Department of Internal Medicine, University of Utah and VA Medical Center, Salt Lake City, UT, USA.
J Mol Med (Berl). 2013 Jan;91(1):59-67. doi: 10.1007/s00109-012-0961-5. Epub 2012 Sep 27.
In Chuvash polycythemia, a homozygous 598C>T mutation in the von Hippel-Lindau gene (VHL) leads to an R200W substitution in VHL protein, impaired degradation of α-subunits of hypoxia-inducible factor (HIF)-1 and HIF-2, and augmented hypoxic responses during normoxia. Chronic hypoxia of high altitude is associated with decreased serum glucose and insulin concentrations. Other investigators reported that HIF-1 promotes cellular glucose uptake by increased expression of GLUT1 and increased glycolysis by increased expression of enzymes such as PDK. On the other hand, inactivation of Vhl in murine liver leads to hypoglycemia associated with a HIF-2-related decrease in the expression of the gluconeogenic enzyme genes Pepck, G6pc, and Glut2. We therefore hypothesized that glucose concentrations are decreased in individuals with Chuvash polycythemia. We found that 88 Chuvash VHL ( R200W ) homozygotes had lower random glucose and glycosylated hemoglobin A1c levels than 52 Chuvash subjects with wild-type VHL alleles. Serum metabolomics revealed higher glycerol and citrate levels in the VHL ( R200W ) homozygotes. We expanded these observations in VHL ( R200W ) homozygote mice and found that they had lower fasting glucose values and lower glucose excursions than wild-type control mice but no change in fasting insulin concentrations. Hepatic expression of Glut2 and G6pc, but not Pdk2, was decreased, and skeletal muscle expression of Glut1, Pdk1, and Pdk4 was increased. These results suggest that both decreased hepatic gluconeogenesis and increased skeletal uptake and glycolysis contribute to the decreased glucose concentrations. Further study is needed to determine whether pharmacologically manipulating HIF expression might be beneficial for treatment of diabetic patients.
在楚瓦什氏红细胞增多症中，von Hippel-Lindau 基因 (VHL) 的纯合 598C>T 突变导致 VHL 蛋白中的 R200W 取代，从而损害缺氧诱导因子 (HIF)-1 和 HIF-2 的 α 亚基的降解，并在常氧条件下增强低氧反应。高海拔的慢性缺氧与血清葡萄糖和胰岛素浓度降低有关。其他研究人员报告称，HIF-1 通过增加 GLUT1 的表达促进细胞葡萄糖摄取，并通过增加 PDK 等酶的表达增加糖酵解。另一方面，在小鼠肝脏中失活 Vhl 会导致低血糖，这与 HIF-2 相关的糖异生酶基因 Pepck、G6pc 和 Glut2 的表达减少有关。因此，我们假设楚瓦什氏红细胞增多症患者的葡萄糖浓度降低。我们发现，88 名楚瓦什 VHL（R200W）纯合子的随机血糖和糖化血红蛋白 A1c 水平低于 52 名携带野生型 VHL 等位基因的楚瓦什个体。血清代谢组学显示 VHL（R200W）纯合子的甘油和柠檬酸水平更高。我们在 VHL（R200W）纯合子小鼠中扩展了这些观察结果，发现它们的空腹血糖值较低，血糖波动低于野生型对照小鼠，但空腹胰岛素浓度没有变化。Glut2 和 G6pc 的肝表达减少，而 Pdk2 的肝表达没有变化，但 Glut1、Pdk1 和 Pdk4 的骨骼肌表达增加。这些结果表明，肝糖异生减少和骨骼肌摄取及糖酵解增加均有助于降低葡萄糖浓度。需要进一步研究以确定是否通过药理学手段操纵 HIF 表达可能有益于治疗糖尿病患者。
