Prevention of diabetes due to growth retardation

描述（由申请人提供）：流行病学研究表明，出生时生长迟缓的人中2型糖尿病的发病率增加。子宫内环境异常导致成年期糖尿病发生的机制尚不清楚。我们建立了一个由双侧子宫动脉结扎引起的啮齿动物胎儿生长迟缓模型，称为IUGR（宫内生长迟缓）。IUGR啮齿类动物发生糖尿病，其表型与2型糖尿病患者中观察到的表型相似：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细胞增殖减少和PDX表达早期减少相关的β细胞质量的进行性下降，PDX是一种胰腺同源框转录因子，其作为胰腺发育和β细胞分化的主要调节因子发挥作用。在新生儿期给予胰腺β细胞营养因子Exendin-4（Ex-4）完全防止了该模型中成人发病糖尿病的发展，表明在新生儿期暴露于Ex-4逆转了胎儿编程的不良后果。在IUGR大鼠中，Ex-4刺激β细胞增殖，将PDX表达恢复至正常水平，并防止β细胞质量下降。我们推测PDX-1转录的减少是β细胞新生和增殖受损的主要原因，这导致了IUGR大鼠β细胞质量的进行性损失和糖尿病的后续发展。此外，我们假设Ex-4预防糖尿病的发展主要是由于其使PDX-1表达正常化的能力。这些假设的实验检验详见以下具体目标：（2）确定Ex-4是否通过增强b细胞新生和增殖和/或减少细胞死亡来防止IUGR啮齿动物中β细胞质量的恶化，（3）确定Ex-4处理是否使IUGR PDX-1 LacZ报告小鼠中的PDX-1启动子活性正常化，和（4）确定Ex-4处理是否通过对B细胞的直接作用改善IUGR啮齿动物中的葡萄糖耐量。通过本文提出的研究可以实现这些目标，这对于为未来关于β细胞在糖尿病中的作用的假设发展和测试奠定基础至关重要。

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.