Brüning J C, Winnay J, Bonner-Weir S, Taylor S I, Accili D, Kahn C R
Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Cell. 1997 Feb 21;88(4):561-72. doi: 10.1016/s0092-8674(00)81896-6.
NIDDM is a polygenic disease characterized by insulin resistance in muscle, fat, and liver, followed by a failure of pancreatic beta cells to adequately compensate for this resistance despite increased insulin secretion. Mice double heterozygous for null alleles in the insulin receptor and insulin receptor substrate-1 genes exhibit the expected approximately 50% reduction in expression of these two proteins, but a synergism at a level of insulin resistance with 5- to 50-fold elevated plasma insulin levels and comparable levels of beta cell hyperplasia. At 4-6 months of age, 40% of these double heterozygotes become overtly diabetic. This NIDDM mouse model in which diabetes arises in an age-dependent manner from the interaction between two genetically determined, subclinical defects in the insulin signaling cascade demonstrates the role of epistatic interactions in the pathogenesis of common diseases with non-Mendelian genetics.
非胰岛素依赖型糖尿病（NIDDM）是一种多基因疾病，其特征为肌肉、脂肪和肝脏出现胰岛素抵抗，随后尽管胰岛素分泌增加，但胰腺β细胞仍无法充分代偿这种抵抗。胰岛素受体和胰岛素受体底物-1基因无效等位基因的双杂合小鼠，这两种蛋白的表达预期会降低约50%，但在胰岛素抵抗水平上存在协同作用，血浆胰岛素水平升高5至50倍，β细胞增生水平相当。在4至6个月大时，这些双杂合子中有40%会明显患糖尿病。这种非胰岛素依赖型糖尿病小鼠模型中，糖尿病以年龄依赖性方式由胰岛素信号级联中两个基因决定的亚临床缺陷之间的相互作用引发，证明了上位性相互作用在具有非孟德尔遗传的常见疾病发病机制中的作用。
