exercise is medicine: translational research in obesity and insulin resistance alice s. ryan, ph.d....

Exercise is Medicine: Translational Research in

Obesity and Insulin Resistance

Alice S. Ryan, Ph.D.Baltimore VA Medical CenterUniversity of MD School of Medicine

“basic muscle-strengthening activities twice a week … and find two and a half more hours in your week for moderate aerobic activity.” – Science of Healthy Living

Advice from Newsweek 2010

Percentage of Adults Who Reported No Leisure-Time Physical Activity by Age in Maryland, 2001-2003

Overweight: By Body Mass IndexNationwide vs. Maryland

30

32

34

36

38

40

42

1990 1992 1994 1996 1998 2000 2002 2004 2006 2008

Med

ian

%

Nationwide Maryland

Data from CDCNational Center for Chronic

Disease Prevention & Health Promotion

Behavioral Risk Factor

Surveillance System

Obese: By Body Mass IndexNationwide vs. Maryland

10

14

18

22

26

30

Med

ian

%

Nationwide Maryland

% BMI>30 28%

% BMI>25 40%

31%

12%

0

10

20

30

40

BMI (kg/m2)<22

22-2526-30

31-35

>35 <22

22-2526-30

31-35

>35

Per

cen

t D

iab

etic

Age (years) 20 - 54 60 - 74

Prevalence of Diabetes by Age and Obesity

Abdominal FatAbdominal Fat Mid-thighMid-thigh

Where is the Fat? is the Fat?

0

50

100

150

200

250

300

350

400

450

500

VAT SAT

1994-19961997-19992000-20022003-20062007-2009

Visceral and Subcutaneous Adipose Depots

Fat Distribution Trends in Postmenopausal Women

Sample: CaucasianN = 50 – 80 per group

Total and Central Obesity

0

10

20

30

40

50

60

70

80

90

100

BMI %FAT Waist

1994-1996

1997-1999

2000-2002

2003-2006

2007-2009

Increased Fasting Glucose & Insulin across VAT quintiles

101979796

908484

71

6151

0

20

40

60

80

100

120

<105 106-139 140-162 163-192 >193

Glucose (mg/dl)Insulin (pmol/L)

VAT quintiles (cm2)

11 1,2,3

1

Numbers signify P<0.05 from quintiles 1, 2, 3Analyses adjusted for age, fat mass, & race

1

1,2,3 1,2,3

Nicklas et al. Diabetes Care, 2003

VAT of ~ 100-110 cm2 is predictive of adverse lipid (HDL, TG) and diabetes risk factors in women.

Depres and Lamarche, Nutr Res Rev, 1993 Williams MJ et al, Int J Obes Relat Metab Disord,

1996 Nicklas et al., Diabetes Care, 2003

Visceral Adipose Tissue Risk

0

20

40

60

80

100

120

Athletes Controls

18-29 yr

30-39 yr

40-49 yr

50-70 yr

Exercise Reduces Visceral Fat in Women Athletes

N = 10 – 14 per group

Ryan et al. Am J of Physiol, 1996

P < 0.01

VA

T (

cm2 )

Visceral Adipose Tissue Decreases with ↑VO2 max

r=-0.47, p<0.01

Lynch et al., J Appl Physiol, 2001

Insulin 80mU/min

BEDSIDE

Measurement of Insulin Sensitivity:Hyperinsulinemic-euglycemic clamp

Chronic Exercise in Older Women Prevents the Decline in Insulin Sensitivity Observed with Aging

Ryan et al. J Appl Physiol, 2001

Glu

cose

Up

take

Glu

cose

Up

take

(um

ol/k

g(u

mo

l/kg

FF

MF

FM/m

in/m

in))

*P < 0.05

.

0

10

20

30

40

50

60

70

ControlsAthletes

18-2930-39

40-49 50-69

18-2940-50

*

Older Elite Football Players have Reduced Cardiac Risk Factors

Former Colts compared to age, BMI, race and current physical activity level matched men: 26% lower visceral fat and lower total body fat

(p<0.01). 13% higher muscle mass (p<0.01) 37% higher HDL-C & 31% lower TG (p<0.05)

Suggests that the high levels of exercise in young adulthood conferred benefits later in life

Lynch et al. Med Sci Sports Exerc, 2007

Can We Modify Obesity and Insulin Resistance with Exercise Training?

Dietary Stabilization

0 m

6 m 12 m

Study Design

InterventionsWL: 1x/wkAEX+WL: 3x/wk

Weight Stable 2 wks

Metabolic Testing

Metabolic Testing

Screening Enrollment

• 45 - 80 year old Caucasian or African American women• Postmenopausal (1 year)• BMI: 25 – 50 kg/m2• Sedentary, Weight stable• Non-smokers (≥ 1 year)• No symptomatic heart disease or medications interfering with muscle metabolism

0 m

6 m 12 m

Study Design

Interventions

Metabolic Testing

•VO2max, Body Composition (DXA, CT)

•3-hr OGTT

•3 hr 80 mU/m2/min Hyperinsulinemic-euglycemic Clamp w/Indirect Calorimetry

•Skeletal Muscle Biopsy (basal & @120min)

•Gluteal & Abdominal Adipose Tissue Biopsy

Metabolic Testing

Study DesignScreeningN ~ 3000

EnrollmentN = 292

AEX+WL N = 88 Entered

WLN = 86

Entered

Metabolic TestingN = 174

AEX+WLN = 53

Completed

WLN = 50

Completed

Dropped N = 63Completed & Noncompliant N=8

60

65

70

75

80

85

90

AEX+WL WL0

0.5

1

1.5

2

2.5

AEX+WL WL

Pre

Post

Weight VO2max

** *

(kg

)

(l/m

in)

Successful Weight Loss with AEX+WL and WL Improvements in Fitness only with AEX+WL

*P<0.001 *P<0.001

14% 8% 8%

‡P<0.05 AEX+WL vs. WL

‡

0

10

20

30

40

50

AEX+WL WL10

20

30

40

50

AEX+WL WL

Pre

Post

Fat Mass FFM

(kg

)

(kg

)

Losses of both Fat Mass and FFM with AEX+WL and WL

16% 13%

**

2% 4%

*P<0.001 ‡P<0.05

‡ ‡

60

80

100

120

140

160

AEX+WL WL

Pre

Post

Visceral Fat Area Mid-thigh Intramyocellular Lipid

Reductions in Abdominal and Intra-muscular Fat

(cm

2 )

(cm

2 )

16% 13%

9%

*P<0.001

* * +

0

5

10

15

20

25

AEX+WL WL

Pre

Post

+

Improvements in Insulin Sensitivity

20

30

40

50

60

70

80

AEX+WL WLGlu

cose

Up

take

(m

ol/

kgF

FM/m

in)

14% 6%

*

*P<0.01 ‡P<0.05

Improvements in Insulin Sensitivity are associated with an Increase in Fitness

-0.40 -0.20 0.00 0.20 0.40 0.60 0.80 1.00

-40.00

-20.00

0.00

20.00

40.00

60.00

80.00

∆ VO2max (l/min)

∆ M

(µ

mo

l/kg

FF

M/m

in)

r=0.30,P<0.05

Mechanisms of Action of Lifestyle Interventions

MuscleAdipose

Insulin Sensitivity

Capillarization Insulin Activation of

Glycogen Synthase↑ Enzymes of Fatty Acid

Metabolism

Inflammation

Fat stores

Exercise Training

Weight Loss

“BEDSIDE TO BENCH”

Skeletal Muscle and Adipose Tissue Mechanisms of Exercise of Exercise

Gluteal Adipose Tissue BiopsyVastus Lateralis Biopsy

Skeletal Muscle Capillarization and Fiber Type

Double Stain Myosin ATPase

CD: Capillary Density (cap/mm2)

CFPE: Capillary-to-fiber perimeter exchange index (cap/mm perimeter)

Type I: stain dark brown/black

Type IIa: stain light brown/white

Type IIx: stain brown

Reduced Skeletal Muscle Capillarization is Associated with Glucose Intolerance

Prior et al. Microcirculation, 2009

glucoseout glucosein G6P G1P UDP-glucose glycogen

IR

GLUT4

insulin

+ GS

HK PGM UPP

glycolysis

Lawrence JC and Roach PJ, Diabetes 46:541-547, 1997

Regulation of Glucose Uptake During Insulin Stimulation in Skeletal Muscle

Insulin Sensitivity is Reduced In Women with Impaired Glucose Tolerance

20

30

40

50

60

70

80

NGT IGT Glu

cose

Up

take

(m

ol/

kgF

FM/m

in)

*

*P<0.01n = 64 n = 34

Glycogen synthaseindependent activity

(nmol/min/mg protein)

In Vivo Insulin Increases GS Activityin Obese Postmenopausal NGT & IGT Women

p<0.0001

0

1

2

3

4p<0.0001

0

1

2

3

4

basal insulin

NGT IGT

basal insulin

Women with IGT have Lower In Vivo InsulinActivation of GS than Women with NGT

3-fold inc

2.4-fold inc

p<0.05

0

1

2

3

4

0

1

2

3

4

basal insulin

NGT IGT

basal insulin

Glycogen synthaseindependent activity

(nmol/min/mg protein)

AEX+WL Increases GS Activityin Obese Postmenopausal Women with IGT

NGT WL NGT AEX+WL

0

1

2

3

4

5

0

1

2

3

4

5

Glycogen synthaseindependent activity

(nmol/min/mg protein)

IGT WL IGT AEX+WL

Glycogen synthaseindependent activity

(nmol/min/mg protein)

p<0.01

basal insulin basal insulinpre post

basal insulin basal insulinpre post

0

1

2

3

4

5

0

1

2

3

4

5

0.7

0.8

0.9

1

Fasting Insulin-Stimulated

Metabolic Inflexibilityin Obese Subjects

lean

obese

Kelly & Mandarino, Diabetes 2000

Metabolic Inflexibility Ability to switch from fat utilization during

fasting to carbohydrate utilization during hyperinsulinemia (Kelley et al. 2000)

Clamp RQ – Fasting RQ

Metabolic Flexibility is Associated with Insulin Sensitivity in Postmenopausal Women

n = 92, r=0.46, P<0.0001

acetyl-CoANAD

NADH

TCAcycle

CPT-1

CPT-2inner membrane

CS

FA-CoA + carnitine FA-carnit ine + CoASH

FA-carnitine + CoASH

CO2

outer membrane

FA + CoA

FA-CoA + carnitine

ACS

TG

mitochondrion

LPL

TGFFA glucose

glucose G6P glycogen

GS

blood

cytosol

PDH

pyruvate

NAD

NADHETC

§-HAD

Regulation of Metabolic Flexibility at the Cellular Level

skeletalmuscle

0

2

4

6

8

10

12

14

WL WL+AEX

nm

ol/

min

/g

Pre Post

=-3%, P=NS =49%, P<0.05

P<0.01

Exercise + Weight Loss Increases Muscle LPL

WL AEX+WL

Pre Post

Skeletal Muscle Lipoprotein Lipase

0

500

1,000

WL WL+AEX

pm

ol/

min

/mg

pro

tein

Pre Post Pre Post

=-6%, P=NS =45%, P<0.05

P<0.05

Muscle Acyl-CoA SynthaseExercise + Weight Loss Increases Skeletal Muscle ACS

0

0.05

0.1

0.15

0.2

WL WL+AEX

µm

ol/

min

/mg

pro

tein

=-1%, p=NS =32%, P=0.05

P<0.08

Muscle Citrate Synthase

Pre Post Pre Post

Exercise + Weight Loss Increases Skeletal Muscle CS

0

5

10

15

20

25

WL WL+AEX

nm

ol/

min

/10

6 c

ell

s

0

4

8

12

WL WL+AEX

nm

ol/

min

/10

6 c

ell

s

=-18%, P=0.01 =-26%, P<0.001 =-14%, P=NS =-28%, P<0.001

Exercise + Weight Loss Decreases Adipose Tissue LPLGluteal Lipoprotein Lipase Abdominal Lipoprotein Lipase

Pre Post Pre Post Pre Post Pre Post

0

1

2

3

WL WL+AEX

=54%, p=NS =-32%, P=0.005

P<0.05

Exercise + Weight Loss Shifts Lipid Partitioning from Storage to Oxidation

Ratio of Abdominal to SM-LPL

Pre Post Pre Post

0

2

4

WL WL+AEX

=47%, p=NS

Ratio of Gluteal to SM-LPL

=-24%, p<0.05

Pre Post Pre Post

P<0.09

acetyl-CoANAD

NADH

TCAcycle

CPT-1

CPT-2inner membrane

CS

FA-CoA + carnitine FA-carnitine + CoASH

FA-carnitine + CoASH

CO2

outer membrane

FA + CoA

FA-CoA + carnitine

ACS

TG

mitochondrion

LPL

TGFFA glucose

glucose G6P glycogen

GS

blood

cytosol

PDH

pyruvate

NAD

NADHETC

§-HAD

Improvement in Metabolic Flexibility after AEX+WL:Fasting

skeletalmuscle

Insulin Suppresses ACS after Exercise Training

Change in insulin’s effect on ACS after AEX+WL in postmenopausal women (n = 17, *P<0.05).

-80

-60

-40

-20

0

20

40

(pm

ol/m

in/m

g p

rote

in)

Pre

Post

*

Insulin Suppresses -HAD after Exercise Training

Change in insulin’s effect on -HAD after AEX+WL in postmenopausal women (n = 17, *P<0.05).

-0.1

-0.08

-0.06

-0.04

-0.02

0

0.02

0.04

0.06

(um

ol/m

in/m

g p

rote

in)

Pre

Post

*

acetyl-CoANAD

NADH

TCAcycle

CPT-1

CPT-2inner membrane

CS

FA-CoA + carnitine FA-carnitine + CoASH

FA-carnitine + CoASH

CO2

outer membrane

FA + CoA

FA-CoA + carnitine

ACS

TG

mitochondrion

LPL

TGFFA glucose

glucose G6P glycogen

GS

blood

cytosol

PDH

pyruvate

NAD

NADHETC

§-HAD

Improvement in Metabolic Flexibility after AEX+WL:Insulin (Euglycemic Clamp)

skeletalmuscle

“Bench to Bedside”

How is this Translated to an Exercise Prescription?

Summary of the ACSM/AHA Updated Physical Activity Guidelines for Healthy Adults Under Age 65

• Do moderate-intensity cardiovascular activity for 30 minutes a day, 5 days a week

or• Do vigorous cardiovascular activity 20 minutes a day, 3 days a

week

and• Do 8 – 10 resistance-training exercises, performing 8 – 12

repetitions for each exercise, twice a week

• Moderate-intensity physical activity means working hard enough to raise your heart rate and break a sweat, yet still being able to carry on a conversation. It should be noted that to lose weight or maintain weight loss, 60 to 90 minutes of physical activity may be necessary. The 30-minute recommendation is for the average healthy adult to maintain health and reduce the risk for chronic disease.

• Med Sci Sports Exercise: 39(8); 1423-1434, 2007

Benefits of Aerobic Exercise Improved cardio-respiratory fitness

Weight Control

Improved Endurance

Stress Relief

Improved energy

Decreased fatigue

Improved immune system

Improved quality of sleep

Psychological benefits

Physical Activity Pyramid

Leisure Time Activity

Cardiovascular Exercise

Strength TrainingFlexibility

Inactivity in moderation

AcknowledgementsMany Thanks!

Investigators: Andrew Goldberg, M.D. Heidi Ortmeyer, Ph.D. Jacob Blumenthal, M.D. Lyndon Joseph, Ph.D. Susan Fried, Ph.D. John McLenithan, Ph.D. Steve Prior, Ph.D.

Clinical Staff: Joyce Evans, R.N. Sarah Witten, R.N. Kathie Brandt, R.N. Ivey Dorsey, R.N. Anita Neal, L.P.N. Cheryl Beasley, L.P.N. Luz Ortiz-Corral, R.N. Lynn Stars-Zorn, N.P. Linda Hatler, N.P. Peter Normandt, N.P.Dieticians: Kelly Ort, R.D. Kathy Simpson, R.D. Andriane Kozlovsky, R.D Amy Matson, R.D. Tara Caulder, R.D.

Exercise Physiologists: Lynda Robey, M.S. Gretchen Zietowski, M.S., R.N. Greig Frietag, M.S. Nicole Fendrick, M.S.. Melinda Erbe, M.S.Research Assistants: Melissa Gray Keisha Galloway, M.S. Agnes Kohler, M.S. Carole St. Clair Sara Herts Jonelle George Linsday Koepper Urmila Sreenivasan Tara McDonald Lisa McFarland Sumi Khan Nikki Glynn

Funding: VA NIH