Dr. Ron’s Research Review – February 20, 2019

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This week’s research review focuses on vanadium for diabetes.

Nutritionally, vanadium is thought to be a cofactor in various enzymatic reactions. Data from animal and human studies suggest vanadium mimics the action of insulin. Dietary sources for vanadium include mushrooms, shellfish, black pepper, parsley, dill seed, and grains. (2009)

A single-blind, placebo-controlled study included eight patients (four men and four women) with non-insulin-dependent diabetes mellitus (NIDDM) that received vanadyl sulfate (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. VS 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. ). (Boden et al., 1996)

Six non-insulin-dependent diabetes mellitus (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. 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]). 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. (Cohen et al., 1995)

11 type 2 diabetic patients were treated with VOSO(4) at a higher dose (150 mg/day) and for a longer period of time (6 weeks) than in previous studies. Treatment significantly improved glycemic control: fasting plasma glucose (FPG) decreased from 194 +/- 16 to 155 +/- 15 mg/dL, hemoglobin A(1c) decreased from 8.1 +/- 0.4 to 7.6 +/- 0.4%, and fructosamine decreased from 348 +/- 26 to 293 +/- 12 micromol/L (all P < 0.01) without any change in body weight. Vanadyl sulfate treatment lowered the plasma total cholesterol (223 +/- 14 vs. 202 +/- 16 mg/dL; P < 0.01) and low density lipoprotein cholesterol (141 +/- 14 vs. 129 +/- 14 mg/dL; P < 0.05). (Cusi et al., 2001)

A study compared 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 and seven NIDDM. Decreases in fasting plasma glucose (by approximately 1.7 mmol/l) and HbAlc (both P < 0.05) were observed in NIDDM subjects during treatment. Vanadyl sulfate did not alter insulin sensitivity in nondiabetic subjects, but it did 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. (Halberstam et al., 1996)

A randomized, double-blind, placebo-controlled clinical trial was carried out in 14 overweight/obese patients with IGT. Intervention consisted of vanadyl sulfate (VS, 50 mg p.o. twice daily) or placebo for 4 weeks. There were no significant differences in basal characteristics between groups. VS did not affect insulin sensitivity [2.7+/-0.8 vs. 2.9+/-0.9 mg/(kg/min), p=0.735] but increased triglyceride levels (1.35+/-0.61 vs. 1.70+/-0.46 mmol/l, p=0.018). (Jacques-Camarena et al., 2008)

Fourteen type 1 diabetic patients received oral vanadyl sulfate (50 - 100 mg TID) for a period of 30 months. Fasting blood sugar (FBS), lipid levels, hematologic, and biochemical parameters were measured before and periodically during the treatment. The daily doses of insulin decreased from 37.2 ± 5.5 to 25.8 ± 17.3 units/day and at the same time the mean fasting blood sugar (FBS) decreased from 238 ± 71 to 152 ± 42 mg/dL. Meanwhile, there was a decrease in plasma total cholesterol without any change in triglyceride level. Vanadium is effective and safe for long- term use in type 1 diabetic patients. (Soveid et al., 2013)

Dr. Ron


 

Articles

Vanadium (vanadyl sulfate). Monograph.
            (2009) Download
Nutritionally, vanadium is thought to be a cofactor in various enzymatic reactions. Data from animal and human studies suggest vanadium mimics the action of insulin.2 Consequently, it may serve a beneficial role in promot- ing healthy glucose metabolism in individuals with diabetes or dysglycemia. Dietary sources for vanadium include mushrooms, shellfish, black pepper, parsley, dill seed, and grains.

Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus.
            (Boden et al., 1996) Download
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 hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus.
            (Cohen et al., 1995) Download
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.

Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes.
            (Cusi et al., 2001) Download
Vanadyl sulfate (VOSO(4)) is an oxidative form of vanadium that in vitro and in animal models of diabetes has been shown to reduce hyperglycemia and insulin resistance. Small clinical studies of 2- to 4-week duration in type 2 diabetes (T2DM) have led to inconsistent results. To define its efficacy and mechanism of action, 11 type 2 diabetic patients were treated with VOSO(4) at a higher dose (150 mg/day) and for a longer period of time (6 weeks) than in previous studies. Before and after treatment we measured insulin secretion during an oral glucose tolerance test, and endogenous glucose production (EGP) and whole body insulin-mediated glucose disposal using the euglycemic insulin clamp technique combined [3-(3)H]glucose infusion. Treatment significantly improved glycemic control: fasting plasma glucose (FPG) decreased from 194 +/- 16 to 155 +/- 15 mg/dL, hemoglobin A(1c) decreased from 8.1 +/- 0.4 to 7.6 +/- 0.4%, and fructosamine decreased from 348 +/- 26 to 293 +/- 12 micromol/L (all P < 0.01) without any change in body weight. Diabetics had an increased rate of EGP compared with nondiabetic controls (4.1 +/- 0.2 vs. 2.7 +/- 0.2 mg/kg lean body mass.min; P< 0.001), which was closely correlated with FPG (r = 0.56; P< 0.006). Vanadyl sulfate reduced EGP by about 20% (P< 0.01), and the decline in EGP was correlated with the reduction in FPG (r = 0.60; P< 0.05). Vanadyl sulfate also caused a modest increase in insulin-mediated glucose disposal (from 4.3 +/- 0.4 to 5.1 +/- 0.6 mg/kg lean body mass x min; P< 0.03), although the improvement in insulin sensitivity did not correlate with the decline in FPG after treatment (r = -0.16; P = NS). Vanadyl sulfate treatment lowered the plasma total cholesterol (223 +/- 14 vs. 202 +/- 16 mg/dL; P < 0.01) and low density lipoprotein cholesterol (141 +/- 14 vs. 129 +/- 14 mg/dL; P < 0.05), whereas 24-h ambulatory blood pressure was unaltered. We conclude that VOSO(4) at maximal tolerated doses for 6 weeks improves hepatic and muscle insulin sensitivity in T2DM. The glucose-lowering effect of VOSO(4) correlated well with the reduction in EGP, but not with insulin-mediated glucose disposal, suggesting that liver, rather than muscle, is the primary target of VOSO(4) action at therapeutic doses in T2DM.

Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjects.
            (Halberstam et al., 1996) Download
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.


 

Effect of vanadium on insulin sensitivity in patients with impaired glucose tolerance.
            (Jacques-Camarena et al., 2008) Download
BACKGROUND/AIM:  Impaired glucose tolerance (IGT) is considered a risk factor for developing type 2 diabetes mellitus (T2DM) and is associated with insulin resistance. Vanadium seems to block protein tyrosine phosphatase with the consequent increment in insulin sensitivity (INS) in T2DM patients, but this effect has not been studied in IGT patients. The aim of this study was to evaluate the effect of vanadium on INS in IGT patients. METHODS:  A randomized, double-blind, placebo-controlled clinical trial was carried out in 14 overweight/obese patients with IGT. Intervention consisted of vanadyl sulfate (VS, 50 mg p.o. twice daily) or placebo for 4 weeks. Before and after the intervention, a metabolic profile was performed and INS was assessed using the euglycemic-hyperinsulinemic clamp technique. Mann-Whitney U and Wilcoxon rank tests were used for statistical analyses. RESULTS:  There were no significant differences in basal characteristics between groups. VS did not affect INS [2.7+/-0.8 vs. 2.9+/-0.9 mg/(kg/min), p=0.735] but increased triglyceride levels (1.35+/-0.61 vs. 1.70+/-0.46 mmol/l, p=0.018). CONCLUSIONS:  VS administration in IGT patients increased triglyceride concentrations without changes in INS.

Long- term efficacy and safety of vanadium in the treatment of type 1 diabetes.
            (Soveid et al., 2013)  Download
BACKGROUND:  Vanadium compounds are able to reduce blood glucose in experimentally- induced diabetic rats and type 2 diabetic patients, but data about their long- term safety and efficacy in diabetic patients are scarce. METHODS:  Fourteen type 1 diabetic patients received oral vanadyl sulfate (50 - 100 mg TID) for a period of 30 months. Fasting blood sugar (FBS), lipid levels, hematologic, and biochemical parameters were measured before and periodically during the treatment. RESULTS:  The daily doses of insulin decreased from 37.2 ± 5.5 to 25.8 ± 17.3 units/day and at the same time the mean FBS decreased from 238 ± 71 to 152 ± 42 mg/dL. Meanwhile, there was a decrease in plasma total cholesterol without any change in triglyceride level. No significant clinical or paraclinical side effects, with the exception for mild diarrhea at the beginning of treatment, were observed during 30 months therapy. CONCLUSION:  Vanadium is effective and safe for long- term use in type 1 diabetic patients.


 

References

Boden, G, et al. (1996), ‘Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus.’, Metabolism, 45 (9), 1130-35. PubMed: 8781301
Cohen, N, et al. (1995), ‘Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus.’, J Clin Invest, 95 (6), 2501-9. PubMed: 7769096
Cusi, K, et al. (2001), ‘Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes.’, J Clin Endocrinol Metab, 86 (3), 1410-17. PubMed: 11238540
Halberstam, M, et al. (1996), ‘Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjects.’, Diabetes, 45 (5), 659-66. PubMed: 8621019
Jacques-Camarena, O, et al. (2008), ‘Effect of vanadium on insulin sensitivity in patients with impaired glucose tolerance.’, Ann Nutr Metab, 53 (3-4), 195-98. PubMed: 19033682
Soveid, M, GA Dehghani, and GR Omrani (2013), ‘Long- term efficacy and safety of vanadium in the treatment of type 1 diabetes.’, Arch Iran Med, 16 (7), 408-11. PubMed: 23808778
(2009), ‘Vanadium (vanadyl sulfate). Monograph.’, Altern Med Rev, 14 (2), 177-80. PubMed: 19594227
(1959), ‘Vanadium inhibition of cholesterol synthesis.’, Nutr Rev, 17 (8), 231-32. PubMed: 13674628