Delaunay F, Khan A, Cintra A, Davani B, Ling Z C, Andersson A, Ostenson C G, Gustafsson J, Efendic S, Okret S
Department of Medical Nutrition, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden.
J Clin Invest. 1997 Oct 15;100(8):2094-8. doi: 10.1172/JCI119743.
Abnormalities contributing to the pathogenesis of non-insulin-dependent diabetes mellitus include impaired beta cell function, peripheral insulin resistance, and increased hepatic glucose production. Glucocorticoids are diabetogenic hormones because they decrease glucose uptake and increase hepatic glucose production. In addition, they may directly inhibit insulin release. To evaluate that possible role of glucocorticoids in beta cell function independent of their other effects, transgenic mice with an increased glucocorticoid sensitivity restricted to their beta cells were generated by overexpressing the glucocorticoid receptor (GR) under the control of the insulin promoter. Intravenous glucose tolerance tests showed that the GR transgenic mice had normal fasting and postabsorptive blood glucose levels but exhibited a reduced glucose tolerance compared with their control littermates. Measurement of plasma insulin levels 5 min after intravenous glucose load demonstrated a dramatic decrease in acute insulin response in the GR transgenic mice. These results show that glucocorticoids directly inhibit insulin release in vivo and identify the pancreatic beta cell as an important target for the diabetogenic action of glucocorticoids.
导致非胰岛素依赖型糖尿病发病机制的异常情况包括β细胞功能受损、外周胰岛素抵抗以及肝脏葡萄糖生成增加。糖皮质激素是致糖尿病激素，因为它们会减少葡萄糖摄取并增加肝脏葡萄糖生成。此外，它们可能直接抑制胰岛素释放。为了评估糖皮质激素在不依赖其其他作用的情况下对β细胞功能的潜在作用，通过在胰岛素启动子的控制下过表达糖皮质激素受体（GR），培育出了仅β细胞对糖皮质激素敏感性增加的转基因小鼠。静脉葡萄糖耐量试验表明，GR转基因小鼠空腹和吸收后血糖水平正常，但与同窝对照小鼠相比，其葡萄糖耐量降低。静脉注射葡萄糖负荷5分钟后血浆胰岛素水平的测量显示，GR转基因小鼠的急性胰岛素反应显著降低。这些结果表明，糖皮质激素在体内直接抑制胰岛素释放，并确定胰腺β细胞是糖皮质激素致糖尿病作用的重要靶点。
