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 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.
Madsen
K L
KL
Department of Medicine, University of Alberta, Edmonton, Canada.
Ariano
D
D
Fedorak
R N
RN
D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D007082:Ileum; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D007583:Jejunum; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D010732:Phosphofructokinase-1 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology*
D001786:Blood Glucose; D014638:Vanadates; D003513:Cycloheximide; D010732:Phosphofructokinase-1; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose