Madsen K L, Ariano D, Fedorak R N
Department of Medicine, University of Alberta, Edmonton, Canada.
Diabetologia. 1995 Apr;38(4):403-12. doi: 10.1007/BF00410277.
The effect of oral vanadate on intestinal sodium-dependent glucose transport and 6-phosphofructo-1-kinase (EC 2.7.1.11) activity was examined in male Sprague-Dawley rats following a 30-day period of non-treated streptozotocin-induced diabetes. Non-treated diabetic rats were hyperglycaemic and demonstrated increased intestinal sodium-dependent glucose transport and Na,K-ATPase activity compared with controls. These increases were associated with a significant decrease in the total activity and activity ratios (activity at 0.5 mmol/l fructose 6-phosphate at pH 7.0/activity at pH 8.0) of intestinal 6-phosphofructo-1-kinase and decreased levels of fructose 2,6-bisphosphate. Supplementation of drinking water with vanadate (0.5 mg/ml) resulted in a rapid decline in blood glucose levels to a slightly hyperglycaemic level. Jejunal glucose transport and Na,K-ATPase activity were normalized after 48 h of vanadate treatment. In contrast, ileal glucose transport was significantly reduced 12 h following beginning vanadate treatment even though Na,K-ATPase activity did not normalize until 36 h later. Km was significantly decreased in both jejunum and ileum by vanadate treatment indicating an increased affinity of the sodium-dependent intestinal glucose transporter for glucose. 6-phosphofructo-1-kinase total activity and susceptibility to ATP inhibition was completely restored after 12 h of vanadate treatment. This increase was associated with a rise in fructose 2,6-bisphosphate levels. Fasting rats for 12 h had no effect on glucose transport or 6-phosphofructo-1-kinase activity, indicating the anorectic effect of vanadate was not responsible for changes in either parameter. In contrast, cycloheximide prevented both the rise in 6-phosphofructo-1-kinase activity and the rise in fructose 2,6-bisphosphate levels, and the subsequent reduction in glucose transport, indicating a requirement for protein synthesis. The removal of vanadate resulted in an immediate return to pre-treatment blood glucose levels. In contrast, intestinal glucose transport and 6-phosphofructo-1-kinase activity remained at treatment levels up until 72 h, indicating that oral vanadate treatment can have prolonged beneficial effects on intestinal function. In conclusion, the treatment of streptozotocin-induced diabetic rats with oral vanadate results in an activation of 6-phosphofructo-1-kinase coupled with a normalization of intestinal sodium-dependent glucose transport. Vanadate may thus have a beneficial effect on intestinal function and may prove useful as oral adjunctive diabetic therapy.
在雄性斯普拉格 - 道利大鼠中，研究了口服钒酸盐对经30天未治疗的链脲佐菌素诱导糖尿病后的肠道钠依赖性葡萄糖转运及6 - 磷酸果糖 -1-激酶（EC 2.7.1.11）活性的影响。未治疗的糖尿病大鼠血糖过高，与对照组相比，其肠道钠依赖性葡萄糖转运及钠钾 - ATP酶活性增加。这些增加与肠道6 - 磷酸果糖 -1-激酶的总活性及活性比率（pH 7.0时0.5 mmol/l 6 - 磷酸果糖的活性/pH 8.0时的活性）显著降低以及2,6 - 二磷酸果糖水平降低有关。饮用水中补充钒酸盐（0.5 mg/ml）导致血糖水平迅速下降至轻度血糖过高水平。钒酸盐治疗48小时后空肠葡萄糖转运及钠钾 - ATP酶活性恢复正常。相比之下，钒酸盐治疗开始12小时后回肠葡萄糖转运显著降低，尽管钠钾 - ATP酶活性直到36小时后才恢复正常。钒酸盐治疗使空肠和回肠的Km均显著降低，表明钠依赖性肠道葡萄糖转运体对葡萄糖的亲和力增加。钒酸盐治疗12小时后，6 - 磷酸果糖 -1-激酶的总活性及对ATP抑制的敏感性完全恢复。这种增加与2,6 - 二磷酸果糖水平升高有关。禁食大鼠12小时对葡萄糖转运或6 - 磷酸果糖 -1-激酶活性无影响，表明钒酸盐的食欲抑制作用并非导致这两个参数变化的原因。相比之下，放线菌酮阻止了6 - 磷酸果糖 -1-激酶活性及2,6 - 二磷酸果糖水平的升高以及随后的葡萄糖转运降低，表明需要蛋白质合成。去除钒酸盐导致血糖水平立即恢复到治疗前水平。相比之下，肠道葡萄糖转运及6 - 磷酸果糖 -1-激酶活性在72小时内一直维持在治疗水平，表明口服钒酸盐治疗对肠道功能可产生持久的有益影响。总之，用口服钒酸盐治疗链脲佐菌素诱导的糖尿病大鼠可导致6 - 磷酸果糖 -1-激酶激活，同时使肠道钠依赖性葡萄糖转运恢复正常。因此，钒酸盐可能对肠道功能有有益作用，可能被证明作为口服辅助糖尿病治疗有用。
