VANADATE TREATMENT RAPIDLY IMPROVES GLUCOSE-TRANSPORT AND ACTIVATES 6-PHOSPHOFRUCTO-1-KINASE IN DIABETIC RAT INTESTINE

The effect of oral vanadate on intestinal sodium-dependent glucose tra nsport and 6-phospho-fructo-1-kinase (EC 2.7.1.11) activity was examin ed in male Sprague-Dawley rats following a 30-day period of non-treate d streptozotocin-induced diabetes. Non-treated diabetic rats were hype rglycaemic and demonstrated increased intestinal sodium-dependent gluc ose transport and Na,K-ATPase activity compared with controls. These i ncreases were associated with a significant decrease in the total acti vity 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 a nd decreased levels of fructose 2,6-bisphosphate. Supplementation of d rinking water with vanadate (0.5 mg/ml) resulted in a rapid decline in blood glucose levels to a slightly hyperglycaemic level. Jejunal gluc ose transport and Na,K-ATPase activity were normalized after 48 h of v anadate treatment. In contrast, ileal glucose transport was significan tly reduced 12 h following beginning vanadate treatment even though Na ,K-ATPase activity did not normalize until 36 h later. K-m was signifi cantly decreased in both jejunum and ileum by vanadate treatment indic ating 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 12h of vanadate treatment. This increase was associated with a rise in fructo se 2,6-bisphosphate levels. Fasting rats for 12 h had no effect on glu cose transport or 6-phosphofructo-1-kinase activity, indicating the an orectic effect of vanadate was not responsible for changes in either p arameter. In contrast, cycloheximide prevented both the rise in 6-phos phofructo-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 contr ast, intestinal glucose transport and 6-phosphofructo-1-kinase activit y remained at treatment levels up until 72 h, indicating that oral van adate treatment can have prolonged beneficial effects on intestinal fu nction. In conclusion, the treatment of streptozotocin-induced diabeti c rats with oral vanadate results in an activation of 6-phosphofructo- 1-kinase coupled with a normalization of intestinal sodium-dependent g lucose transport. Vanadate may thus have a beneficial effect on intest inal function and may prove useful as oral adjunctive diabetic therapy .