Chapter 28
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Vanadium Salts in the Treatment of Human Diabetes Mellitus 1
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A. B. Goldfine , G. Willsky , and C. R. Kahn
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Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215 State University of New York, Buffalo, NY 14214 2
Oral insulinmimetic properties and safety of sodium metavanadate (NaVO ) in human IDDM and NIDDM, and vanadyl sulfate (VOSO ) in NIDDM are reviewed and new studies are presented. In a single blind placebo lead in trial with VOSO , glucose metabolism in a two-step euglycemic insulin clamp did not increase in any of three subjects (age 57.7±0.9 yrs; M/F1/2;BMI 39±10 kg/m ; HbA1 10.7±1.3%) after 6 weeks vanadyl therapy dosed at 25 mg V daily. However, insulin sensitivity improved in 3 of 5 subjects (age 56.2±6.0 yrs; M/F 5/0; BMI 31.9±5.4 kg/m ; HbA1 10.7±2.1%) when dosed at 50 mg V daily, from 30-83% and 9-230% at 0.5 and 1.0 mU/kg insulin, respectively; and insulin sensitivity improved in 3 of 5 subjects (age 52.0±8.6 yrs; M/F 3/2; BMI 39.0±7.8 kg/m ; HbA1 6.9±1.0%) when dosed at 100 mg V daily, from 47-775% and 16-75% at 0.5 and 1.0 mU/kg insulin, respectively. Basal hepatic glucose production (HGP) and suppression of HGP by insulin were unchanged at both doses. There was no change in fasting blood glucose, glycohemoglobin, or mean systolic, diastolic, mean arterial blood pressures or in mean heart rates on 24 hr ambulatory monitors. Peak serum V levels for the 25 and 50 mg V dose were 15.7±3.7 and 79.1±24.0 ng/ml, respectively. 50 and 100 mg V doses caused some gastrointestinal intolerance, without biochemical evidence of toxicity. V is well tolerated for six weeks, but at these doses do not dramatically improve insulin sensitivity or glycemic control in all individuals. 3
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In the late 1800' s vanadium was proposed to have medicinal value and to be of benefit in nutrition, diabetes, atherosclerosis, anemia, metabolism of lipids, prevention of dental caries, and treatment of infection, especially tuberculosis and syphilis . Since 1980, 1,2
©1998 American Chemical Society In Vanadium Compounds; Tracey, Alan S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
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354 considerable evidence has accumulated to show that vanadium salts, specifically tetravalent vanadyl, usually found as the divalent cation V 0 , and pentavalent vanadate, V0 ", will mimic insulin action in a number of isolated cell systems and produce dramatic glucose lowering effects when given orally to animal models of both Types I and II diabetes mellitus . In the STZ-diabetic rodent, glucose lowering effects are dramatic and occur within the first 2-4 days after oral administration. In 1995, human clinical trials evaluating the safety and efficacy of vanadium salts in the treatment of diabetes mellitus were first reported . These studies administered the vanadium over a 2-3 week interval of time, about 4-7 times the duration required to see an effect in the STZ-diabetic rodent model. 2 +
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Noninsulin Dependent Diabetes Mellitus In an open label study of four weeks including a one week baseline period, two weeks of treatment with sodium metavanadate, and a one week post-treatment period, 5 subjects with N I D D M (age 52 ± 3 yrs, BMI 28.7 ± 1.7 kg/m , H b A l c 10.9 ± 2.0%) were studied before and after oral sodium metavanadate (NaV0 ) 125 mg/day (-50 mg elemental V ) . As a primary end-point of short term therapy, insulin sensitivity was measured using two-step euglycemic, hyperinsulinemic clamps at 0.5 mU insulin/kg/min and 1.0 mU insulin/kg/min , and improved in all NIDDM subjects with therapy; glucose disposal increased by 29% at the 0.5 mU insulin dose (1.7 ± 0.4 vs 2.2 ± 0.3 mg/kg/min) and by 39% at the 1.0 mU insulin dose (4.1 ± 1.0 vs 5.7 ± 1.3 mg/kg/min) (combined p=0.03) (Figure 1). In this study, patients were studied after blood glucose was normalized by administration of a low-dose insulin infusion overnight prior to the clamp. In contrast to the effect on peripheral glucose utilization, vanadate had no effect on basal or insulin suppression of hepatic glucose production (HGP). These data suggest that the improvement in glucose utilization was due to enhanced insulin sensitivity in peripheral tissues (i.e. muscle) without a change in hepatic insulin sensitivity. The clamp studies were performed with continuous indirect calorimetry to assess oxidative versus non-oxidative glucose disposal at baseline and during the last 60 min of each step of the clamp. Basal oxidative and non-oxidative glucose disposal were similar before and after treatment. The improved insulin sensitivity during vanadate therapy appeared to be accounted for by increased non-oxidative glucose disposal (1.6 ± 1.0 2.9 ± 0.8 mg/kg/min, at the higher insulin dose; ρ < 0.03), with no change in oxidative glucose utilization. There was no apparent correlation between the serum vanadium level achieved and the change in insulin sensitivity. To assess the effects of vanadate on insulin secretion in subjects with N I D D M not requiring insulin, hyperglycemic clamps were performed before and at the end of treatment. There was no change in basal, first or second phase insulin or c-peptide secretion. Despite improved insulin sensitivity by euglycemic clamp studies, no clinical evidence for improvement in glycemia could be measured. There was no change in the dose of the oral hypoglycemic agent in any NIDDM subject. Fructosamine decreased slightly during the baseline week, but no further drop was seen after two weeks on 2
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In Vanadium Compounds; Tracey, Alan S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
355 vanadate. No significant changes in average blood glucose or weight were demon strated. In view of the short duration of the study, it was not surprising that there was no significant change in glycohemoglobin (10.9 ± 2.0 vs 10.2 ± 1.1%). Serum cholesterol decreased (267.6 ± 29.0 vs 204.2 ± 17.9, ρ < 0.05), without significant change in apolipoprotein A - l and apolipoprotein Β levels. These results are comparable to those seen by Cohen et. al. , who evaluated six N I D D M subjects (age 50 ± 4 yrs, B M I 27.3 ± 2.2 kg/m , H b A l c 9.6 ± 0.6%) on either diet or sulfonylurea therapy at end of three treatment periods [2 weeks placebo; 3 weeks VS (50 mg orally bid) (-33 mg elemental V); 2 weeks placebo] and demonstrated increased glucose infusion rates to maintain euglycemia during hyperinsulinemic clamps, (by -88%, 1.80 to 3.38 mg/kg/min, p
