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Presented By Christopher Theberge, B.S.

The Potential Role of Vanadyl Sulfate As An Anti-diabetic Agent Used to Treat Non-Insulin-Dependent Diabetes Mellitus. Presented By Christopher Theberge, B.S. NIDDM Statistics. 90%-95% of diabetes diagnoses 15.7 million Americans inflicted About 800,000 new diagnoses per year

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Presented By Christopher Theberge, B.S.

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  1. The Potential Role of Vanadyl Sulfate As An Anti-diabetic Agent Used to Treat Non-Insulin-Dependent Diabetes Mellitus Presented By Christopher Theberge, B.S.

  2. NIDDM Statistics • 90%-95% of diabetes diagnoses • 15.7 million Americans inflicted • About 800,000 new diagnoses per year • Increases risk of other life-threatening diseases • Costs taxpayers $105 billion dollars per year

  3. Vanadium • Shellfish, mushrooms, and parsley rich in the element • Upper limit 1.8 mg/day of elemental vanadium set for adults 19 years and older • Most diets supply ~15 ug/day • Needed for normal growth and development but exact role undefined

  4. Why Vanadium? High doses In Vivo and In Vitro: • Insulin mimetic-effects • Inhibit Phosphotyrosine Phosphatases leading to • enhanced receptor Phosphorylation and tyrosine • kinase activity (IRTK) • Stimulate glucose uptake without any change in • IRTK activity

  5. Previous Animal Studies Vanadium Salts Shown To Fasting and Fed Glucose Levels Hexose Transport Lipogenesis Improve OGT Glucose Oxidation Restore Early Insulin Secretion Glycogen synthase Mimic Insulin

  6. Previous Human Studies Vanadium Salts Shown To Skeletal Muscle Liver Augment glucose uptake by Glycolysis Glycogen synthesis Glycogen Formation Lipogenesis Gluconeogenesis

  7. Some Reasoning Behind the Following Studies • VOSO4 most active intracellular form • Takes at least 4 weeks to exert its effects • VOSO4 dose dependent • Sample sizes of 8 or less subjects • Conflicting results • Safety and efficacy of Vanadium unknown

  8. Metabolic Effects of Vanadyl Sulfate in Humans With Non-Insulin -Dependent Diabetes Mellitus: In Vivo and In Vitro Studies Goldfine et al. Metabolism, Vol 49, No 3 (March), 2000: pp 400-410

  9. Goldfine et al. Investigated efficacy and mechanism of action of VOSO4 as an oral hypoglycemic agent Subjects • 16 Type II diabetics (11 Males, 5 Females) • Age 45.9 +/- 10.2 years • BMI 33.8 +/- 8.1 kg/m2 • Not using Vanadium supplementation

  10. Weeks 4-10: VOSO4 ingested at 25, 50, or 100 mg doses 3x/day 75, 150, and 300 mg/day Weeks 10-12: Insulin sensitivity with 2-step euglycemic clamp Week 1: Baseline lab testing Weeks 2 & 3: Placebo 3x/day Week 4: Insulin sensitivity with 2-step euglycemic clamp Goldfine et al. Self-Controlled Study Design 12 weeks

  11. Goldfine et al. Methods/Measurements • Hepatic glucose production (HGP) • Oxidative vs nonoxidative glucose disposal • Serum levels of thiobarbituric acid-reactive • substances (TBARS) • Serum triglyceride (TG) Apo A & B

  12. Goldfine et al. Methods/Measurements (cont.) • Muscle biopsy to test effect of VOSO4 on • insulin-sensitive cellular enzymes • Phosphatidylinositol 3-kinase (PI 3-K) & • Insulin Receptor Substrate 1 (IRS-1) • Glycogen synthase • Phosphotyrosine phosphatase

  13. Goldfine et al. Results • GI disturbances with 150 mg VOSO4/day in some subjects • Cramping, abdominal discomfort, or diarrhea in all with 300 mg VOSO4/day • Peak serum levels and time to achieve them varied greatly between subjects • Linear correlation between peak serum level and VOSO4 dose

  14. Goldfine et al. Effect of VOSO4 on HbA1c P<0.05 P=0.05 HbA1c (%) Adapted from Goldfine et al. Metabolic Effects of Vanadyl in Human NIDDM. Metabolism, 2000.

  15. Goldfine et al. Results (cont.) • Mean fasting glucose significantly only in 300 mg group • Insulin sensitivity improved in several subjects at 150 mg and 300 mg doses only.

  16. Goldfine et al. Results (cont.) No Significant Changes In: • Basal HGP and suppression from insulin at all doses • Oxidative and nonoxidative glucose metabolism • TBARS @ 300 mg/day • Glycogen synthase • Phosphotyrosine phosphatase • Subject weight • Serum TG Apo A or Apo B

  17. Effect of 150 mg/day VOSO4 on PI 3-K, insulin receptor, IRS-1 and Shc *p=0.02 **p<0.01 vs basal PI 3-K IRS-1 ** * Fold Stimulation Insulin Receptor ** * * Shc * Insulin - + - + - + - + - + - + - + - + Pre-VPost-V Pre-VPost-V Pre-VPost-V Pre-VPost-V Adapted from Goldfine et al. Metabolic Effects of Vanadyl in Human NIDDM. Metabolism, 2000.

  18. Results/Conclusions • Tissue Phosphatases may not accurately reflect tissue • target for VOSO4 to enhance insulin signaling • Vanadyl may act at other steps of insulin action • Serum Vanadium levels hardly detectable after 2 weeks

  19. Limitations • Lower levels of peak serum could not be assessed by pill count or patient adherence • <5% of ingested Vanadium normally absorbed • Peak serum levels may not reflect levels achieved at cellular site of action • VOSO4 relatively weak Ptase inhibitor • Small sample size (More Males) • Significant distribution of age and BMI • Meal content and inconsistent meal timings • Absorption rates and GI side effects

  20. Vanadyl Sulfate Improves Hepatic and Muscle Insulin Sensitivity in Type 2 Diabetes Cusi et al. JCE & M, Vol. 86, Np. 3, 2001: pp 1410-1417

  21. Cusi et al. Reexamine effects of VOSO4on glycemic control, insulin secretion, EGP, and insulin-mediated whole body glucose disposal.

  22. Cusi et al. Subjects • 11 poorly controlled Type II diabetics • (7 Males, 4 Females) • 5 Non-diabetics (3 Males, 2 Females) • Ages 59 +/- 2 years • BMI 28.9 +/- 1.1 kg/m2 • 6 subjects being treated with sulfonylurea

  23. Cusi et al. Study Design Non-diabetics received euglycemic clamp and served as control group

  24. Cusi et al. Study Design (cont.) Baseline Testing in Treatment Group 1. Instructed on weight-maintaining ADA diet 2. 75-g Oral Glucose Tolerance Test (OGTT) after 12 hour fast 3. Euglycemic clamp at interval of 3-7 days

  25. Cusi et al. Study Design (cont.) 2 week titration period with 25 mg VOSO4 2x/day 4 weeks-50 mg doses 3x/day Total Daily Dose: 150 mg/day Plasma Vanadium levels determined before and after 6 week treatment and 6 weeks thereafter

  26. Cusi et al. Methods/Measurements • Fasting Plasma Glucose (FPG) during OGTT • Treatment response to FPG, HbA1c & fructosamine Euglycemic Clamp: • Endogenous Glucose Production (EGP) • Whole body insulin-mediated glucose disposal

  27. Cusi et al. FPG After 6 Weeks of VOSO4 Treatment * P<0.01 (mg/dL) * * 0 2 4 6 Week Adapted from Cusi et al. VOSO4 Improves Hepatic and Muscle Sensitivity In NIDDM. JCE &M, 2001.

  28. Cusi et al. Results • Plasma fructosamine significantly decreased at 4 weeks and HbA1c at 6 weeks • Diarrhea (n=4) & abdominal discomfort (n=2) • Plasma glucose concentration reduced about 30 mg/dL during OGTT • Plasma insulin lower during OGTT suggesting improved insulin sensitivity

  29. Cusi et al. Results (cont.) No Change in: Subject Weights

  30. Basal EGP Before and After VOSO4 Treatment P<0.01 *P<0.01 * EGP (mg/kg LBM.min) Diabetics Adapted from Cusi et al. VOSO4 Improves Hepatic and Muscle Sensitivity In NIDDM. JCE &M, 2001.

  31. Whole Body Insulin-Mediated Glucose Disposal Before and After VOSO4 Treatment * P<0.01 * P<0.03 Insulin-Mediated Glucose Uptake (mg/kg LBM.min) Diabetics Adapted from Cusi et al. VOSO4 Improves Hepatic and Muscle Sensitivity In NIDDM. JCE &M, 2001.

  32. Cusi et al. Conclusions • Close correlation between basal EGP reduction and improved FPG suggesting VOSO4 has an impact on liver • Insulin sensitivity did not correlate with the decline in FPG after treatment with skeletal muscle • VOSO4 did not stimulate insulin secretion • Serum Vanadium levels returned to normal after 6 weeks discontinuation

  33. Cusi et al. Limitations • Small sample size (Again, more males) • Changing diet for study may have affected results • Subjects had poorly controlled diabetes • Sulfonylureas and diet or alone

  34. Conclusions • VOSO4 appears to be effective on lowering glucose levels through improved insulin sensitivity in muscle tissue without change in weight • Appears to be relatively well-tolerated and safe short-term • Vanadium reduced basal EGP suggesting has ability to ameliorate hepatic insulin resistance

  35. Conclusions • VOSO4 did not correlate with overall muscle tissue phosphatases • Activity of specific phosphatases hard to isolate may be affected by VOSO4 • Phosphatases in specific tissues differentially affected • Inhibition in vivo is lost in vitro

  36. Finally: VOSO4 is capable of becoming oxidized to vanadate in vivo, leading to less activating potential Effects may be different in non-Caucasian population Conclusions

  37. Future Implications • Long term effects of Vanadium must be assessed • More studies needed on humans (Races?) • Effects are minimal to consider it a pharmacological option • Newer and more effective Vanadium analogues are under development

  38. Thank You

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