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Exercise is Medicine: Translational Research in
Obesity and Insulin Resistance
Alice S. Ryan, Ph.D.Baltimore VA Medical CenterUniversity of MD School of Medicine
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“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
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Percentage of Adults Who Reported No Leisure-Time Physical Activity by Age in Maryland, 2001-2003
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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%
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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
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Abdominal FatAbdominal Fat Mid-thighMid-thigh
Where is the Fat? is the Fat?
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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
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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
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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
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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 )
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Visceral Adipose Tissue Decreases with ↑VO2 max
r=-0.47, p<0.01
Lynch et al., J Appl Physiol, 2001
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Insulin 80mU/min
BEDSIDE
Measurement of Insulin Sensitivity:Hyperinsulinemic-euglycemic clamp
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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
*
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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
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Can We Modify Obesity and Insulin Resistance with Exercise Training?
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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
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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
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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
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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
‡
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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
‡ ‡
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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
+
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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
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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
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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
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“BEDSIDE TO BENCH”
Skeletal Muscle and Adipose Tissue Mechanisms of Exercise of Exercise
Gluteal Adipose Tissue BiopsyVastus Lateralis Biopsy
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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
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Reduced Skeletal Muscle Capillarization is Associated with Glucose Intolerance
Prior et al. Microcirculation, 2009
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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
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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
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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
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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)
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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
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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
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Metabolic Flexibility is Associated with Insulin Sensitivity in Postmenopausal Women
n = 92, r=0.46, P<0.0001
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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
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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
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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
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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
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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
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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
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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
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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
*
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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
*
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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
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“Bench to Bedside”
How is this Translated to an Exercise Prescription?
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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
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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
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Physical Activity Pyramid
Leisure Time Activity
Cardiovascular Exercise
Strength TrainingFlexibility
Inactivity in moderation
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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