NEW MODELS FOR IDENTIFYING NIDDM POLYGENES

这项提议的目的是为新的 小鼠模型可能更准确地类似于糖尿病的发病机制 人类的非胰岛素依赖型糖尿病(NIDDM)。一只老鼠 NIDDM模型应该理想地结合两种遗传易感性 肥胖/胰岛素抵抗的发生具有先天缺陷 胰岛β细胞功能。Non/Lt株以及 NZO/H1株，表现为多基因肥胖。这两个菌株也都表现出 胰岛β细胞对葡萄糖反应的固有缺陷 挑战。非/轻小鼠仅进展为糖耐量受损， 而一些NZO/H1男性会出现高血糖。恩佐的异交 雌性对非雄性产生F1后代，这些后代都是逐渐发育的 肥胖，但只有F1男性会出现成熟期高血糖。不像 其他肥胖诱导的糖尿病小鼠模型，这些F1雄性是 以低胰岛素血症为特征，而不是高胰岛素血症。目标 通过F2分离分析确定 影响NIDDM易感基因的染色体区域。第二 目的是建立携带NZO/Lt的非/Lt小鼠的多基因群体 携带Nzo衍生易感基因的小鼠将偏离 非小鼠对显性NIDDM的糖耐量受损。这将允许 Niddm基因的精细定位，并检验β细胞 非亲本菌株和NZO亲本菌株的缺陷特征 共同表达会产生更严重的NIDDM综合征。决赛 目的是阐明男性的遗传和内分泌学基础。 在这一新的小鼠模型中，NIDDM综合征的性别受限性质。如果 控制β细胞缺陷的基因被识别出来，这个新的模型将 对于测试和设计更有效的药物很重要 用于恢复正常β细胞功能的试剂。

The aim of this proposal is to establish the genetic basis for a new mouse model that may more accurately resemble the etiopathogenesis of non-insulin dependent diabetes mellitus (NIDDM) in humans. A mouse model of NIDDM should ideally combine both a genetic predisposition to development of obesity/insulin resistance with an intrinsic defect in pancreatic beta cell function. Both the NON/Lt strain, as well as the NZO/H1 strain, exhibit polygenic obesity. Both strains also exhibit intrinsic defects in pancreatic beta cell responsiveness to glucose challenge. NON/Lt mice progress only to impaired glucose tolerance, whereas hyperglycemia develops in some NZO/H1 males. Outcrossing of NZO females to NON males produces F1 progeny which all progressively develop obesity, but only F1 males develop maturity-onset hyperglycemia. Unlike other murine obesity-induced diabetes models, these F1 males are characterized by hypoinsulinemia rather than hyperinsulinemia. The aims of this proposal are to identify by F2 segregation analysis the chromosomal regions contributing Niddm susceptibility genes. The second aim is to establish polycongenic stocks of NON/Lt mice carrying NZO/Lt mice carrying NZO-derived susceptibility genes that will deviate the impaired glucose tolerance of NON mice to overt NIDDM. This will allow fine mapping of the Niddm genes, and test the hypothesis that beta cell defects characteristic of both the NON and NZO parental strains codominantly express to produce a more severe NIDDM syndrome. The final aim is to elucidate the genetic and endocrinologic basis for the male sex-limited nature of the NIDDM syndrome in this new mouse model. If genes controlling beta cell defects are identified, this new model will be important for testing and design of more effective pharmacologic agents for restoration of normal beta cell functions.