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The in vivo glucose lowering effect of orally administered inorganic vanadium compounds in diabetes was first reported in our laboratory in 1985. While both vanadate and vanadyl forms of vanadium are orally active, they are still not well absorbed. We have synthesized several organic vanadium compounds and one compound, bis(maltolato)oxovanadium(lV) or BMOV, has been extensively investigated. BMOV proved effective in lowering plasma glucose and lipids in STZ-diabetic rats when administered in drinking water over a 25 week period. The maintenance dose (0.18 mmol/kg/day) was approximately 50% of that required for vanadyl sulfate (VS). Secondary complications of diabetes were prevented by BMOV and no marked toxicity was noted. Oral gavage of STZ-diabetic rats with BMOV also reduced blood glucose levels. The ED50 for BMOV was 0.5 mmol/kg, while for VS the estimated ED50 was 0.9 mmol/kg. BMOV was also effective by the intraperitoneal route in STZ-diabetic rats. The ED50 was 0.08 mmol/kg compared to 0.22 mmol/kg for VS. Some animals treated p.o. or i.p. remained euglycemic for up to 14 weeks. An i.v. infusion of BMOV of 0.05 mmol/kg over a 30 min period reduced plasma glucose levels by 50% while VS was not effective.

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The fatty Zucker rat, characterized by obesity, hyperinsulinemia, hyperlipidemia, and mild hyperglycemia, has been suggested as an animal model of non-insulin-dependent diabetes mellitus. The present study examined the chronic dose-dependent effect of bis(maltolato)oxovanadium(IV), a potent insulin mimetic, in this animal model of diabetes. Chronic (6 weeks) oral administration of bis(maltolato)oxovanadium(IV) (0.06 mmol.kg-1.day-1, low dose study) was effective in reducing the hyperinsulinemia associated with the fatty Zucker rat model (termination insulin: lean, 82.8 +/- 21.6; fatty, 732 +/- 89.4; fatty treated, 336 +/- 126.6 pmol/L; p < 0.05). Pancreatic perfusion data indicated a significant improvement in insulin secretory function in the fatty rats. The dose dependency of this relationship was observed in the high dose study (0.128 mmol.kg-1.day-1 for 14 weeks), wherein bis(maltolato)oxovanadium(IV) treatment restored plasma insulin levels in the fatty rats to lean levels (termination insulin: lean, 199.2 +/- 17.4; fatty 660.6 +/- 12.6; fatty treated, 153.6 +/- 9.6 pmol/L; p < 0.05) and significantly improved insulin response to a glucose challenge. In addition, bis(maltolato)oxovanadium(IV) treatment (high dose study) ameliorated the age-dependent increase in blood pressure observed in fatty Zucker rats (systolic blood pressure: lean, 127 +/- 10; fatty, 176 +/- 5; fatty treated, 156 +/- 9 mmHg (1 mmHg = 133.3 Pa)). These data indicate that chronic oral administration of bis(maltolato)oxovanadium(IV) in the drinking water was effective in reducing hyperinsulinemia, insulin resistance, glucose intolerance, and hypertension in the fatty Zucker rat.

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Streptozotocin-diabetic and non-diabetic rats were given vanadyl sulphate in drinking water at concentrations of 0.5-1.5 mg/ml for one year. It was found that vanadyl treatment did not produce persistent changes in plasma aspartate aminotransferase, alanine aminotransferase, and urea, specific morphological abnormalities in the brain, thymus, heart, lung, liver, spleen, pancreas, kidney, adrenal, or testis, or abnormal organ weight/body weight ratio for these organs in either non-diabetic or diabetic animals. Treatment significantly reduced the incidence of the occurrence of urinary stones in non-diabetic rats. In diabetic animals vanadyl treatment significantly reduced the mortality rate and prevented the elevation of plasma levels of alanine aminotransferase and urea, the increases in organ size, and the occurrence of megacolon but did not affect the development of renal and testicular tumours. Plasma and tissue concentrations of vanadium were determined and found to have the following order of distribution: bone > kidney > testis > liver > pancreas > plasma > brain. Vanadium was retained in these organs at 16 weeks following vanadyl withdrawal while the plasma levels were beneath detection limits. It is concluded that vanadyl sulphate at antidiabetic doses is not significantly toxic to rats following a one-year administration in drinking water, but vanadium may be retained in various organs for months after cessation of treatment.

Circulatory and haematological effects of chronic administration of vanadyl sulphate in drinking water for one year in non-diabetic and streptozotocin-diabetic rats were investigated. At various time points during the treatment period and at 13 weeks following its withdrawal, systolic blood pressure and pulse rate were measured using a tail-cuff method and some selected haematological indices, including haematocrit, haemoglobin, erythrocyte count, reticulocyte percentage, leukocyte count, platelet count, and leukocyte composition of the peripheral blood were determined using standard methods. It was found that prolonged treatment of either nondiabetic or streptozotocin-diabetic rats with vanadyl sulphate did not cause significant changes in the parameters observed but significantly alleviated the occurrence of bradycardia and the decreased leukocyte count in the peripheral blood in streptozotocin-diabetic animals. No significant changes in systolic blood pressure, pulse rate, or haematological indices were observed following the withdrawal of vanadyl sulphate, except that the previously vanadyl-treated diabetic rats were found to have higher leukocyte count, platelet count and neutrophil percentage, and lower lymphocyte percentage in their leukocyte composition. It is concluded that vanadyl sulphate does not have a hypertensive effect nor is it significantly toxic to the haemopoietic system in rats.

The effects of fructose loading on the integrated cardiovascular function in vivo, glycemic control, glucose tolerance, and plasma lipid levels in nondiabetic and streptozotocin (STZ) diabetic rats were investigated. Endothelial morphology of the thoracic aorta was also assessed with scanning electron microscopy. Fructose-loaded nondiabetic rats exhibited elevated blood pressure and pulse rate, and signs of arterial atherogenesis, such as focal adherence of leukocytes and fibrin to the endothelium. Intraperitoneal glucose tolerance tests revealed a greater increase in plasma insulin in response to glucose challenge in these animals than in the control. Compared with the untreated STZ-diabetic animals, fructose-loaded diabetic rats had significantly greater hyperglycemia, glucose intolerance, and hyperlipidemia and higher blood pressure, but had a similar degree of hypoinsulinemia, cardiac dysfunction, and cardiac enlargement. They also showed signs of early atherogenesis. The central venous pressure and the susceptibilities of the rats to the induction of ventricular arrhythmias by intravenous infusion of aconitine were not significantly affected by either STZ injection or fructose loading. It is concluded that prolonged intake of an excessive amount of fructose has detrimental effects on the cardiovascular system, glucose metabolism, and plasma lipid levels in both nondiabetic and STZ-diabetic rats.