Acute and chronic response to vanadium
following two methods of streptozotocin-diabetes
induction.
Can J Physiol Pharmacol (CANADA) Feb 1997, 75 (2) p83-90
Controversial reports on the efficacy and possible toxicity of
vanadium obtained from various studies may be attributed to
differences in the method of diabetes induction and (or) to
differences in animal strains. The objective of this study was to
evaluate the contribution of these two factors to the effects of
vanadium in the treatment of experimental diabetes. Two methods
of streptozotocin induction of diabetes in rats have been used
for studying the antidiabetic effects of vanadium. One involves a
single intravenous injection of 60 mg/kg streptozotocin, and the
other uses two subcutaneous injections of 40 mg/kg
streptozotocin, to either Wistar or Sprague-Dawley rats. In a
7-week chronic study, Sprague-Dawley rats appeared to develop a
more severe diabetes (indicated by higher plasma cholesterol and
higher fasting plasma glucose levels) following the single
intravenous injection of streptozotocin than rats made diabetic
by two subcutaneous injections of streptozotocin. Irrespective of
the method of diabetes induction, the responses of all the
diabetic animals to chronic vanadyl sulphate treatment were
similar. In an acute study, Wistar diabetic rats were more
responsive than Sprague-Dawley diabetic rats to vanadyl sulphate
and to lower doses (0.6 and 0.8 mmol/kg) of a new organic
vanadium compound, bis(maltolato)oxovanadium(i.v.).
Effects of vanadyl sulfate on
carbohydrate and lipid metabolism in patients with
non-insulin-dependent diabetes mellitus.
Metabolism (UNITED STATES) Sep 1996, 45 (9) p1130-5
The safety and efficacy of vanadyl sulfate (VS) was tested in
a single-blind, placebo-controlled study. Eight patients (four
men and four women) with non-insulin-dependent diabetes mellitus
(NIDDM) received VS (50 mg twice daily orally) for 4 weeks. Six
of these patients (four men and two women) continued in the study
and were given a placebo for an additional 4 weeks.
Euglycemic-hyperinsulinemic clamps were performed before and
after the VS and placebo phases. VS was associated with
gastrointestinal side effects in six of eight patients during the
first week, but was well tolerated after that. VS administration
was associated with a 20% decrease in fasting glucose
concentration (from 9.3 +/- 1.8 to 7.4 +/- 1.4 mmol/L, P <
.05) and a decrease in hepatic glucose output (HGO) during
hyperinsulinemia (from 5.0 +/- 1.0 pre-VS to 3.1 +/- 0.9
micromol/kg x min post-VS, P < .02). The improvement in
fasting plasma glucose and HGO that occurred during VS treatment
was maintained during the placebo phase. VS had no significant
effects on rates of total-body glucose uptake, glycogen
synthesis, glycolysis, carbohydrate (CHO) oxidation, or lipolysis
during euglycemic-hyperinsulinemic clamps. We conclude that VS at
the dose used was well tolerated and resulted in modest
reductions of fasting plasma glucose and hepatic insulin
resistance. However, the safety of larger doses and use of
vanadium salts for longer periods remains uncertain.
Oral vanadyl sulfate improves insulin
sensitivity in NIDDM but not in obese nondiabetic
subjects.
Diabetes (UNITED STATES) May 1996, 45 (5) p659-66
We compared the effects of oral vanadyl sulfate (100 mg/day)
in moderately obese NIDDM and nondiabetic subjects. Three-hour
euglycemic-hyperinsulinemic (insulin infusion 30 mU / m / min)
clamps were performed after 2 weeks of placebo and 3 weeks of
vanadyl sulfate treatment in six nondiabetic control subjects
(age 37 +/- 3 years; BMI 29.5 +/- 2.4 kg/m2 ) and seven NIDDM
subjects (age 53 +/- 2 years; BMI 28.7 +/-1.8 kg/m2). Glucose
turnover ([3-3 H]glucose), glycolysis from plasma glucose,
glycogen synthesis, and whole-body carbohydrate and lipid
oxidation were evaluated. Decreases in fasting plasma glucose (by
approximately 1.7 mmol/l) and HbAlc (both P < 0.05) were
observed in NIDDM subjects during treatment; plasma glucose was
unchanged in control subjects. In the latter, the glucose
infusion rate (GIR) required to maintain euglycemia (40.1 +/- 5.7
and 38.1 +/- 4.8 micromol / kg fat-free mass FFM / min) and
glucose disposal (Rd) (41.7 +/- 5.7 and 38.9 +/-4.7 micromol / kg
FFM / min were similar during placebo and vanadyl sulfate
administration, respectively. Hepatic glucose output (HGO) was
completely suppressed in both studies. In contrast, in NIDDM
subjects, vanadyl sulfate increased GIR approximately 82% (17.3
+/- 4.7 to 30.9 +/- 2.7 micromol / kg FFM / min, P < 0.05);
this improvement in insulin sensitivity was due to both augmented
stimulation of Rd (26.0 +/-4.0 vs. 33.6 +/- 2.22 micromol / kg
FFM / min, P < 0.05) and enhanced suppression of HGO (7.7 +/-
3.1 vs. 1.3 +/- 0.9 micromol / kg FFM / min, P < 0.05).
Increased insulin-stimulated glycogen synthesis accounted for
>80% of the increased Rd with vanadyl sulfate (P < 0.005),
but plasma glucose flux via glycolysis was unchanged. In NIDDM
subjects, vanadyl sulfate was also associated with greater
suppression of plasma free fatty acids (FFAs) (P < 0.01) and
lipid oxidation (P < 0.05) during clamps. The reduction in HGO
and increase in Rd were both highly correlated with the decline
in plasma FFA concentrations during the clamp period (P <
0.001). In conclusion, small oral doses of vanadyl sulfate do not
alter insulin sensitivity in nondiabetic subjects, but it does
improve both hepatic and skeletal muscle insulin sensitivity in
NIDDM subjects in part by enhancing insulin's inhibitory effect
on lipolysis. These data suggest that vanadyl sulfate may improve
a defect in insulin signaling specific to NIDDM.
Oral vanadyl sulfate improves hepatic
and peripheral insulin sensitivity in patients with
non-insulin-dependent diabetes mellitus.
J Clin Invest (UNITED STATES) Jun 1995, 95 (6) p2501-9
We examined the in vivo metabolic effects of vanadyl sulfate
(VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six
NIDDM subjects treated with diet and/or sulfonylureas were
examined at the end of three consecutive periods: placebo for 2
wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic
hyperinsulinemic (30 mU/m2.min) clamps and oral glucose tolerance
tests were performed at the end of each study period. Glycemic
control at baseline was poor (fasting plasma glucose 210 +/- 19
mg/dl; HbA1c 9.6 +/- 0.6%) and improved after treatment (181 +/-
14 mg/dl [P < 0.05], 8.8 +/- 0.6%, [P < 0.002]); fasting
and post-glucose tolerance test plasma insulin concentrations
were unchanged. After VS, the glucose infusion rate during the
clamp was increased (by approximately 88%, from 1.80 to 3.38
mg/kg.min, P < 0.0001). This improvement was due to both
enhanced insulin-mediated stimulation of glucose uptake (rate of
glucose disposal [Rd], +0.89 mg/kg.min) and increased inhibition
of HGP (-0.74 mg/kg.min) (P < 0.0001 for both). Increased
insulin-stimulated glycogen synthesis (+0.74 mg/kg.min, P <
0.0003) accounted for > 80% of the increased Rd after VS, and
the improvement in insulin sensitivity was maintained after the
second placebo period. The Km of skeletal muscle glycogen
synthase was lowered by approximately 30% after VS treatment (P
< 0.05). These results indicate that 3 wk of treatment with VS
improves hepatic and peripheral insulin sensitivity in
insulin-resistant NIDDM humans. These effects were sustained for
up to 2 wk after discontinuation of VS.
Toxicity studies on one-year treatment
of non-diabetic and treptozotocin-diabetic rats with vanadyl
sulphate.
Pharmacol Toxicol (DENMARK) Nov 1994, 75 (5) p265-73
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.
Antidiabetic action of vanadyl in rats
independent of in vivo insulin-receptor kinase
activity.
Diabetes (UNITED STATES) Apr 1991, 40 (4) p492-8
The effects of oral vanadyl sulfate administration for 9-12
days on carbohydrate and lipid metabolism in the basal state and
on glucose dynamics during submaximal hyperinsulinemic clamps
were investigated in nondiabetic and streptozocin-induced
diabetic rats. Decreases in growth rate and water and food
consumption were the only significant alterations noted in
control animals receiving vanadyl. Administration of vanadyl to
diabetic rats resulted in weight loss; a significant decrease in
plasma glucose, triglyceride, and cholesterol levels; and
decreases in food and water intake, without a concomitant change
in plasma insulin concentrations. Vanadyl treatment did not
modify either peripheral glucose utilization or hepatic glucose
production in control rats during submaximal insulin clamps. In
contrast, vanadyl therapy increased insulin-induced glucose
utilization significantly and had a small but nonsignificant
effect on insulin-mediated suppression of glucose production in
diabetic rats. The tyrosine kinase activity of liver- and
muscle-derived insulin receptors from diabetic rats that
underwent clamp study, which reflected the in vivo
phosphorylation state of insulin receptor, was not altered by
vanadyl treatment. In conclusion, these results show that
augmentation of peripheral glucose utilization is the major
determinant of the antidiabetic action of vanadyl and support the
notion that the action of vanadyl is independent of
insulin-receptor kinase activity.
