Henry C. Lukaski,Henry C. Lukaski, PhPh.D..D.

USDA, ARS Grand Forks Human Nutrition Research CenterGrand Forks, ND 58202

Lessons from Micronutrient Studies in Lessons from Micronutrient Studies in Patients with Glucose Intolerance and Patients with Glucose Intolerance and

Diabetes Mellitus: Diabetes Mellitus: Chromium and VanadiumChromium and Vanadium

CrCr+3+3 facilitates insulin action facilitates insulin action in vitroin vitroinsulin receptor number ininsulin receptor number in adipocytesadipocytesinsulin binding at receptorsinsulin binding at receptors

CrCr+3+3 supplementation of longsupplementation of long--term TPN term TPN patients improves symptoms of patients improves symptoms of glucose intolerance glucose intolerance

Chromium in Glucose MetabolismChromium in Glucose Metabolism

Dietary Cr intake is lowDietary Cr intake is lowStressorsStressors promote acute Cr losspromote acute Cr loss

ExerciseExerciseInfectionInfectionPharmaceuticalsPharmaceuticals

Chromium and Glucose/Insulin: Chromium and Glucose/Insulin: HypothesisHypothesis

Responses to Chromium SupplementationResponses to Chromium Supplementation

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

aa

aa

bb

bb

aa

bb

Glu

cose

mg/

Glu

cose

mg/

dLdL

HyperHyperGlycemicGlycemic

HypoHypoGlycemicGlycemic

ControlControl DiabeticDiabetic

PlaceboPlacebo

600600µµµµµµµµg/dg/d

00

5050

200200

150150

100100

250250

NormalNormalvaluesvalues

180 adults in Beijing, China (35180 adults in Beijing, China (35--65 y)65 y)BMI: 24BMI: 24--25 kg/m25 kg/m22

DoubleDouble--blind, placeboblind, placebo--controlled designcontrolled designMaintain medication* use, usual diet and life styleMaintain medication* use, usual diet and life styleRandomized: placebo, 200, 1000 µg Cr as CrPicRandomized: placebo, 200, 1000 µg Cr as CrPicFasting and OGTT glucose and insulinFasting and OGTT glucose and insulin

**SulfonylureasSulfonylureas,, metforminmetformin, insulin, traditional , insulin, traditional medsmeds

Anderson et al, Diabetes 46:1786, 1997Anderson et al, Diabetes 46:1786, 1997

Chromium Supplementation in Chromium Supplementation in Type II DiabetesType II Diabetes

Effects of Chromium on Fasting Serum GlucoseEffects of Chromium on Fasting Serum Glucose

Months

Fast

ing

Glu

cose

mg/

dL

Anderson et al, Diabetes 46:1786, 1997

NorNor mal valuesmal values

aa

a a aa a

b b140140

120120

180180

160160

100100

8080

6060

200200

00 22 44

Placebo200 µµµµg/d

1000 µµµµg/d

Effects of Chromium on Fasting InsulinEffects of Chromium on Fasting Insulin

NorNor mal valuesmal values

MonthsMonths

Fast

ing

Insu

lin

Fast

ing

Insu

lin WW WWWW WW

U/mU/m

LL aa aa aaaa

aabb bb bb bb

00

55

25

20

1515

1010

00 22 44

PlaceboPlacebo200 200 µµµµµµµµg/dg/d

1000 1000 µµµµµµµµg/dg/d

Anderson et al, Diabetes 46:1786, 1997

Effects of Chromium on Hemoglobin A1CEffects of Chromium on Hemoglobin A1C

NorNor mal valuesmal values

MonthsMonths

HbA

1CH

bA1C

(%)

(%)

aa aa aaaa bb aa

bb bbcc

PlaceboPlacebo200 200 µµµµµµµµg/dg/d

1000 1000 µµµµµµµµg/dg/d

00

22

88

66

44

00 22 44

1010

Anderson et al, Diabetes 46:1786, 1997

Glu

cose

mg/

Glu

cose

mg/

dLdL

0 0 2 2 4 4 6 6 8 8 1010

Time (months)Time (months)

**

100100

140140

180180

6060

NormalNormalvaluesvalues

Cheng et al, J Trace Cheng et al, J Trace Elem Exp Med Elem Exp Med 12:55 199912:55 1999

Reduced Fasting Glucose withCr Supplementation

500 µµµµg/d

CefaluCefalu et al, J Trace et al, J Trace ElemElem ExpExp MedMed 12:71, 199912:71, 1999

Insu

lin S

ensi

tivity

In

sulin

Sen

sitiv

ity

BaselineBaseline 4 Months4 Months 8 Months8 Months

** **** PlaceboPlacebo

1000 1000 µµµµµµµµg/dg/d

11

22

55

44

33

00

Improved Insulin Sensitivity withCr Supplementation

SteroidSteroid--induced diabetesinduced diabetes•• 47 out of 50 patients improved with 600 µg Cr as 47 out of 50 patients improved with 600 µg Cr as

CrPic for 14 dCrPic for 14 dRavinaRavina et al, J Traceet al, J Trace Elem Exp MedElem Exp Med 12: 375, 200012: 375, 2000

Gestational diabetesGestational diabetes•• 4 and 8 µg Cr/kg as CrPic for 8 wk decreased 4 and 8 µg Cr/kg as CrPic for 8 wk decreased

fasting insulin, glucose and insulinfasting insulin, glucose and insulin concconc. during OGTT. during OGTT•• With severe glucose intolerance, Cr did not reduce With severe glucose intolerance, Cr did not reduce

insulin requirementinsulin requirementJovanovicJovanovic et al, J Traceet al, J Trace Elem Exp MedElem Exp Med 12: 91, 199912: 91, 1999

Reported Beneficial Effects Reported Beneficial Effects of Chromium Supplementationof Chromium Supplementation

Cr Supplementation and Human Cr Supplementation and Human Diabetes: SummaryDiabetes: Summary

Doses of Cr > 200 µg/d as CrPic elicit positive effectsDoses of Cr > 200 µg/d as CrPic elicit positive effectsIncreased insulin sensitivityIncreased insulin sensitivityImproved diabetic controlImproved diabetic control

fasting glucosefasting glucosefasting insulinfasting insulinHbA1CHbA1C

No relationship between serum Cr and diabetic controlNo relationship between serum Cr and diabetic control

I R

II

II

Chromodulin Chromodulin loaded with Crloaded with CrInsulin receptor fully activatedInsulin receptor fully activated

Insulin receptor activatedInsulin receptor activatedInsulinInsulin--sensitive cellsensitive cell

CrCr+3+3--TransferrinTransferrin

Cr+3

apochromodulinapochromodulin+ 4 Cr+ 4 Cr+3+3

[[insulininsulin]]in bloodin bloodchromodulinchromodulin

chromodulinchromodulin

apoapochromodulinchromodulin

KKff ~ 10~ 1018 18 m Mm M--11

KKmm~ 250 ~ 250 pMpM

Activation of Insulin Receptor Activity by ChromiumActivation of Insulin Receptor Activity by Chromium

UrineUrine

I R

III RIII R

Adapted from Vincent, J Adapted from Vincent, J Nutr Nutr 130:715, 2000130:715, 2000

IRSIRS--11

Proposed Sites of Chromium & Vanadium ActionProposed Sites of Chromium & Vanadium Action

PhosporylationPhosporylationCascadesCascades

GlucoseGlucose ProteinProtein LipidLipid GlycogenGlycogen GrowthGrowthTransporterTransporter SynthesisSynthesis SynthesisSynthesis SynthesisSynthesis Gene ExpressionGene Expression

αααααααα unitunit

ββββββββ unitunit

InsulinInsulinReceptorReceptor

CrCr (Insulin binding)(Insulin binding)

ATPATPGlucoseGlucose

VV ( ( PTPasePTPase))

CrCr, , VV ( ( PTPasePTPase))

CrCr ( Receptor ( Receptor kinasekinase))

PP

PPPP

PTPasePTPase = = phosphotyrosylphosphotyrosyl protein protein phosphatasephosphatase

InsulinInsulin

V salts, V salts, vanadylvanadyl (VO(VO+2+2) and) and vanadatevanadate (VO(VO33--), mimic ), mimic

insulin action insulin action In vitro, In vitro, vanadatevanadate: : hexosehexose uptake in muscle &uptake in muscle &adipocytesadipocytes, , lipid and glycogen synthesislipid and glycogen synthesisIn vivo,In vivo, vanadatevanadate andand vanadylvanadyl are effective are effective

treatments for Type I and II diabetes in treatments for Type I and II diabetes in rodentsrodentsV improves blood glucose without increasing V improves blood glucose without increasing

blood insulinblood insulinPrimary action of V is at target tissuesPrimary action of V is at target tissues

Vanadium in Glucose Metabolism Vanadium in Glucose Metabolism and Diabetesand Diabetes

Glucose use Glucose use -- in NIDDM, no change in IDDMin NIDDM, no change in IDDMNon oxidative disposal Non oxidative disposal -- in NIDDMin NIDDMHepatic glucose production Hepatic glucose production -- no change in NIDDM orno change in NIDDM or

IDDMIDDMInsulin requirement Insulin requirement -- in IDDMin IDDMNo significant change in fasting glucose or No significant change in fasting glucose or

HbA1CHbA1C

SodiumSodium metavanadatemetavanadate (NaVO(NaVO33; 125 mg or ~ 50 mg V) for 2 wk; 125 mg or ~ 50 mg V) for 2 wkGlucose metabolism: 2Glucose metabolism: 2--stepstep euglycemiceuglycemic,, hyperinsulinichyperinsulinic clampclamp

GoldfineGoldfine et al, Jet al, J Clin Endocrinol MetabClin Endocrinol Metab 80: 3311, 199580: 3311, 1995

Vanadium Supplementation in DiabetesVanadium Supplementation in Diabetes

GoldfineGoldfine et al, Metabolism 49:400, 2000et al, Metabolism 49:400, 2000

Glu

cose

G

luco

se

mg/

mg/

dLdL

150 mg/d150 mg/d 300 mg/d300 mg/d

** ** PrePre

PostPost

300300100100

1010

44250250

100100

**

**

Vanadyl Vanadyl Sulfate: Diabetic ControlSulfate: Diabetic Control

Cho

lest

erol

Cho

lest

erol

mg/

mg/

dLdLH

bA1C

HbA

1C%%

0 0 20 40 60 20 40 60 80 100 80 100 120120Dose, mg V/dDose, mg V/d

100100

00

200200

600600

300300

400400

500500

Seru

m V

, ng/

mL

Seru

m V

, ng/

mL

RR22=0.993=0.993

Changes in Serum Vanadium Changes in Serum Vanadium with Vanadium Supplementation with Vanadium Supplementation

GoldfineGoldfine et al, Metabolism 49: 400, 2000et al, Metabolism 49: 400, 2000

Serum Vanadium ConcentrationsSerum Vanadium ConcentrationsVa

nadi

um, n

g / m

LVa

nadi

um, n

g / m

L

25 mg V (VOSO25 mg V (VOSO44)) 50 mg V (VOSO50 mg V (VOSO44)) 50 mg V (NaVO50 mg V (NaVO33))00

200200

400400

600600

800800

10001000

12001200

Therapeutic Levels in STZTherapeutic Levels in STZ--diabetic ratsdiabetic rats

Dose of Vanadium AdministeredDose of Vanadium Administered

Serum Vanadium ConcentrationsSerum Vanadium ConcentrationsPT

Pase

PT

Pase

Act

ivity

(% c

ontr

ol)

Activ

ity (%

con

trol

)

00

2020

4040

6060

8080

100100

120120

RodentRodentstudiesstudies

Vanadium Concentration (µM)Vanadium Concentration (µM)

Human Human studiesstudies

ParticulateParticulate

CytosolicCytosolic

1 1 2 2 7 7 15 25 50 15 25 50 100 200100 200

11..5 mg 5 mg kgkg

14 d14 d

100 mg 100 mg kgkg

3 d3 d

Generally ineffective in IDDMGenerally ineffective in IDDMImprove insulin sensitivityImprove insulin sensitivity

glucose use glucose use -- non oxidative disposalnon oxidative disposalImprove diabetic controlImprove diabetic control

HbA1C (50 & 100 mg/d): 7.8 to 6.8 %HbA1C (50 & 100 mg/d): 7.8 to 6.8 %fasting glucose (100 mg/d): 167 to 144 mg/fasting glucose (100 mg/d): 167 to 144 mg/dLdLtotal cholesterol (100 mg/d): 204 to 165 mg/total cholesterol (100 mg/d): 204 to 165 mg/dLdLHDL (100 mg/d): 39 to 31 mg/HDL (100 mg/d): 39 to 31 mg/dLdL

No relationship between serum V and insulin sensitivityNo relationship between serum V and insulin sensitivity

V Supplementation and Human Diabetes: V Supplementation and Human Diabetes: SummarySummary

Cr & V Supplementation in DiabetesCr & V Supplementation in Diabetes

Common mechanism of action:Common mechanism of action: PTPasePTPase

Increased diabetic control in NIDDMIncreased diabetic control in NIDDM

Serum concentration not predictive of efficacySerum concentration not predictive of efficacy

Inconsistent response among patientsInconsistent response among patients

Pharmaceutical doses needed for beneficial effectsPharmaceutical doses needed for beneficial effects

ChromiumChromiumIn vitro In vitro evidence of DNA damageevidence of DNA damage

VanadiumVanadiumGastrointestinal intolerance (V doses Gastrointestinal intolerance (V doses �������� 25 mg/d)25 mg/d)

VanadateVanadate >> vanadylvanadyl salts salts HDLHDL--cholesterolcholesterol

“Green tongue”“Green tongue”

Adverse Effects of Cr & V SupplementationAdverse Effects of Cr & V Supplementation

ChromiumChromiumESADDI: 50 ESADDI: 50 -- 200 µg/d200 µg/dTherapeutic dose: 500 Therapeutic dose: 500 -- 1000 µg/d1000 µg/d

VanadiumVanadiumPostulated requirement: 10 µg/dPostulated requirement: 10 µg/dTherapeutic dose: 25 Therapeutic dose: 25 -- 50 mg/d50 mg/dToxic dose: > 10 mg/dToxic dose: > 10 mg/d

Cr & V Supplementation:Cr & V Supplementation:Nutrition or PharmacologyNutrition or Pharmacology