Opherk Christian, Tronche François, Kellendonk Christoph, Kohlmüller Dirk, Schulze Andreas, Schmid Wolfgang, Schütz Günther
Molecular Biology of the Cell I, Deutsches Krebsforschungszentrum, University Children's Hospital, Heidelberg, Germany.
Mol Endocrinol. 2004 Jun;18(6):1346-53. doi: 10.1210/me.2003-0283. Epub 2004 Mar 18.
Hepatic glucose production by gluconeogenesis is the main source of glucose during fasting and contributes significantly to hyperglycemia in diabetes mellitus. Accordingly, glucose metabolism is tightly controlled by a variety of hormones including insulin, epinephrine, glucagon, and glucocorticoids (GCs) acting on various cell types. GC effects are mediated by the GC receptor (GR), a ligand-dependent transcription factor, which in the liver and kidney controls gluconeogenesis by induction of gluconeogenic enzymes. To specifically study the contribution of GC on liver carbohydrate metabolism, we generated mice with an inactivation of the GR gene exclusively in hepatocytes using the Cre/loxP technology. Half of the mutant mice die within the first 2 d after birth most likely due to hypoglycemia. Adult mice have normal blood sugar under basal conditions but show hypoglycemia after prolonged starvation due to reduced expression of genes involved in gluconeogenesis. We further demonstrate that absence of GR in hepatocytes limits the development of hyperglycemia in streptozotocin-induced diabetes mellitus probably due to impaired induction of gluconeogenesis. These findings show the essential role of GR function in liver glucose metabolism during fasting and in diabetic mice and indicate that liver-specific GC antagonists could be beneficial in control of diabetic hyperglycemia.
通过糖异生作用产生的肝脏葡萄糖是禁食期间葡萄糖的主要来源，并且在糖尿病患者的高血糖症中起重要作用。因此，葡萄糖代谢受到多种激素的严格控制，这些激素包括作用于各种细胞类型的胰岛素、肾上腺素、胰高血糖素和糖皮质激素（GCs）。GC的作用由GC受体（GR）介导，GR是一种依赖配体的转录因子，在肝脏和肾脏中通过诱导糖异生酶来控制糖异生。为了专门研究GC对肝脏碳水化合物代谢的作用，我们使用Cre/loxP技术构建了仅在肝细胞中GR基因失活的小鼠。一半的突变小鼠在出生后的头2天内死亡，最可能的原因是低血糖。成年小鼠在基础条件下血糖正常，但在长期饥饿后会出现低血糖，这是由于参与糖异生的基因表达减少所致。我们进一步证明，肝细胞中GR的缺失可能由于糖异生诱导受损而限制了链脲佐菌素诱导的糖尿病中高血糖症的发展。这些发现表明GR功能在禁食期间以及糖尿病小鼠的肝脏葡萄糖代谢中起着至关重要的作用，并表明肝脏特异性GC拮抗剂可能有助于控制糖尿病性高血糖症。
