Sustained prevention of myocardial and metabolic abnormalities in diabetic rats following withdrawal from oral vanadyl treatment.

Earlier studies revealed a general amelioration of diabetes-induced alterations in the rat following chronic oral vanadyl treatment. Recently, some streptozotocin-diabetic animals treated similarly were observed to remain euglycemic after withdrawal from vanadyl. In the present study, the diabetic profile of these animals (STZ-T) was investigated. After 3 weeks of treatment with vanadyl followed by 13 weeks of withdrawal, plasma concentrations of glucose, insulin, lipids, and thyroid hormones in the STZ-T animals were returned to control levels. Myocardial dysfunction and increased glycerol output from adipose tissue in untreated-diabetic (STZ) rats were also found to be normalized in the STZ-T group. Furthermore, there was no evidence of cataracts in these animals compared with age-matched STZ rats. These findings indicate that short-term oral treatment of diabetic rats with vanadyl induces beneficial changes that persist following withdrawal of the treatment. The results of these studies may suggest a possible new treatment protocol that could be incorporated into the management of diabetes.

Vanadyl sulphate differently influences insulin response to glucose in isolated pancreas of normal rats after in vivo or in vitro exposure.

The effect of the antidiabetic agent vanadyl sulphate (VOSO4) on the endocrine pancreas function of normal rats was studied using the isolated pancreas preparation. A short-term (8 days) i.p. treatment (15 mg/kg per day) resulted in attenuation of high glucose-stimulated insulin release, at day 9 but also at days 19, i.e., after full recovery of appetite and weight, while blood and pancreas vanadium concentrations were still elevated. Six months of oral VOSO4 treatment (0.75 mg/ml in drinking water) resulted in elevated vanadium concentrations while glucose-stimulated insulin release was attenuated as compared to pair-fed animals. Conversely, when directly perfused in pancreas, VOSO4 potentiated glucose-stimulated insulin release. These apparently opposite effects may be related to the ability of VOSO4 to exert both peripheral insulinomimetic effects-leading to chronic reduction in insulin demand-, and a direct pancreatic insulinotropic activity.

Diabetes-induced rat tracheal segment supersensitivity to carbachol.

Contractile responses to carbachol of tracheal segments isolated (i) from rats made diabetic 4 months prior by a single intravenous injection (50 mg/kg) of streptozotocin (group B), and (ii) from diabetic rats that had been treated during the same period with a daily dose (2-4 U/animal) of long-acting insulin (group C) were compared with the contractile responses of trachea isolated from age-matched control animals (group A). Tracheal segments from group B were significantly more responsive to carbachol than those from group A or C at low, but not at high carbachol concentrations. Carbachol pD2 values were higher in group B (6.85 +/- 0.05) than in groups A (6.46 +/- 0.07) or C (6.37 +/- 0.06), but were not significantly different between groups A and C. These data indicate that diabetes induces a supersensitivity to carbachol in airway smooth muscles, possibly related to a diabetes-induced vagal autonomic neuropathy.

Oral vanadyl sulfate in treatment of diabetes mellitus in rats.

Recent reports have suggested that vanadium in the form of vanadyl (+IV) possesses insulin-like activity. Therefore, in the present study we examined the effects of administering oral vanadyl to diabetic animals. Wistar rats made diabetic with streptozotocin and age-matched controls were maintained for 10 wk in the absence and presence of vanadyl sulfate trihydrate in the drinking water. In the presence of vanadyl, decreases in rate of growth and circulating levels of insulin were the only significant alterations recorded in control animals. In contrast, diabetic animals treated with vanadyl, despite having lower body weights and insulin levels, had normal plasma concentrations of glucose, lipid, creatinine, and thyroid hormone. In addition, abnormalities in isolated working heart function and glycerol output from adipose tissue of diabetic animals were also corrected after vanadyl treatment. These results suggest that vanadium when used in the vanadyl form is effective in diminishing the diabetic state in the rat by substituting for and replacing insulin or possibly by enhancing the effects of endogenous insulin.

Enhanced in vivo sensitivity of vanadyl-treated diabetic rats to insulin.

Vanadium has been reported to have insulin-like properties and has recently been demonstrated to be beneficial in the treatment of diabetic animals. In the present study, concentration dependence of the therapeutic effects of vanadium and the nature of interaction under in vivo conditions between vanadium and insulin were examined in streptozotocin-diabetic rats. During a 2-week period, blood glucose levels in all treated animals were decreased. At higher concentrations of vanadyl this decrease was greater and more rapid, and remained consistently lower for the entire treatment period. Daily intake of vanadyl, however, reached a similar steady state in all groups. Acute administration of submaximal doses of insulin, which had minimal effects in untreated diabetic rats, lowered blood glucose concentrations in vanadyl-treated and vanadyl-withdrawn animals to control levels. Chronic treatment of streptozotocin-diabetic rats with submaximal levels of vanadyl and insulin, ineffective alone, also produced significant decreases in blood glucose levels when used in combination. Finally, the insulin dosage required to maintain a nonglycosuric state in spontaneously diabetic (BB) rats was reduced in the presence of vanadyl. These studies indicate that chronic oral vanadyl treatment (a) produces a concentration-related lowering of blood glucose in diabetic rats, (b) potentiates the in vivo glucose lowering effects of acute and chronic administrations of insulin in streptozotocin-diabetic rats, and (c) substitutes for, or potentiates, the effects of chronic insulin therapy in spontaneously diabetic BB rats.

Impairment of contractility associated with muscarinic supersensitivity in trachea isolated from diabetic rats: lack of correlation with ultrastructural changes or quinuclidinyl benzylate binding to lung membranes.

Evolution of cholinergic response of rat isolated trachea was determined after various durations of diabetes (17, 40, 90, 150 and 210 days). Long-term diabetes was associated with both impairment of contractility and supersensitivity to cholinergic stimulation. However, the mechanism of these alterations remains to be determined, as response to field stimulation was not specifically altered while electron microscopy studies could not detect any significant change in the aspect of nerves, smooth muscle or epithelium. As well, binding studies of lung cholinergic receptors using the antagonist ligand [3H]-quinuclidinyl benzylate and the agonist carbachol did not detect any change in diabetic animals.

Toxicological aspects of vanadyl sulphate on diabetic rats: effects on vanadium levels and pancreatic B-cell morphology.

This study explored some toxicological aspects of vanadyl sulphate (VOSO4) treatment of rats made diabetic with a single intravenous injection of streptozotocin (60 mg/kg). Administered in drinking water (0.25, 0.5, 0.75 or 1 mg of VOSO4, 5H2O ml) VOSO4 treatment partially or totally corrected some of the alterations associated with the diabetic state (hyperglycaemia, polydipsia, polyphagia, high cholesterol and triglycerides levels) and did not produce any changes in various plasma or blood cell parameters which were not previously altered by diabetes. Measurement of vanadium levels indicated that tissues accumulated vanadium in the following order of concentrations: bone greater than kidney greater than spleen greater than liver greater than lung greater than or equal to muscle greater than blood. Histopathological studies did not reveal any difference in liver, stomach, ileum, spleen, heart and lung from control, non-treated diabetic or VOSO4-treated diabetic animals. Kidney of all non-treated diabetic animals showed an epithelial cellular swelling of distal tubules while only 2 of 6 VOSO4-treated diabetic animals showed this alteration. Cellular degeneration of pancreas B-cells was less marked in VOSO4-treated that in non-treated diabetic animals. The study indicates that VOSO4 may be a potential antidiabetic agent.