Magnetic resonance examinations on lipid metabolism in insulin

Magnetic resonance examinations

on lipid metabolism in

insulin resistance and beyond

Chris Boesch PhD & MD

Departments of Clinical Research and Radiology

MR Spectroscopy and Methodology

University and Inselspital Bern

International Conference on Diabetes Washington D.C. July 18th – 19th, 2014

Learning Objectives

• How can Magnetic Resonance Imaging (MRI) and

Spectroscopy (MRS) elucidate lipid metabolism in vivo?

• Pertinent studies on insulin resistance and diabetes type 2

using MRI and MRS

• Future developments and limitations of MRI/MRS

for studies of lipid metabolism in vivo

Outline of the talk

• Insulin resistance => lipid vs. glucose metabolism

• Why such an emphasis on Magnetic Resonance

Imaging and (multinuclear) Spectroscopy?

• Different organs affected

• Lipid compartments, body composition, visceral fat

• Lipid composition of adipose tissue and hepatic fat

• Intra- (IMCL) vs. extramyocellular (EMCL) lipids

• Lipids in liver (IHCL), heart (ICCL), pancreas (IPCL)

• Developments and limitations of MRI/MRS

Terminology

Metabolic

syndrome

Obesity

Insulin

resistance

Diabetes

Ep

idem

iolo

gy

Path

op

hysio

log

y

an

d C

linic

s

2010

Obesity (BMI≥30 kg/m2) Diabetes

Age-Adjusted Prevalence of Obesity and Diagnosed Diabetes Among U.S. Adults

<4.5% Missing data

4.5%–5.9% 6.0%–7.4%

7.5%–8.9% ≥9.0%

18.0%–21.9%

<14.0% Missing Data

14.0%–17.9%

22.0%–25.9% ≥26.0%

http://www.cdc.gov/diabetes/statistics

Cardiovascular Risk of Metabolic Syndrome / Insulin Resistance

nwhc.net, yogiwellnessjourney.blogspot.com

Magnetic Resonance: Non invasive access to the organs

Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 365: 1415 (2005)

Liver Adipose

Tissue Skeletal

Muscle

Pancreas

Heart

That you may already know….

e.g. SIEMENS TIM TRIO

3.0 Tesla = 128 MHz 1H

“Contrast mechanism” in MR

Petersen (GE), Golman et al (PNAS), Basford et al. (Arch.Phys.Med.Rehabil.), Finn (Radiology), radiologie-city-plaza, SIEMENS, Uni Freiburg, AMSM Bern

1 ppm 2 3 4

MR Spectrum

4 3 2 1

e.g. Lactate

chemical shift => chemical identity

sig

nal in

tensity

=>

co

nce

ntr

atio

ns

OH

-OOC-CH-CH3

-

Multinuclear MR imaging/spectroscopy

Glucose extra Glucose intra Glucose-6-Phosphate

Transport Hexokinase

UDP-Glucose Glycogen

Glycogen-synthase

Glycogen-phosphorylase

Glycolysis

TCA-Cycle

ATP PCr Beta-oxidation IMCL, IHCL, ICCL

Glutamate (labeled)

Acetylcarnitine

Acetyl-CoA

Glucose-1-Phosphate

Pyruvate Lactate Adipose tissue

1H-MRS

1H-MRS

1H-MRS

1H-MRI

13C-MRS

13C-MRS

13C-MRS

Hyperpolarized metabolites

13C-MRS

31P-MRS

31P-MRS

31P-MRS

Phospholipid metabolism

Metabolic Syndrome / Insulin Resistance Pathophysiology, Different Organs


Functional MRI of skeletal muscle: Whole Body Assessment of Adipose Tissue Compartments during a Lifestyle Intervention

Machann J et al. Radiology 257: 353 (2010)

Insulin resistant Insulin sensitive

Insulin

resistant

Insulin

sensitive

TULIP intervention

Kantartzis K, Machann J, Schick F, et al. Effects of a lifestyle intervention in metabolically

benign and malign obesity. Diabetologia 2011;54:864-868.

OIR = Obese, insulin resistant

MHO = metabolically benign

or healthy obesity

Lipid Composition: 1H spectra

Machann J, Stefan N, Schabel C, Schleicher E, Fritsche A,

Wurslin C, Haring HU, Claussen CD, Schick F (2013) Fraction of

unsaturated fatty acids in visceral adipose tissue (VAT) is lower

in subjects with high total VAT volume - a combined 1 H MRS

and volumetric MRI study in male subjects. NMR Biomed 26:

232-236.

Lipid composition: Visceral adipose tissue

Machann J, Stefan N, Schabel C, Schleicher E, Fritsche A, Wurslin C, Haring HU, Claussen CD, Schick F (2013)

Fraction of unsaturated fatty acids in visceral adipose tissue (VAT) is lower in subjects with high total VAT volume

- a combined 1 H MRS and volumetric MRI study in male subjects. NMR Biomed 26: 232-236.

Lipid composition: 13C spectra Effects of diet

Hwang JH, Bluml S, Leaf A, Ross BD. In vivo characterization of fatty acids in human adipose tissue using natural

abundance 1H decoupled 13C MRS at 1.5 T: clinical applications to dietary therapy. NMR Biomed. 2003; 16: 160-167.

(1) -CH=CH- or

-CH=CH-CH2-CH=CH-

(2) -CH=CH-CH2-CH=CH-

Lipid composition of neonates: Development with age

Thomas EL, Hanrahan JD, Ala-Korpela M, Jenkinson G,

Azzopardi D, Iles RA, Bell JD. Noninvasive characterization

of neonatal adipose tissue by 13C magnetic resonance

spectroscopy. Lipids 1997; 32: 645-651.

Lipid composition of membranes: Hepatic phospholipid metabolism

Schlemmer HP, Sawatzki T, Sammet S, Dornacher I, Bachert P, van Kaick G, Waldherr R, Seitz HK. Hepatic phospholipids in

alcoholic liver disease assessed by proton-decoupled 31P magnetic resonance spectroscopy. J.Hepatol. 2005; 42: 752-759.

55y, female, fibrosis 49y, male, cirrhosis



Fat-selective MRI of skeletal muscle: Spectral-spatial-selective pulses and correlation with metabolic data

Machann J, Bachmann OP, Brechtel K, et al. J Magn Reson Imaging 2003;17:350-357.

32y, male, IS 34y, male, IR

27y, male, IR 34y, female, IS

TA m.tibialis anterior

TP m.tibialis posterior

GL m.gastrocnemius lateralis

GM m.gastrocnemius medialis

SOL m.soleus

PLB m.peroneus longus et brevis

1H MR spectrum of skeletal muscle

Arbitrary vertical scales

ppm 7 4 2 ppm 78 3 ppm 8

Deoxy-

myoglobin Carnosine

Creatine

TMA

Taurine

IMCL

EMCL

Acetyl-

Carnitine

Lactate

Two types of lipids: Schick et al. Magn.Reson.Med. 29: 158-167 (1993)

soleus muscle yellow bone marrow

Origin of the two lipid compartments: Rotation of skeletal muscle in the magnetic field B0

Boesch, Slotboom, Hoppeler, Kreis.

Magn.Reson.Med. 37: 484 (1997)

M. tibialis anterior

32 yr old woman

PRESS, 20ms TE

Myocellular lipids:

EMCL (extra) is

affected by orientation,

IMCL (intra) is not

Cr-CH2

Cr-CH3

EMCL CH2

IMCL CH2

4 3 2 1 0 ppm

[degrees]

-16

0

31

52

68

80

Adipose tissue vs. intramyocellular lipids [EMCL vs. IMCL]

subcutaneous fat

muscular fasciae

Intramyocellular

Lipids = IMCL

Extramyocellular

Lipids = EMCL

EMCL vs. IMCL signals with varying adipose tissue

C.Boesch & R.Kreis.

Ann.NY Acad.Sci.

904: 25-31 (2000)

EMCL

IMCL

10 % 0.1 %

subcutaneous fat

muscular fasciae

muscle tissue

1 %

0.0 2.0 4.0 6.0 8.0 10.0 12.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

0.0 2.0 4.0 6.0 8.0 10.0 0.0

2.0

4.0

6.0

8.0

10.0

12.0

12.0

Morphometry: Vv (lit, f) [mmol/kg ww] Biochemistry: triglycerides [mmol/kg ww]

Vv (

lit, f)

[m

mo

l/kg

ww

]

MR

S: IM

CL [m

mo

l/kg

ww

]

Howald, Boesch, Kreis et al.

J.Appl.Physiol. 92: 2264 (2002)

trained

untrained

r = 0.934

r = 0.475

r = 0.413

MR

S: IM

CL [m

mo

l/kg

ww

]

Biochemistry: triglycerides [mmol/kg ww]

Same subject examined 48 h and

1 week after exhaustive exercise

Comparison MRS, biochemical analysis and morphometry

Comparison MRS, biochemical analysis and morphometry

Howald, Boesch, Kreis et al. J.Appl.Physiol. 92: 2264 (2002)

Correlation coefficient r

Slope Intercept

[mmol/kg ww]

1H-MRS vs.

EM morphometry 0.934

0.467 ± 0.059 p < 0.001

0.367 ± 0.305 n.s.

1H-MRS vs.

biochemical assay 0.413

0.196 ± 0.153 n.s.

1.414 ± 0.859 n.s.

EM morphometry vs.

biochemical assay 0.475

0.445 ± 0.292 n.s.

2.352 ±1.639 n.s.

Lipoproteins and phospholipids

http://www.uwsp.edu/

EM MRS

1H-MRS: Diffusion in IMCL Droplets

Fujimoto T et al. Histochem Cell Biol 130: 263. 2008

Classical view Hypothesis

Lipid droplets

in Leukocytes

1H-MRS: Diffusion in IMCL Droplets M

ag

neti

c f

ield

gra

die

nt

Free Restricted or Hindered

0.611.52ppm

b = 6.0x103

s/mm2

0.611.52ppm

b = 1.4x104

s/mm2

0.611.52ppm

b = 2.4x104

s/mm2

0.611.52ppm

b = 3.8x104

s/mm2

0.611.52ppm

b = 5.4x104

s/mm2

EMCL vs. IMCL: Decay due to diffusion

IMCL

EMCL

IMCL IMCL IMCL

IMCL

EMCL

EMCL

EMCL

EMCL

Brandejsky V, Kreis R, Boesch C. Restricted or severely hindered diffusion of intramyocellular lipids in

human skeletal muscle shown by in vivo proton MR spectroscopy. Magn Reson Med 2012;67:310-316.

Depletion and replenishment of intramyocellular lipids

IMCL

4 4 4 3 3 3 2 2 2 1 1 1 ppm ppm ppm

Susceptibility

1H-MRS: Intramyocellular Lipids (IMCL) Other Influences: Exercise and Diet

low lipid diet

(6 % fat)

0.0

4.0

2.0

6.0

8.0

0 1 2 3 4 5

high lipid diet

(63 % fat)

[days post marathon]

M.vastus medialis M.vastus intermedius M.tibialis anterior

0 1 2 3 4 5 0.0

4.0

8.0 diet

12.0

[mm

ol/kg w

w]

[mm

ol/kg w

w]

work

Boesch C, Decombaz J, Slotboom J, Kreis R. Proc Nutr Soc 1999;58:841-850.

1H-MRS: Intramyocellular Lipids (IMCL) Relation with Insulin Sensitivity

Stein, Szczepaniak,

Dobbins, Snell, McGarry.

ISMRM Annual Meeting

(1998), p.388 (abstract)

Krssak, Petersen,

Dresner, DiPietro, Vogel,

Rothman, Shulman,

Roden. Diabetologia

42:113-116 (1999)

Jacob, Machann, Rett,

Brechtel, Volk, Renn, Maerker,

Matthaei, Schick, Claussen,

Häring.

Diabetes 48: 1113-1119 (1999)

Obese diabetes patients

show higher IMCL levels

(TML = Total muscle lipids)

Higher IMCL related to lower

insulin sensitivity

Higher IMCL levels in insulin

resistant patients

Stein et al. ISMRM Abstract 1998

Krssak et al. Diabetologia 1999

Jacob et al. Diabetes 1999


1/HOMA: Insulin sensitive >>>

0

1

2

3

4

5

6

0 1 2

Resting IMCL [mmol/kg ww]

endurance runners

sedentary subjects

Decombaz, Schmitt, Ith, Decarli, Diem, Kreis, Hoppeler, Boesch. Am.J.Physiol. 281: R760 (2001)

HOMA = homeostasis model assessment

= (fasting GLU x fasting INS) / 22.5

1/HOMA : T>UT p<0.05 1H-MRS in tibialis ant m.


Three-dimensional relationship between VO2max, IMCL in tibialis anterior muscle

and insulin sensitivity.

Thamer, Machann,

Bachmann, Haap, Dahl,

Wietek, Tschritter, Niess,

Brechtel, Fritsche,

Claussen, Jacob, Schick,

Haring, Stumvoll. J Clin

Endocrinol Metab 2003,

88:1785-1791.

IR

IS

low high

IS

high

IR

high

Intramyocellular lipids (IMCL) Cause or consequence?

Petersen KF, Shulman GI.

Etiology of insulin resistance.

Am.J.Med. 2006; 119: S10-S16.

Thamer, Machann, Bachmann, Haap, Dahl,

Wietek, Tschritter, Niess, Brechtel, Fritsche,

Claussen, Jacob, Schick, Haring, Stumvoll.

J Clin Endocrinol Metab 2003, 88:1785-1791.


Insulin resistant Sedentary Athletes

Intr

am

yocellu

lar

lipid

s (

IMC

L)

“Bad” IMCL? “Good” IMCL?

Intramyocellular lipids (IMCL) Cause or consequence?

Ith M, Zwygart K, Stettler R, Le KA, Christ E, Schmid JP, Kreis R, Vermathen P, Boesch C.

Proc.Intl.Soc.Magn.Reson.Med. 2007; 15: 2604.

m.quadriceps femoris

Effect of fructose overconsumption in offspring T2D and controls

Le KA, Ith M, Kreis R, Faeh D, Bortolotti M, Tran C, Boesch C, Tappy L (2009) Am J Clin Nutr 89: 1760-1765.

Vegan diet: IMCL and HOMA

Goff LM, Bell JD, So PW, Dornhorst A, Frost GS (2005)

Veganism and its relationship with insulin resistance and intramyocellular lipid. Eur J Clin Nutr 59: 291-298.

<= Insulin Sensitivity

<= Beta Cell Activity

IMCL: Influence of 2 Weeks Training

IMCL content, expressed as percentage of the water resonance. White bars, before cycling

test; black bars, after cycling test. *, Significant differences.

“The Increase in Intramyocellular Lipid Content Is a Very Early Response to Training”

Schrauwen-Hinderling,

Schrauwen, Hesselink,

van Engelshoven,

Nicolay, Saris, Kessels,

Kooi.

J Clin Endocrinol Metab

2003, 88:1610-1616.

1H-MRS: Intramyocellular Lipids (IMCL) Influence of free fatty acids

Examples of 1H-spectra of one subject at different time points for TA during

hyperinsulinemia + lipid infusion (a), and during hyperinsulinemia alone (c).

Brechtel, Dahl, Machann, Bachmann, Wenzel, Maier, Claussen, Haring, Jacob, Schick.

Magn Reson Med 2001, 45:179-183

13C-MRS: Glycogen depletion and recovery

ppm 150 100

Creatine Glycogen

Rest

6 h

2 h

30 min

recovery

& nutrition

1.5 h 70 % VO2max in intervals

Rotman S, Slotboom J, Kreis R, Boesch C, Jequier E.

Magn Reson Mater Phy 2000;11:114-121.

IMCL and Glycogen: Influence of hyperglycemia

S.Jenni, C.Oetliker,

S.Allemann, M.Ith, L.Tappy,

S.Wuerth, A.Egger, C.Boesch,

Ph.Schneiter, P.Diem,

E.Christ, C.Stettler,

Diabetologia 2008, 51, 1457

IMCL and Glycogen: Influence of hyperglycemia Substrate selection by the body

S.Jenni, C.Oetliker, S.Allemann, M.Ith, L.Tappy, S.Wuerth, A.Egger, C.Boesch,

Ph.Schneiter, P.Diem, E.Christ, C.Stettler, Diabetologia 2008, 51, 1457

Percent

Euglycaemia

Hyperglycaemia

0 20 40 60 80 100 Proteins

Lipids

Endogenous

glucose

Glucose

infusion

Glycogen

1H-MRS 13C-MRS

1H-MRS: Acetylcarnitine

ppm 1.0 2.0 3.0 4.0 5.0

> Exercise leads to:

— Utilization of IMCL

(1) Kreis R et al., NMR Biomed 1999; 12:471.

— Production of

acetylcarnitine (AcCar1)

IMCL

TMA

AcCar

N +

O

COO -

O

TMA

AG - AcCar

N +

O

COO -

O

TMA

-

Acetylcarnitine after heavy workload

0 0

2

3

1

5 20 25 30 time [min]

workload

Metabolites

Acetylcarnitine

S [au]

Acetylcarnitine as marker for Acetyl-CoA from increased fat oxidation?

-1

0

1

2

3

4

5

6

∆ A

cety

lcarn

itin

e [a

.u.]

Euglycemia Hyperglycemia

p < 0.01 B

Boss A, Kreis R, Jenni S, Ith M, Nuoffer JM, Christ E, Boesch C, Stettler C, Diabetes Care 2011; 34:220.

Acetylcarnitine

Acetyl-CoA ~103

1H-MRS: Acetylcarnitine

> Car: involved in transport of fatty acids into mitochondria

> Car: buffers excess acetyl-CoA by producing AcCar

From Carlin JI et al., J Appl Physiol 1990;69:42.

Muscle biopsies

Acetylcarnitine

Acetyl-CoA ~103

Acetylcarnitine

Lindeboom L, Nabuurs C, Hoeks J, Vosselman M, Brouwers B,

van de Weijer T, Timmers S, Phielix E, Kooi E, Hesselink M,

Wildberger J, Schrauwen P, Schrauwen-Hinderling V. Resting

acetylcarnitine concentration in skeletal muscle, as measured

with long TE 1H-MRS, is associated with insulin sensitivity.

Proc.Intl.Soc.Magn.Reson.Med. 2014; 22: 3604.

How is the excess acetyl-CoA produced?

Mitochondrion

TCA

cycle

Acetyl-CoA

Harris RC et al., J Appl Physiol 1987; 63:440. Spriet LL et al., Am J Physiol 1992; 263:C653.

Pyruvate

Glycogen Glucose /

CARBOHYDRATE OXIDATION

PDC

FAT OXIDATION

Free fatty acids / IMCL

CPT-I

Acetylcarnitine

Acetylcarnitine Carnitine

Carnitine

Cytoplasm

13C-MRS: Mitochondrial Activity, TCA cycle

-> [2-13C] acetate infusion

-> 13C incorporation into glutamate C4 (33.6 - 35.0 ppm)

-> modeling (Cwave software) -> TCA cycle flux

Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline

GW, Shulman GI. Science 2003; 300: 1140-1142.

PYR

AcCoA

OAA

CIT

a-Keto-

glutarate

TCA-

cycle

Glutamate C4

[2-13C] Acetate



MRS vs. Imaging based methods

Kim H, Taksali SE, Dufour S, Befroy D,

Goodman TR, Petersen KF, Shulman

GI, Caprio S, Constable RT.

Comparative MR study of hepatic fat

quantification using single-voxel proton

spectroscopy, two-point dixon and three-

point IDEAL.

Magn.Reson.Med. 2008; 59: 521-527.

Effects of a short-term overfeeding with

fructose or glucose in healthy young males

Eleven subjects, 7 days diet:

(1) weight maintenance, control diet

(2) High Fructose Diet (3·5 g

fructose/kg fat-free mass per day)

(3) High Glucose Diet (3·5 g

glucose/kg fat free mass per day)

muscle

liv

er

Ngo Sock ET, Le KA, Ith M, Kreis R,

Boesch C, Tappy L. Effects of a short-

term overfeeding with fructose or glucose

in healthy young males. Br J Nutr 103:

939-943 (2010).

Effect of fructose overconsumption in offspring T2D and controls

Le KA, Ith M, Kreis R, Faeh D, Bortolotti M, Tran C, Boesch C, Tappy L (2009) Am J Clin Nutr 89: 1760-1765.

Effect of exercise: Average DIMCL/IMCLpre and DIHCL/IHCLpre

DIMCL DIHCL+/- SEM +/- SEM

-40%

-30%

-20%

-10%

0%

10%

20%

30%

40%

50%

Skeletal

muscle:

IMCL

p = 0.006

Liver:

IHCL

p = 0.026

Effect of exercise on IMCL and IHCL

Adipose

tissue

Liver

Working

muscle

Glycogen

Glucose

FFA

IHCL FFA

IMCL

Lipid Composition: Liver vs. subcutaneous/visceral fat

Lundbom J, Hakkarainen A,

Soderlund S, Westerbacka J,

Lundbom N, Taskinen MR

(2011) Long-TE 1H MRS

suggests that liver fat is more

saturated than subcutaneous

and visceral fat. NMR Biomed

24: 238-245.



Intracardiomyocellular lipids: ICCL

Ith M, Stettler C, Xu J, Boesch C,

Kreis R. Cardiac lipids show diurnal

changes and long-term variations in

healthy human subjects. NMR

Biomed. 2014; minor revision.

Intracardiomyocellular lipids: ICCL Diurnal changes and long-term variations

Ith M, Stettler C, Xu

J, Boesch C, Kreis

R.

Cardiac lipids show

diurnal changes and

long-term variations

in healthy human

subjects.

NMR Biomed. 2014;

minor revision.

IMCL, IHCL, ICCL: Effects of exercise

Bucher J, Kruesi M, Zueger T, Ith M, Stettler C, Diem P, Boesch C, Kreis R, Christ E. The effect of a single bout of a 2h

aerobic exercise on ectopic lipids in skeletal muscle, liver and the myocardium. Diabetologia 2014; 57: 1001-1005.

ICCL cardio

IHCL hepato

IMCL myo

Myocardial fat in metabolic syndrome

Nyman K, Graner M, Pentikainen MO, Lundbom J, Hakkarainen A, Siren R, Nieminen MS, Taskinen MR, Lundbom N, Lauerma

K (2013) Cardiac steatosis and left ventricular function in men with metabolic syndrome. J Cardiovasc Magn Reson 15: 103.

Cardiac Steatosis in DM2 Dallas Heart Study

McGavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R, Levine BD, Raskin P, Victor RG, Szczepaniak LS.

Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study.

Circulation 2007; 116: 1170-1175.

Myocardial fat in dilated cardiomyopathy

Graner M, Pentikainen MO, Nyman K, Siren R, Lundbom J,

Hakkarainen A, Lauerma K, Lundbom N, Nieminen MS, Petzold

M, Taskinen MR (2014) Cardiac steatosis in patients with dilated

cardiomyopathy. Heart [doi: heartjnl-2013-304961]

Myocardial triglyceride Epicardial fat Pericardial fat

(TG) content



Pancreatic fat: Multiecho

Thomas EL, Fitzpatrick JA, Malik SJ,

Taylor-Robinson SD, Bell JD.

Whole body fat: Content and

distribution.

Prog.NMR Spectroscopy 2013; 73:

56-80.

Pancreatic fat – measured by MRS

Lingvay I, Esser V, Legendre JL, et al.

Noninvasive quantification of pancreatic fat in humans.

J Clin Endocrinol Metab 2009;94:4070-4076.

Pancreatic fat – Fat selective imaging

Heni M, Machann J, Staiger H, Schwenzer NF,

Peter A, Schick F, Claussen CD, Stefan N,

Haring HU, Fritsche A.

Pancreatic fat is negatively associated with

insulin secretion in individuals with impaired

fasting glucose and/or impaired glucose

tolerance: a nuclear magnetic resonance study.

Diabetes Metab.Res.Rev. 2010; 26: 200-205.

Pancreatic fat: MRS vs. IDEAL

Hu HH, Kim HW, Nayak KS, Goran

MI. Comparison of fat-water MRI and

single-voxel MRS in the assessment

of hepatic and pancreatic fat

fractions in humans. Obesity 2010;

18: 841-847.

Summary and Outlook

> Advantages / disadvantages

> Development

> Methodological competitors

Magnetic resonance imaging and (multinuclear) spectroscopy vs. other methods

> PRO‘s > Non invasive Biopsy

> Non ionizing PET, CT

> Repeatable External tracers, biopsy

> Localized Body fluids, breathing air

> CON‘s > Insensitive PET, PET/CT, PET/MR etc.

> Not beside, not mobile US, blood sample, etc

> Expenses, availability US, blood sample, etc

MRI and MRS: Future developments

> Stronger magnetic fields (7 Tesla, 9.4 Tesla, …)

— Increased sensitivity (signal-to-noise-ratio)

— Better spectral resolution (MR spectroscopy)

— Increased effects (e.g. signals of brain activation)

> New acquisition techniques (e.g. coil arrays, sampling scheme)

— Faster acquisition

— Increased sensitivity

> Hyperpolarized substances

— Increased sensitivity

— Better spatial resolution (Metabolite images)

> Availability

— Neurosciences (fact)

— Physiology, sports medicine, endocrinology (wishful thinking?)

Advantages of ultra-high magnetic fields Examples at 7 Tesla

Wijsman CA, van Opstal AM, Kan HE,

Maier AB, Westendorp RG, Slagboom PE,

Webb AG, Mooijaart SP, van Heemst D.

Proton magnetic resonance spectroscopy

shows lower intramyocellular lipid

accumulation in middle-aged subjects

predisposed to familial longevity.

Am.J.Physiol. 2012; 302: E344-E348.

Ren J, Dimitrov I, Sherry AD, Malloy CR.

Composition of adipose tissue and marrow fat in

humans by 1H NMR at 7 Tesla. J.Lipid Res.

2008; 49: 2055-2062.

4 3 2 1 ppm

13C-MRS: Hyperpolarized substances [13C1]-pyruvate metabolism in human prostate cancer

Nelson SJ, Kurhanewicz J, Vigneron DB, Larson

PE, Harzstark AL, Ferrone M, Van CM, Chang

JW, Bok R, Park I, Reed G, Carvajal L, Small EJ,

Munster P, Weinberg VK, rdenkjaer-Larsen JH,

Chen AP, Hurd RE, Odegardstuen LI, Robb FJ,

Tropp J, Murray JA.

Metabolic imaging of patients with prostate cancer

using hyperpolarized [1-13C]-pyruvate.

Sci.Transl.Med. 2013; 5: 198ra108.

Images of lactate/pyruvate

indicate cancer

Studies of metabolism in

insulin resistance limited by

time restrictions of

hyperpolarization -

nonetheless enormous

potential

Take home message

• Insulin resistance: prominent application of multinuclear MRI/MRS

• MR is non-invasive, non-ionizing, localized, and repeatable

• Multiple organs accessible

• Insulin resistance involves lipid and carbohydrate metabolism

• Body composition, fat compartments

• Lipid composition

• IMCL, IHCL, ICCL, IPCL

• Further development, stronger magnetic fields, techniques

• Availability for physiologists, endocrinologists, sports medicine, etc.

Thank you….

Documents

Magnetic resonance examinations on lipid metabolism in insulin