Serum- and glucocorticoid-inducible kinase 1 mediates salt sensitivity of glucose tolerance
Serum- and glucocorticoid-inducible kinase 1 mediates salt sensitivity of glucose tolerance
复制标题
DOI：
10.2337/db05-1038
复制
发表时间：
2006-07-01
期刊：
影响因子：
7.7
通讯作者：
Lang, Florian
中科院分区：
文献类型：
--
作者：
Boini, Krishna M.;Hennige, Anita M.;Lang, Florian
过量的食盐摄入会减少外周葡萄糖摄取，从而损害葡萄糖耐量。细胞葡萄糖摄取的刺激涉及依赖磷脂酰肌醇-3-激酶(PI-3K)的蛋白激酶B/Akt的激活。PI-3K下游的另一个蛋白是血清和糖皮质激素诱导的蛋白激酶(SGK)1，该蛋白受盐摄入量的影响而上调。为了探讨SGK1在盐依赖葡萄糖摄取中的作用，SGK1基因敲除小鼠(SGK1(-/-))和它们的野生型仔鼠(SGK1(+/+))被允许自由饮用自来水(对照组)或1%生理盐水(高盐)。Western blotting显示，高盐降低SGK1(+/+)小鼠骨骼肌和脂肪组织中SGK1蛋白的丰度，而脱氧皮质酮醋酸酯(DOCA；35 mg/kg体重)可增加SGK1蛋白丰度。给SGK1(+/+)小鼠腹腔注射葡萄糖(3g/kg体重)后，高盐组小鼠的血糖浓度(281+/-39 mg/dl)显著高于对照组(164+/-23 mg/dl)。DOCA对对照组SGK1(+/+)小鼠的[葡萄糖]p，max无明显影响，但显著降低高盐SGK1(+/+)小鼠的[血糖]p，max，这一作用可被螺内酯(50 mg/kg体重)逆转。[血糖]p，max在SGK1(-/-)小鼠对高盐不敏感，显著高于对照SGK1(+/+)小鼠。SGK1(-/-)小鼠骨骼肌和脂肪组织对2-脱氧-D[1，2H-3]葡萄糖的摄取显著低于SGK1(+/+)小鼠，高盐降低了SGK1(+/+)小鼠对2-脱氧-D[1，2H-3]葡萄糖的摄取。将有活性的(S422D)SGK1而不是无活性的(K127N)SGK导入HEK-293细胞，可刺激对根癌激素敏感的葡萄糖摄取。综上所述，高盐降低了依赖SGK1的细胞葡萄糖摄取。因此，SGK1参与了盐摄入量和葡萄糖耐量之间的联系。
Excess salt intake decreases peripheral glucose uptake, thus impairing glucose tolerance. Stimulation of cellular glucose uptake involves phosphatidylinositide-3-kinase (PI-3K)-dependent activation of protein kinase B/Akt. A further kinase downstream of PI-3K is serum- and glucocorticoid-inducible kinase (SGK)1, which is upregulated by mineralocorticoids and, thus, downregulated by salt intake. To explore the role of SGK1 in salt-dependent glucose uptake, SGK1 knockout mice (sgk1(-/-)) and their wild-type littermates (sgk1(+/+)) were allowed free access to either tap water (control) or 1% saline (high salt). According to Western blotting, high salt decreased and deoxycorticosterone acetate (DOCA; 35 mg/kg body wt) increased SGK1 protein abundance in skeletal muscle and fat tissue of sgk1(+/+) mice. Intraperitoneal injection of glucose (3 g/kg body wt) into sgk1(+/+) mice transiently increased plasma glucose concentration approaching significantly higher values ([glucose]p,max) in high salt (281 +/- 39 mg/dl) than in control (164 +/- 23 mg/dl) animals. DOCA did not significantly modify [glucose]p,max in control sgk1(+/+) mice but significantly decreased [glucose]p, max in high-salt sgk1(+/+) mice, an effect reversed by spironolactone (50 mg/kg body wt). [Glucose]p,max was in sgk1(-/-) mice insensitive to high salt and significantly higher than in control sgk1(+/+) mice. Uptake of 2-deoxy-D[1,2 H-3]glucose into skeletal muscle and fat tissue was significantly smaller in sgk1(-/-) mice than in sgk1(+/+) mice and decreased by high salt in sgk1(+/+) mice. Transfection of HEK-293 cells with active (S422D)SGK1, but not inactive (K127N)SGK, stimulated phloretin-sensitive glucose uptake. In conclusion, high salt decreases SGK1-dependent cellular glucose uptake. SGK1 thus participates in the link between salt intake and glucose tolerance.