRIPTION (provided by applicant): Epidemiological studies show an increased incidence of type 2 diabetes in humans who were growth retarded at birth. The mechanisms by which an abnormal intrauterine milieu leads to the development of diabetes in adulthood are not known. We have developed a model of fetal growth retardation, designated as IUGR (intrauterine growth retarded), in the rodent, induced by bilateral uterine artery ligation. IUGR rodents develop diabetes with a phenotype similar to that observed in the human with type 2 diabetes: progressive dysfunction in insulin secretion and insulin action. Most importantly, IUGR rodents exhibit a progressive decline in beta-cell mass associated with decrease b-cell proliferation and an early reduction in expression of PDX, a pancreatic homeobox transcription factor that functions as a master regulator of pancreas development and beta-cell differentiation. Administration of a pancreatic beta-cell trophic factor, Exendin-4 (Ex-4), during the neonatal period completely prevents the development of adult-onset diabetes in this model, indicating that exposure to Ex-4 in the newborn period reverses the adverse consequences of fetal programming. In the IUGR rat, Ex-4 stimulates beta-cell proliferation, restores PDX expression to normal levels, and prevents the decline in beta-cell mass. We hypothesize that reduced PDX-1 transcription is the primary cause of impaired beta-cell neogenesis and proliferation, which leads to the progressive loss of beta-cell mass and the subsequence development of diabetes in IUGR rats. Further we hypothesize that Ex-4 prevents the development of diabetes largely due to its ability to normalize PDX-1 expression. Experimental testing of these hypotheses is detailed in the following Specific Aims: (1) Establish that reduced PDX-1 expression causes the progressive loss of beta-mass in IUGR animals, (2) Determine whether Ex-4 prevents the deterioration of beta-cell mass in IUGR rodents by enhancing b-cell neogenesis and proliferation, and/or decreasing cell death, (3) Determine whether Ex-4 treatment normalizes PDX-1 promoter activity in IUGR PDX-1 LacZ reporter mice, and (4) Determine whether Ex-4 treatment improves glucose tolerance in IUGR rodents through a direct action on the b cell. These aims, achievable through the studies proposed here, are critical in laying the groundwork for future hypothesis development and testing regarding the role of the beta-cell in diabetes.