Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor foxo1 in liver
Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor foxo1 in liver
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DOI：
10.1016/j.cmet.2007.08.006
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发表时间：
2007-09-01
期刊：
影响因子：
29
通讯作者：
Accili, Domenico
中科院分区：
文献类型：
--
作者：
Matsumoto, Michihiro;Pocai, Alessandro;Accili, Domenico
2型糖尿病的标志是肝脏葡萄糖产生过多。几种转录因子和辅激活因子调节培养细胞中的这一过程。但是基因消融实验对体内这一过程的生理介质几乎没有线索。我们发现，在小鼠肝脏中编码叉头蛋白Foxo1的基因的失活导致出生时葡萄糖水平降低40%，成年小鼠禁食48小时后葡萄糖水平降低30%。基因表达和葡萄糖钳夹研究表明，Foxo1消融损害空腹和cAMP诱导的糖原分解和新生血管生成。Pgcl α不能诱导Foxol缺陷肝细胞中的肝细胞生成，而cAMP反应显著减弱。相反，肝脏中的Foxol缺失减少了由胰岛素受体的广泛消融引起的过量葡萄糖产生，并防止胰岛素受体敲除小鼠中的新生儿糖尿病和脂肪肝。这些数据为cAMP和胰岛素调节肝脏葡萄糖产生提供了统一的机制。
The hallmark of type 2 diabetes is excessive hepatic glucose production. Several transcription factors and coactivators regulate this process in cultured cells. But gene ablation experiments have yielded few clues as to the physiologic mediators of this process in vivo. We show that inactivation of the gene encoding forkhead protein Foxo1 in mouse liver results in 40% reduction of glucose levels at birth and 30% reduction in adult mice after a 48 hr fast. Gene expression and glucose clamp studies demonstrate that Foxo1 ablation impairs fasting- and cAMP-induced glycogenolysis; and gluconeogenesis. Pgcl alpha is unable to induce gluconeogenesis in Foxol-deficient hepatocytes, while the cAMP response is significantly blunted. Conversely, Foxol deletion in liver curtails excessive glucose production caused by generalized ablation of insulin receptors and prevents neonatal diabetes and hepatosteatosis in insulin receptor knockout mice. The data provide a unifying mechanism for regulation of hepatic glucose production by cAMP and insulin.