Lessons from Micronutrient Studies in Patients with Glucose ...
Lessons from Micronutrient Studies in Patients with Glucose ...
Lessons from Micronutrient Studies in Patients with Glucose ...
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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