Otani Kenichi, Kulkarni Rohit N, Baldwin Aaron C, Krutzfeldt Jan, Ueki Kohjiro, Stoffel Markus, Kahn C Ronald, Polonsky Kenneth S
Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8066, St. Louis, MO 63110, USA.
Am J Physiol Endocrinol Metab. 2004 Jan;286(1):E41-9. doi: 10.1152/ajpendo.00533.2001. Epub 2003 Sep 30.
Pancreatic beta-cell-restricted knockout of the insulin receptor results in hyperglycemia due to impaired insulin secretion, suggesting that this cell is an important target of insulin action. The present studies were undertaken in beta-cell insulin receptor knockout (betaIRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, approximately 7-mo-old betaIRKO mice were either diabetic (25%) or normally glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared with controls. Both groups also exhibited reduced beta-cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic betaIRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic betaIRKOs and to a lesser degree in the nondiabetic betaIRKO group. Pancreatic islets of nondiabetic betaIRKO animals also exhibited defects in glyceraldehyde- and KCl-stimulated insulin release that were milder than in the diabetic animals. Gene expression analysis of islets revealed a modest reduction of GLUT2 and glucokinase gene expression in both the nondiabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in beta-cells leads primarily to profound defects in postnatal beta-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.
胰腺β细胞特异性敲除胰岛素受体会因胰岛素分泌受损导致高血糖，这表明该细胞是胰岛素作用的重要靶点。本研究在β细胞胰岛素受体敲除（betaIRKO）小鼠中进行，以确定胰岛素分泌缺陷的潜在机制。根据对腹腔注射葡萄糖的反应，约7月龄的betaIRKO小鼠要么患有糖尿病（25%），要么糖耐量正常（75%）。与对照组相比，突变小鼠胰腺中的总胰岛素含量显著降低。两组小鼠的β细胞质量和胰岛数量也都减少。然而，与对照组相比，糖尿病和血糖正常的betaIRKO小鼠胰岛中的胰岛素mRNA和蛋白质水平相似。在糖尿病betaIRKO小鼠中，分离灌注胰腺对胰岛素促分泌剂的胰岛素分泌显著减少，在非糖尿病betaIRKO组中减少程度较小。非糖尿病betaIRKO动物的胰岛在甘油醛和氯化钾刺激的胰岛素释放方面也存在缺陷，但其程度比糖尿病动物轻。胰岛的基因表达分析显示，非糖尿病和糖尿病突变体中GLUT2和葡萄糖激酶基因表达均有适度降低。综上所述，这些数据表明β细胞中功能性胰岛素受体的缺失主要导致出生后β细胞生长的严重缺陷。此外，葡萄糖感知的改变也可能导致发生糖尿病的突变动物胰岛素分泌缺陷。
