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<strong>Lessons</strong> <strong>from</strong> <strong>Micronutrient</strong> <strong>Studies</strong> <strong>in</strong><br />

<strong>Patients</strong> <strong>with</strong> <strong>Glucose</strong> Intolerance and<br />

Diabetes Mellitus:<br />

Chromium and Vanadium<br />

Henry C. Lukaski, Ph.D.<br />

USDA, ARS Grand Forks Human<br />

Nutrition Research Center<br />

Grand Forks, ND 58202


Chromium <strong>in</strong> <strong>Glucose</strong> Metabolism<br />

Cr +3 facilitates <strong>in</strong>sul<strong>in</strong> action <strong>in</strong> vitro<br />

<strong>in</strong>sul<strong>in</strong> receptor number <strong>in</strong> adipocytes<br />

<strong>in</strong>sul<strong>in</strong> b<strong>in</strong>d<strong>in</strong>g at receptors<br />

Cr +3 supplementation of long-term TPN<br />

patients improves symptoms of<br />

glucose <strong>in</strong>tolerance


Chromium and <strong>Glucose</strong>/Insul<strong>in</strong>:<br />

Hypothesis<br />

Dietary Cr <strong>in</strong>take is low<br />

Stressors promote acute Cr loss<br />

Exercise<br />

Infection<br />

Pharmaceuticals


Responses to Chromium Supplementation<br />

250<br />

a<br />

Placebo<br />

200<br />

600µg/d<br />

<strong>Glucose</strong> mg/dL<br />

150<br />

100<br />

a<br />

b<br />

a<br />

b<br />

b<br />

Normal<br />

values<br />

50<br />

0<br />

Hyper<br />

Glycemic<br />

Hypo<br />

Glycemic<br />

Control<br />

Diabetic<br />

Anderson, J Am Coll Nutr, , 16:404, 1997


Chromium Supplementation <strong>in</strong><br />

Type II Diabetes<br />

180 adults <strong>in</strong> Beij<strong>in</strong>g, Ch<strong>in</strong>a (35-65 y)<br />

BMI: 24-25 25 kg/m 2<br />

Double-bl<strong>in</strong>d, bl<strong>in</strong>d, placebo-controlled controlled design<br />

Ma<strong>in</strong>ta<strong>in</strong> medication* use, usual diet and life style<br />

Randomized: placebo, 200, 1000 µg Cr as CrPic<br />

Fast<strong>in</strong>g and OGTT glucose and <strong>in</strong>sul<strong>in</strong><br />

*Sulfonylureas, metform<strong>in</strong>, , <strong>in</strong>sul<strong>in</strong>, traditional meds<br />

Anderson et al, Diabetes 46:1786, 1997


Effects of Chromium on Fast<strong>in</strong>g Serum <strong>Glucose</strong><br />

200<br />

Fast<strong>in</strong>g <strong>Glucose</strong> mg/dL<br />

180<br />

160<br />

140<br />

120<br />

100<br />

a a a<br />

a a<br />

a a<br />

b<br />

b<br />

Placebo<br />

200 µg/d<br />

1000 µg/d<br />

Nor mal values<br />

80<br />

60<br />

Anderson et al, Diabetes 46:1786, 1997<br />

0 2 4<br />

Months


Effects of Chromium on Fast<strong>in</strong>g Insul<strong>in</strong><br />

Fast<strong>in</strong>g Insul<strong>in</strong> WU/m U/mL<br />

25<br />

20<br />

15<br />

10<br />

5<br />

a<br />

a<br />

a<br />

a<br />

b<br />

b<br />

a<br />

b<br />

b<br />

Placebo<br />

200 µg/d<br />

1000 µg/d<br />

Nor mal values<br />

0<br />

0 2 4<br />

Months<br />

Anderson et al, Diabetes 46:1786, 1997


Effects of Chromium on Hemoglob<strong>in</strong> A1C<br />

10<br />

8<br />

a<br />

a<br />

a<br />

a<br />

b<br />

b<br />

a<br />

b<br />

c<br />

Placebo<br />

200 µg/d<br />

1000 µg/d<br />

HbA1C (%)<br />

6<br />

4<br />

Nor mal values<br />

2<br />

0<br />

0 2 4<br />

Months<br />

Anderson et al, Diabetes 46:1786, 1997


180<br />

Reduced Fast<strong>in</strong>g <strong>Glucose</strong> <strong>with</strong><br />

*<br />

Cr Supplementation<br />

500 µg/d<br />

<strong>Glucose</strong> mg/dL<br />

140<br />

100<br />

Normal<br />

values<br />

60<br />

0 2 4 6 8 10<br />

Time (months)<br />

Cheng et al, J Trace Elem Exp Med 12:55 1999


5<br />

4<br />

Improved Insul<strong>in</strong> Sensitivity <strong>with</strong><br />

Cr Supplementation<br />

* **<br />

** Placebo<br />

1000 µg/d<br />

Insul<strong>in</strong> Sensitivity<br />

3<br />

2<br />

1<br />

0<br />

Basel<strong>in</strong>e<br />

4 Months 8 Months<br />

Cefalu et al, J Trace Elem Exp Med 12:71, 1999


Reported Beneficial Effects<br />

of Chromium Supplementation<br />

Steroid-<strong>in</strong>duced <strong>in</strong>duced diabetes<br />

• 47 out of 50 patients improved <strong>with</strong> 600 µg Cr as<br />

CrPic for 14 d<br />

Rav<strong>in</strong>a et al, J Trace Elem Exp Med 12: 375, 2000<br />

Gestational diabetes<br />

• 4 and 8 µg Cr/kg as CrPic for 8 wk decreased<br />

fast<strong>in</strong>g <strong>in</strong>sul<strong>in</strong>, glucose and <strong>in</strong>sul<strong>in</strong> conc. . dur<strong>in</strong>g OGTT<br />

• With severe glucose <strong>in</strong>tolerance, Cr did not reduce<br />

<strong>in</strong>sul<strong>in</strong> requirement<br />

Jovanovic et al, J Trace Elem Exp Med 12: 91, 1999


Cr Supplementation and Human<br />

Diabetes: Summary<br />

Doses of Cr > 200 µg/d as CrPic elicit positive effects<br />

Increased <strong>in</strong>sul<strong>in</strong> sensitivity<br />

Improved diabetic control<br />

fast<strong>in</strong>g glucose<br />

fast<strong>in</strong>g <strong>in</strong>sul<strong>in</strong><br />

HbA1C<br />

No relationship between serum Cr and diabetic control


Activation of Insul<strong>in</strong> Receptor Activity by Chromium<br />

apo<br />

chromodul<strong>in</strong><br />

IR<br />

I<br />

Cr +3<br />

Cr +3 -Transferr<strong>in</strong><br />

IR<br />

I<br />

Insul<strong>in</strong>-sensitive sensitive cell<br />

Insul<strong>in</strong> receptor activated<br />

chromodul<strong>in</strong><br />

[<strong>in</strong>sul<strong>in</strong>]<br />

<strong>in</strong> blood<br />

apochromodul<strong>in</strong><br />

+3<br />

+ 4 Cr +3<br />

K f<br />

~ 10 18 m M -1<br />

chromodul<strong>in</strong><br />

Ur<strong>in</strong>e<br />

IR<br />

I<br />

K m<br />

~ 250 pM<br />

IR<br />

I<br />

Insul<strong>in</strong> receptor fully activated<br />

Chromodul<strong>in</strong> loaded <strong>with</strong> Cr<br />

Adapted <strong>from</strong> V<strong>in</strong>cent, J Nutr 130:715, 2000


Proposed Sites of Chromium & Vanadium Action<br />

<strong>Glucose</strong><br />

Insul<strong>in</strong><br />

Insul<strong>in</strong><br />

Receptor<br />

α unit<br />

β unit<br />

P<br />

Cr (Insul<strong>in</strong> b<strong>in</strong>d<strong>in</strong>g)<br />

ATP<br />

Cr, V ( PTPase)<br />

Cr ( Receptor k<strong>in</strong>ase)<br />

P<br />

IRS-1<br />

P<br />

V ( PTPase)<br />

Phosporylation<br />

Cascades<br />

<strong>Glucose</strong><br />

Transporter<br />

Prote<strong>in</strong><br />

Synthesis<br />

Lipid<br />

Synthesis<br />

Glycogen<br />

Synthesis<br />

Growth<br />

Gene Expression<br />

PTPase = phosphotyrosyl prote<strong>in</strong> phosphatase


Vanadium <strong>in</strong> <strong>Glucose</strong> Metabolism<br />

and Diabetes<br />

V salts, vanadyl (VO +2 ) and vanadate (VO 3- ), mimic<br />

<strong>in</strong>sul<strong>in</strong> action<br />

In vitro, vanadate: hexose uptake <strong>in</strong> muscle &<br />

adipocytes,<br />

lipid and glycogen synthesis<br />

In vivo, vanadate and vanadyl are effective<br />

treatments for Type I and II diabetes <strong>in</strong><br />

rodents<br />

V improves blood glucose <strong>with</strong>out <strong>in</strong>creas<strong>in</strong>g<br />

blood <strong>in</strong>sul<strong>in</strong><br />

Primary action of V is at target tissues


Vanadium Supplementation <strong>in</strong> Diabetes<br />

<strong>Glucose</strong> use - <strong>in</strong> NIDDM, no change <strong>in</strong> IDDM<br />

Non oxidative disposal - <strong>in</strong> NIDDM<br />

Hepatic glucose production - no change <strong>in</strong> NIDDM or<br />

IDDM<br />

Insul<strong>in</strong> requirement - <strong>in</strong> IDDM<br />

No significant change <strong>in</strong> fast<strong>in</strong>g glucose or<br />

HbA1C<br />

Sodium metavanadate (NaVO 3 ; 125 mg or ~ 50 mg V) for 2 wk<br />

<strong>Glucose</strong> metabolism: 2-step2<br />

euglycemic, hyper<strong>in</strong>sul<strong>in</strong>ic clamp<br />

Goldf<strong>in</strong>e et al, J Cl<strong>in</strong> Endocr<strong>in</strong>ol Metab 80: 3311, 1995


Vanadyl Sulfate: Diabetic Control<br />

HbA1C<br />

%<br />

<strong>Glucose</strong><br />

Cholesterol<br />

mg/dL<br />

10<br />

4<br />

250<br />

100<br />

300<br />

mg/dL<br />

100<br />

*<br />

150 mg/d 300 mg/d<br />

Pre<br />

*<br />

*<br />

*<br />

Post<br />

Goldf<strong>in</strong>e et al, Metabolism 49:400, 2000


600<br />

Changes <strong>in</strong> Serum Vanadium<br />

<strong>with</strong> Vanadium Supplementation<br />

500<br />

Serum V, ng/mL<br />

400<br />

300<br />

200<br />

100<br />

R 2 =0.993<br />

0<br />

0 20 40 60 80 100 120<br />

Goldf<strong>in</strong>e et al, Metabolism 49: 400, 2000<br />

Dose, mg V/d


1200<br />

Serum Vanadium Concentrations<br />

1000<br />

Vanadium, ng / mL<br />

800<br />

600<br />

400<br />

Therapeutic Levels <strong>in</strong> STZ-diabetic rats<br />

200<br />

0<br />

25 mg V (VOSO 4 ) 50 mg V (VOSO 4 ) 50 mg V (NaVO 3 )<br />

Dose of Vanadium Adm<strong>in</strong>istered


Serum Vanadium Concentrations<br />

120<br />

PTPase Activity (% control)<br />

100<br />

80<br />

60<br />

40<br />

20<br />

Human<br />

studies<br />

1.55 mg<br />

kg<br />

14 d<br />

Rodent<br />

studies<br />

100 mg<br />

kg<br />

3 d<br />

Particulate<br />

Cytosolic<br />

0<br />

1 2 7 15 25 50 100 200<br />

Vanadium Concentration (µM)


V Supplementation and Human Diabetes:<br />

Summary<br />

Generally <strong>in</strong>effective <strong>in</strong> IDDM<br />

Improve <strong>in</strong>sul<strong>in</strong> sensitivity<br />

glucose use - non oxidative disposal<br />

Improve diabetic control<br />

HbA1C (50 & 100 mg/d): 7.8 to 6.8 %<br />

fast<strong>in</strong>g glucose (100 mg/d): 167 to 144 mg/dL<br />

total cholesterol (100 mg/d): 204 to 165 mg/dL<br />

HDL (100 mg/d): 39 to 31 mg/dL<br />

No relationship between serum V and <strong>in</strong>sul<strong>in</strong> sensitivity


Cr & V Supplementation <strong>in</strong> Diabetes<br />

Common mechanism of action:<br />

Increased diabetic control <strong>in</strong> NIDDM<br />

PTPase<br />

Serum concentration not predictive of efficacy<br />

Inconsistent response among patients<br />

Pharmaceutical doses needed for beneficial effects


Adverse Effects of Cr & V Supplementation<br />

Chromium<br />

In vitro evidence of DNA damage<br />

Vanadium<br />

Gastro<strong>in</strong>test<strong>in</strong>al <strong>in</strong>tolerance (V doses 25 mg/d)<br />

Vanadate > vanadyl salts<br />

HDL-cholesterol<br />

“Green tongue”


Cr & V Supplementation:<br />

Nutrition or Pharmacology<br />

Chromium<br />

ESADDI: 50 - 200 µg/d<br />

Therapeutic dose: 500 - 1000 µg/d<br />

Vanadium<br />

Postulated requirement: 10 µg/d<br />

Therapeutic dose: 25 - 50 mg/d<br />

Toxic dose: > 10 mg/d

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