the potential role of vanadyl sulfate as an anti-diabetic agent used to treat non- insulin-dependent...
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The Potential Role of Vanadyl Sulfate As An Anti-diabetic Agent
Used to Treat Non-Insulin-Dependent Diabetes Mellitus
Presented ByChristopher Theberge, B.S.
NIDDM Statistics90%-95% of diabetes diagnoses15.7 million Americans inflicted About 800,000 new diagnoses per yearIncreases risk of other life-threatening
diseasesCosts taxpayers $105 billion dollars per
year
VanadiumShellfish, mushrooms, and parsley rich
in the elementUpper limit 1.8 mg/day of elemental
vanadium set for adults 19 years and older
Most diets supply ~15 ug/dayNeeded for normal growth and
development but exact role undefined
Why Vanadium?
• Inhibit Phosphotyrosine Phosphatases leading to enhanced receptor Phosphorylation and tyrosine kinase activity (IRTK)• Stimulate glucose uptake without any change in IRTK activity
High doses In Vivo and In Vitro:
•Insulin mimetic-effects
Previous Animal Studies
Vanadium Salts Shown To
Hexose Transport
Lipogenesis
Glucose Oxidation
Glycogen synthase
Fasting and FedGlucose Levels
Improve OGT
Restore Early Insulin Secretion
Mimic Insulin
Previous Human Studies
Vanadium Salts Shown To
Glycolysis
Glycogen synthesis
Lipogenesis
Gluconeogenesis
Liver Skeletal Muscle
Augment glucose uptake by
Glycogen Formation
Some Reasoning Behind the Following Studies
•Takes at least 4 weeks to exert its effects
•VOSO4 most active intracellular form
•Sample sizes of 8 or less subjects
•Conflicting results
•Safety and efficacy of Vanadium unknown
•VOSO4 dose dependent
Metabolic Effects of Vanadyl Sulfate Metabolic Effects of Vanadyl Sulfate in Humans With Non-Insulin -in Humans With Non-Insulin -
Dependent Diabetes Mellitus: In Vivo Dependent Diabetes Mellitus: In Vivo and In Vitro Studiesand In Vitro Studies
Metabolism, Vol 49, No 3 (March), 2000: pp 400-410Metabolism, Vol 49, No 3 (March), 2000: pp 400-410
Goldfine et al.Goldfine et al.
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
• Not using Vanadium supplementation• BMI 33.8 +/- 8.1 kg/m2
Goldfine et al. Self-Controlled Study Design
12 weeks
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.
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
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
Goldfine et al.
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
Results
Goldfine et al.
Effect of VOSO4 on HbA1c
6
7
8
9
Placebo Vanadyl
150 mg
300 mg
P<0.05
P=0.05
HbA1c (%)
Adapted from Goldfine et al. Metabolic Effects of Vanadyl in Human NIDDM. Metabolism, 2000.
Goldfine et al.
Mean fasting glucose significantly only in 300 mg group
Insulin sensitivity improved in several subjects at 150 mg and 300 mg doses only.
Results (cont.)
Goldfine et al.
Basal HGP and suppression from insulin at all doses
Oxidative and nonoxidative glucose metabolism
TBARS @ 300 mg/dayGlycogen synthase Phosphotyrosine phosphataseSubject weightSerum TG Apo A or Apo B
Results (cont.)
No Significant Changes In:
Effect of 150 mg/day VOSO4 on PI 3-K, insulin receptor, IRS-1 and Shc
0
1
2
3
4
5
6
- + - + - + - + - + - + - + - +
PI 3-K
InsulinPre-V Post-V Pre-V Post-V Pre-V Post-VPre-V Post-V
InsulinReceptor
IRS-1
Shc
FoldStimulation
*p=0.02**p<0.01 vs basal
*
**
*
**
**
Adapted from Goldfine et al. Metabolic Effects of Vanadyl in Human NIDDM. Metabolism, 2000.
Results/Conclusions
•Vanadyl may act at other steps of insulin action
•Tissue Phosphatases may not accurately reflect tissue target for VOSO4 to enhance insulin signaling
•Serum Vanadium levels hardly detectable after 2 weeks
Limitations Small sample size (More
Males)
Significant distribution of age and BMI
Meal content and inconsistent meal timings
Absorption rates and GI side effects
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
Vanadyl Sulfate Improves Vanadyl Sulfate Improves Hepatic and Muscle Insulin Hepatic and Muscle Insulin
Sensitivity in Type 2 DiabetesSensitivity in Type 2 Diabetes
JCE & M, Vol. 86, Np. 3, 2001: pp 1410-1417JCE & M, Vol. 86, Np. 3, 2001: pp 1410-1417
Cusi et al.Cusi et al.
Cusi et al.
Reexamine effects of VOSO4on glycemic control, insulin secretion, EGP, and
insulin-mediated whole body glucose disposal.
Subjects
Cusi et al.
• 11 poorly controlled Type II diabetics (7 Males, 4 Females)
•Ages 59 +/- 2 years
•BMI 28.9 +/- 1.1 kg/m2
•6 subjects being treated with sulfonylurea
•5 Non-diabetics (3 Males, 2 Females)
Study DesignCusi et al.
Non-diabetics received euglycemic clamp and served as control group
Study Design (cont.)
Cusi et al.
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
Baseline Testing in Treatment Group
Study Design (cont.)
Cusi et al.
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
Methods/MeasurementsCusi et al.
•Fasting Plasma Glucose (FPG) during OGTT
•Endogenous Glucose Production (EGP)
•Whole body insulin-mediated glucose disposal
•Treatment response to FPG, HbA1c & fructosamine
Euglycemic Clamp:
150
160
170
180
190
200
210
Cusi et al.
0 2 4 6 Week
(mg/dL)
FPG After 6 Weeks of VOSO4 Treatment
* *
* P<0.01
Adapted from Cusi et al. VOSO4 Improves Hepatic and Muscle Sensitivity In NIDDM. JCE &M, 2001.
ResultsPlasma 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
Cusi et al.
Cusi et al.
Results (cont.)No Change in:
Subject Weights
Basal EGP Before and After VOSO4 Treatment
0
1
2
3
4
5
BeforeTreatment
VOSO4 Non-DiabeticControls
EGP(mg/kg LBM.min)
Diabetics
P<0.01
Adapted from Cusi et al. VOSO4 Improves Hepatic and Muscle Sensitivity In NIDDM. JCE &M, 2001.
*
*P<0.01
Whole Body Insulin-Mediated Glucose Disposal Before and After VOSO4 Treatment
0
2
4
6
8
10
BeforeTreatment
VOSO4 Non-DiabeticControls
Insulin-Mediated Glucose Uptake
(mg/kg LBM.min)
Diabetics
P<0.03*
* P<0.01
Adapted from Cusi et al. VOSO4 Improves Hepatic and Muscle Sensitivity In NIDDM. JCE &M, 2001.
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
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
Cusi et al.
ConclusionsVOSO4 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
ConclusionsVOSO4 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
Conclusions
Finally:
VOSO4 is capable of becoming oxidized to vanadate in vivo, leading to less activating potential
Effects may be different in non-Caucasian population
Future ImplicationsLong term effects of Vanadium must
be assessed More studies needed on humans
(Races?)Effects are minimal to consider it a
pharmacological optionNewer and more effective Vanadium
analogues are under development
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