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