handout

2/6/2014
APTA CSM 2014 Las Vegas, NV
Effects of Exercise Intervention on Metabolic
Abnormalities Associated with Metabolic
Syndrome: Cellular Perspective
Abraham D. Lee, Ph.D., P.T.
Associate Professor
Dept. of Rehabilitation Sciences
The University of Toledo
[email protected]
Learning Objectives
At the end of the session, participants will be able to
• Know diagnostic criteria for metabolic syndrome.
• Know the prevalence of metabolic syndrome.
• Explain etiologies of metabolic abnormalities
occurring in multiple organs (endothelium,
adipocytes, the liver, pancreas, and skeletal muscle),
which lead to the development of metabolic
syndrome.
• Explain the concept of metabolic inflexibility.
• Explain how exercise intervention improves the
components of metabolic syndrome.
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What is metabolic syndrome?
• Metabolic syndrome (MetS) refers to a clustering of
several interrelated cardiovascular risk factors of
metabolic origin, which promote the development
of cardiovascular disease and diabetes.
• Abnormalities associated with MetS (the
components of MetS) include:
–
–
–
–
–
Elevated plasma glucose ( Glucose)
Elevated plasma triglyceride ( TG)
Low high density lipoprotein ( HDL)
High blood pressure ( BP)
Abdominal obesity ( WC (waist circumference))
Criteria for MetS
Several organization contributed to establishment of the
criteria of MetS.
• World Health Organization (WHO)
• Adult Treatment Panel (ATP III) of National Cholesterol
Education Program (NCEP): NCEP ATP III
• International Diabetes Federation (IDF)
• American Heart Association (AHA)/National Heart
Lung Blood Institute (NHLBI)
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Criteria for MetS
WHO (1998)
NCEP ATP III (2005) IDF (2005)
Insulin resistance
IGT, IFG, T2DM or
lowered insulin
sensitivity
Plus 2 of the following
None
Any 3 of the following 5 features
None
Obesity/
Abdominal
obesity
M: WHR>0.90
F: WHR>0.85
&/or BMI> 30
kg/m2
WC 102 cm (40”) in men
WC 88 cm (35”) in women
Increased WC in population
specific group; for Europids
94 cm Men; 80 cm Women
WC: waist circumference
Plus any 2 of the following
TG 150 mg/dl or drug Tx for
elevated level
FTG
TG 150 mg/dl
HDL
HDL < 35 mg/dl in HDL < 40 mg/dl in men & <50
mg/dl in women or drug Tx for
men or <39
mg/dl in women low level
Blood pressure
140/90 mmHg
Glucose
IGT, IFG, or T2DM
Other
Microalbuminuria,
>30 mg/g creatinine
TG 150 mg/dl or drug Tx for
elevated level
HDL < 40 mg/dl in men & <50
mg/dl in women or drug Tx for
low level
130/85 or HTN Tx
130/85 mmHg or HTN Tx
100 mg/dl (include diabetes)
110 mg/dl (2001 version)
100 mg/dl (includes diabetes)
Adapted from Grundy et al., Circulation 2005, 112:2735 2752
Unified Definition of MetS
Alberti et al., Circulation 2009, 120:1640 1645
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Unified criteria for Metabolic Syndrome
Variable
Criteria
Waist circumference
Population specific
Triglyceride (TG)*
150 mg/dl (1.7 mmol/L)
HDL cholesterol*
<40 mg/dl (1.0 mmol/L) for males
<50 mg/dl (1.3 mmol/L) for females
Blood pressure
SBP 130 mmHg or DBP 85 mmHg
Fasting glucose
100 mg/dl
*People with elevated TG and low HDL take fibrates and nicotinic acid.
These people are presumed to have high TG and low HDL.
Alberti et al., Circulation 2009, 120:1640 1645
Recommended Waist Circumference
Population
Organization
Europid
IDF
94 cm
80 cm
Caucasian
WHO
94 cm (increased risk)
102 cm (still higher risk)
80 cm (increased risk)
88 cm (still higher risk)
U. S.
AHA/NHLBI (ATPIII)
102 cm
88 cm
Asian
WHO
90 cm
80 cm
Chinese
Cooperative Task Force
85 cm
80 cm
Japan
JSSO
85 cm
90 cm
Middle East,
Mediterranean
IDF
94 cm
80 cm
Sub Saharan African
IDF
94 cm
80 cm
Ethnic Central &
South American
IDF
90 cm
80 cm
Men
Women
Europids: people of European origin
Alberti et al., Circulation 2009, 120:1640 1645
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Prevalence of Metabolic Syndrome in the U.S.
Survey Year
# subjects
%
Change
Source
1988 1994
NHANES
N=6436
28.0
1999 2000
NHANES
N=1677
31.9
14%
for ~8 yrs
Ford et al.,
Diabetes Care 2004,
27:2444 2449
2003 2006
NHANES
N=3423
34.0
6.5%
for ~4 yrs
Ervin, Nat. Health
Stat. Reports, May
2009, No. 13
Ford et al.,
Diabetes Care 2004,
27:2444 2449
Subjects were US adults (men and women) 20 yrs old.
Prevalence % per revised criteria of National Cholesterol Education Program (NCEP),
Adults Treatment Panel (ATP) III
Men
NHANES in 1988 1991
among US adults
African American: n=3305
Mexican American: n=3477
White: n=5581
Women
Metabolic prevalence was
analyzed by ethnicity and
age.
Y.W. Park et al., Arch Intern. Med., 2003, 163: 427 436
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Prevalence of Metabolic Syndrome in Asia
Pan et al., Asia Pac. J. Clin. Nutr. 2008, 17(S1):37 42
Cause of Metabolic Syndrome
What causes the metabolic syndrome?
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Cause of Metabolic Syndrome?
R. Kahn, Lancet 2008, 371:1892 1893
Development of MetS
Physical Inactivity
Genetic factors
Abdominal Obesity
WC
Insulin resistance
Dyslipidemia
HDL
HTN
TG
CVD
Hyperglycemia
Diabetes
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Metabolic Syndrome associated diseases
T2DM
CVD
Metabolic
Syndrome
Cancer
NAFLD
(Non Alcoholic Fatty
Liver Disease)
Obesity associated metabolic risk factors
Jean Pierre Despres et al., Annals of Medicine, 2008, 40:514 523
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Effect of Metabolic Syndrome on Risk
of Cardiovascular Disease & Diabetes
• Relative Risk (RR): refers to the probability of
developing a particular disease with the
presence of a risk factor in relation with that
without a risk factor.
Met. Synd.
CV Disease
Yes
Yes
No
Total #
a
b
a+b
No
c
d
c+d
Total #
a+c
b+d
N = a+b+c+d
RR = [a/(a+b)] / [c/(c+d)]
RR = 1, no effect of metabolic syndrome on CVD
RR > 1, Met. synd. causes an increase of developing CVD
Relative risk of developing CVD with Metabolic Syndrome
Metabolic syndrome per the criteria of NCEP ATP III
Data from E. Ford, Diabetes Care, 2005, 28:1769 1778
H.N. Ginsberg et al., J. Cardiometabolic Syndrome 2009, 4:113 119
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Relative risk of developing CV events
with Metabolic Syndrome
•
•
RR
95% CI interval
Cardiovascular
disease
2.35
2.02 2.73
CVD Mortality
2.40
1.87 3.08
Myocardial infarction
1.99
1.61 2.46
Stroke
2.27
1.80 2.85
Metabolic syndrome per the criteria of NCEP ATP III or revised NCEP ATP III
87 studies including 951,083 patients were analyzed using systematic review
and meta analysis technique.
S. Mottillo et al., J. Am. College of Cardiology, 2010, 56:1113 1132
Prevalence of CHF in individuals with Metabolic Syndrome
•
•
•
Data from people who participated in the 3rd National Health & Nutrition Examination
Survey (NHANES III) during 1988 1994 were analyzed.
Investigators determined if there is an association between CHF & metabolic syndrome
(MetS).
MetS was determined by IDF criteria:
–
–
–
–
–
WC 94 cm from men & >80 cm for women
TG 150 mg/dl
HDL<40 mg/dl for men & <50 mg/dl for women
Glucose 100 mg/dl
BP 130/85 mmHg
C. Li et al., J. Epidemiol. Community Health, 2007, 61:67 73
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Relative risk of developing diabetes
with Metabolic Syndrome
Data from E. Ford, Diabetes Care, 2005, 28:1769 1778
H.N. Ginsberg et al., J. Cardiometabolic Syndrome 2009, 4:113 119
Relative risk of developing diabetes with Metabolic
Syndrome
Glucose 110 mg/dl
WC 102 cm for M
WC 88 cm for W
HDL<40 mg/dl for M
HDL<50 mg/dl for W
TG 150 mg/dl
SBP 130 mmHg or
DBP 85 mmHg
Glucose 100 mg/dl
WC 102 cm for M
WC 88 cm for W
HDL<40 mg/dl for M
HDL<50 mg/dl for W
TG 150 mg/dl
SBP 130 mmHg or
DBP 85 mmHg
Pooled data from different studies were analyzed using meta analysis technique.
E. Ford et al., Diabetes Care, 2008, 31:1898 1904
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Development of MetS
Physical Inactivity
Genetic factors
Abdominal Obesity
WC
Insulin resistance
Dyslipidemia
HDL
HTN
TG
CVD
Hyperglycemia
Diabetes
Overweight/Obesity
• Why do we develop overweight/obesity?
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Obesity Is Caused by Long Term Caloric Imbalance
Energy Intake
No weight gain
Energy Expenditure
How does overweight/obesity occur?
• Caloric balance: No gain
– Energy Intake = Energy Expenditure
• Chronic positive caloric imbalance: weight
gain
– +50 kcal/day
> ~5 lbs/yr
– Epidemiological studies: 0.5 2 lbs/yr
Excess Calorie Intake or Physical Inactivity?
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Evidence to support Physical Inactivity
Inactivity and Obesity
Men
Women
Inactivity
Inactivity
Obesity
Obesity
Calorie intake
Calorie intake
MSSE 31 Suppl.S537, 1999
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Prevalence of diabetes in the U.S.
WV
KT
TN
SC
TX
LA
MS
AL
GA
Barker et al. Am J Prev Med 2011, 40:434 439
County-level Estimates of Leisure-time Physical Inactivity among adults
aged 20 years: United States 2008
Highest diabetes prevalence associated with Physical Inactivity
Centers for Disease Control & Prevention
http://apps.nccd.cdc.gov/DDT_STRS2/NationalDiabetesPrevalenceEstimates.aspx?mode=PHY
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Progression of obesity
http://www.google.com/search?q=picture+of+obesity&hl=en&qscrl=1&nord=1&rlz=1T4SNNT_
en___US406&biw=1366&bih=613&site=webhp&prmd=ivns&tbm=isch&tbo=u&source=univ&s
a=X&ei=_Mc8TorQJIPq0gHNnJn9Dw&sqi=2&ved=0CCkQsAQ
BMI 25
BMI 30
BMI 40
http://www.cdc.gov/NCHS/data/hestat/obesity_adult_07_08/obesity_adult_07_08.pdf
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Projection of overweight & obesity
Wang et al., Obesity 2008, 16:2323 2330
Overweight/Obesity causes many
modern diseases
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Type of Obesity
Central obesity
Android-type obesity
Peripheral obesity
Gynoid-type obesity
ttp://www.google.com/imgres?imgurl=http://www.drkrider.com/Assets/Pictures/Formula%2520for%2520Life/measurments/bodyfat.gif&imgrefurl=ht
tp://www.drkrider.com/fORMULA%2520FOR%2520LIFE/bodycomp/bodyfat.htm&h=204&w=300&sz=14&tbnid=0Jv3quzGo9xpKM:&tbnh=79&tb
nw=116&prev=/search%3Fq%3Dpicture%2Bof%2Bvisceral%2Bfat%26tbm%3Disch%26tbo%3Du&zoom=1&q=picture+of+visceral+fat&hl=en&usg=
__oryIuOcWiEmg3O_hsANmqGogv18=&sa=X&ei=K0w8TobRKKqQsQKptJQG&ved=0CBwQ9QEwAA
Disease risk per BMI & waist circumference
Morbidity & mortality risk
BMI, kg/m2
Under wt.
<18.5
Normal wt.
Overweight
18.5 24.9
25 29.9
30 34.9
35 39.9
40
Obesity class I
Obesity class II
Obesity class III
M: WC<40” (102 cm)
WC>40” (102 cm)
F: WC<35” (88 cm)
WC>35” (88 cm)
Increased
High
Very high
High
Very high
Very high
Extremely high Extremely high
Disease risk for Type 2 DM, HTN & CVD
From “Preventing & managing the global epidemic of obesity.
Report of WHO Consultation of obesity” WHO, Geneva, 1997
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Visceral Fat Accumulation
Insulin resistance in
the liver
Insulin resistance in skeletal
muscle & fat tissues
Gluconeogenesis
Hyperglycemia
Hyperinsulinemia
Dyslipidemia
Intra abdominal fat
Retroperitoneal fat
Intra peritoneal fat
Mesenteric fat
Omental fat
Visceral fat
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Intra abdominal fat
http://flexions.com.au/blog/wp content/uploads/2010/09/visceral fat.jpg
Assessment of visceral fat area using computed tomography
www.hologic.com/data/DXA Visceral Fat Assessment.pdf
Practical & technical advantages of DXA visceral fat assessment compared with computed tomography
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Establishment of VFA threshold for MetS
• Subjected were recruited among patients who visited St. James
Hospital, Dublin, Ireland in 2007 2011 for Tx of GI resection for
malignancy.
• Male Subjects (n= 170, Age range = 29 88 yrs)
n = 95 w/o MetS; n = 75 W/ MetS
• Female subjects (n = 66, age range = 42 94 yrs)
n = 41 w/o MetS; n = 25 w/ MetS
• MetS Criteria
– International diabetes Federation (IDF) guideline.
– WC 94 cm for male and WC 80 cm plus 2 of followings
•
•
•
•
Fasting plasma glucose 5.6 mmol/L ( 100 mg/dl) or Tx for high glucose
HDL<1.03 mmol/l (<40 mg/dl) for males or HDL<1.29 mmol/l (<50 mg/dl) for females
TG 1.7 mmol/l ( 150 mg/dl)
SBP 130 mmHg or DBP 85 mmHg
The threshold of visceral fat area for the
diagnosis of MetS in European
Visceral fat area
Cut off value
163.8 cm2
VFA for female 80.1 cm2
VFA for male
Sensitivity
Specificity
WC
83.6%
96.0%
62.5%
73.2%
96.1 cm
83.2 cm
S. L. Doyle et al., Nutr. Research 2013, 2013, 33:171 179
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The threshold of visceral fat area for the
diagnosis of MetS for Japanese
Visceral fat area
Cut off value
103.0 cm2
VFA for female 69.0 cm2
VFA for male
•
•
•
Sensitivity
Specificity
WC
68.7%
80.8%
61.8%
70.0%
90 cm
85 cm
Male Subjects (n= 5080, Age range = 30 74 yrs)
n = 1969 w/ 1 risk; n= 708 w/ 2 risks; n = 155 w/ 3 risks
Female subjects (n = 1656, age range = 30 74 yrs)
n = 336 w/ 1 risk; n = 66 w/ 2 risks; n = 7 w/ 3 risks
MetS Criteria
–
2 or more of following per Japanese Committee of the Criteria for Metabolic Syndrome guideline.
•
•
•
•
Fasting plasma glucose 110 mg/dl
HDL<1.03 mmol/l (<40 mg/dl)
TG>1.7 mmol/l (>150 mg/dl)
SBP 130 mmHg or DBP 85 mmHg
H. Kashihara et al., Circ. J. 2009, 73:1881 1886
WC is closely correlated with VFA
Male
Female
S. L. Doyle et al., Nutr. Research 2013, 2013, 33:171 179
The Exam. Committee of JSSO, Circ. J. 2002, 66:987 992
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Association of MetS risk factors with visceral fat
N= 1193 Japanese men &
women (55±12 yrs, 20 84 yrs)
with BMI range of 14.9 56.4
kg/cm2
VFA with computer tomography
Waist circum. at umbilicus level
Obesity related disorder:
FPG 6.11 mmol/l ( 110 mg/dl)
TC 5.69 mmol/l ( 220 mg/dl)
TG 1.69 mmol/l ( 150 mg/dl)
HDL<1.03 mmol/l (<40 mg/dl)
SBP 140 mmHg
DBP 90 mmHg
The Exam. Committee of JSSO, Circ. J. 2002, 66:987 992
Visceral fat impairs insulin action
• That is, visceral fat causes insulin resistance.
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Visceral fat on glucose disposal
N=44 obese postmenopausal
women w/ BMI of 35.4±5
Visceral adipose tissue area: 190±75
cm2, (range 67 366 cm2)
Glucose disposal assessed by
hyperinsulinemic euglycemic clamp:
• High insulin infusion
• Variable glucose infusion
M. Brouchu et al., J Clin Endocrinol & Metab
2000, 85:2378 2384
Association of glucose tolerance w/ obesity
Oral glucose tolerance test
Healthy premenopopausal white women
Evans et al, Metabolism 33:68 75, 1984
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Development of MetS
Physical Inactivity
Genetic factors
Abdominal Obesity
WC
Insulin resistance
Dyslipidemia
HDL
HTN
TG
CVD
Hyperglycemia
Diabetes
Dyslipidemia with Metabolic Syndrome
• Triglyceride
• HDL
• VLDL
• LDL
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Overview of Lipoprotein Metabolism
K. Jain et al., Bioorganic & Medicinal Chem., 2007, 15:4674 4699
What causes triglyceride elevated in
the presence of MetS?
Glycerol
Fatty acids
https://courses.ecampus.oregonstate.edu/ans312/one/lipids_story.htm
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Triglyceride is energy source
TG
DG
Fatty acid
MG
Fatty acid
Glycerol
Fatty acid
Visceral Fat Accumulation
Insulin resistance in skeletal
muscle & fat tissues
Insulin resistance in
the liver
Gluconeogenesis
Hyperglycemia
Hyperinsulinemia
Dyslipidemia: TG
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Hepatic portal vein
http://www.biologycorner.com/resources/hepatic.gif
http://www.netterimages.com/images/vpv/000/000/003/3003 0550x0475.jpg
FFA in hepatic portal vein on the liver metabolism
•
•
•
•
The liver develops insulin resistance.
It causes the liver to secrete more VLDL.
It stimulate hepatic gluconeogenesis.
It inhibits insulin to bind with its receptors
on the liver, causing the interference of
hepatic insulin clearance.
P. Bjorntorp, Arterioscler. Thromb. Vasc Biol. 1990, 10:493 496
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Athrogenic dyslipidemia
Lipid
MetS
T2DM
HDL C
LDL C
sdLDL
TG
apoB
sdLDL: small dense low density lipoprotein
Adapted from J.D. Brunzell et al., Am J. Med 2003, 115 Suppl. 8A:24S 28S
Insulin resistance is associated with
hypertriglyceridemia
A. Kamagate & H.H. Dong, Cell Cycle 2008, 7:3162 3170
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Regulation of Hepatic VLDL Synthesis
Synthesis of hepatic VLDL
Three important elements:
1) ApoB synthesis
2) Microsomal triglyceride transfer protein (MTP)
3) Availability of triglyceride (TG)
A. Kamagate & H.H. Dong, Cell Cycle 2008, 7:3162 3170
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Overview of VLDL Synthesis
(ADP rybosylation factor 1)
(PLD1)
B. Verges, Atherosclerosis, 2010, 211:353 360
Insulin inhibits VLDL production
Phosphatidyl 4,5 bisphospahte (PIP2)
Phosphatidyl 3,4,5 bisphospahte (PIP3)
B. Verges, Atherosclerosis, 2010, 211:353 360
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Role of FOXO1 in hepatic VLDL production
• FoxO1 is a transcriptional factor.
• The transcriptional activity of FoxO1 is
regulated by insulin.
• FoxO1 regulates VLDL production.
• It also promotes hepatic gluconeogenesis.
Regulation of VLDL production by FoxO1
A. Kamagate et al., Cell Cycle 2008, 7:3162 3170
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Insulin regulates FoxO1
H. Huang et al., Biochimica et Biophysia Acta, 2011, 1813:1961 1964
Evidence of hepatic fat synthesis regulated by FoxO1
Fat feeding
Obesity
Diabetic condition
Insulin resistance
Expected findings
FOXO1
MTP
VLDL & TG
Remaining in nucleus
Increased expression
Increased levels
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Obesity on FOXO & MTP?
• Male C57BL/6J mice fed on high fat diet for 8
weeks
Blood glucose and insulin after high fat diet
Fasting glucose
Open bar: control
Black bar: high fat fed
*P<0.05; **P<0.001
Fasting insulin
Signs of insulin resistance
Shen Qu et al., Endocrinology 2006, 147:5641 5652
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Glucose tolerance, Foxo1 protein and mRNA level
after high fat diet
*P<0.05; **P<0.001
Shen Qu et al., Endocrinology 2006, 147:5641 5652
Body mass & plasma lipid in mice on high fat diet
High Fat Feeding
Body mass:
51±3.8 g high fat diet
mice (n=6; P<0.001)
23±1.8 g regular chow
(n=6)
Plasma total cholesterol level
138±9 mg/dl high fat diet
mice (n=6; P<0.01)
85±5 mg/dl regular show
(n=6)
A. Kamagate et al., J. Clin. Invest. 2008, 118:2347 2364
Plasma VLDL TG level
187±21 mg/dl high
fat diet mice (n=6;
P<0.01)
120±8 mg/dl regular
show (n=6)
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Hepatic MTP level in obese mice
A. Kamagate et al., J. Clin. Invest. 2008, 118:2347 2364 Supplemental data Fig. 4c
Diabetic mice
• Diabetic db/db mice compared with db/+ control
mice
• Body mass:
– 51.1±1.52 g diabetic mice mice (n=6; P<?)
– 25.2±0.6 g db/+ control mice(n=6)
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Plasma TG & cholesterol
Plasma TG
Cholesterol
A. Kamagate et al., J. Clin. Invest. 2008, 118:2347 2364 Supplemental data Fig. 4d and 4e
Hepatic MTP level
A. Kamagate et al., J. Clin. Invest. 2008, 118:2347 2364 Supplemental data Fig. 4f
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J. Sparks & H. Dong, Curr. Opinion Lipidology. 2009, 20:217 226
TG is an independent risk factor for heart disease
• 3,387 men living in Copenhagen were studied for 8 years
• End points were deaths and event of ischemic heart disease.
J. Jeppesen et al., Circulation, 1998, 97:1029 1036
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TG is an independent risk factor for heart disease
J. Jeppesen et al., Circulation, 1998, 97:1029 1036
The Effect of Exercise on the Liver
If exercise increases hepatic insulin sensitivity,
Less glucose production
Better lipid profile
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Fatty Liver
Verna et al., Seminars in liver disease, 2008, 28:407 426
Effect of exercise on hepatic fat
Visceral fat
Hepatic fat
P<0.05
P<0.05
• 15 obese adolescents (15.6 yrs, 33.7 kg/m2, & 38.3% body fat)
• 14 lean adolescents (15.1 yrs, 20.6 kg/me, 18.9% body fat)
• 12 wk aerobic exercise program (4x30 min/wk at 70% VO2 peak; treadmill,
elliptical & bicycle)
• Magnetic resonance imaging for visceral fat & Magnetic resonance spectroscopy for hepatic fat
• Insulin resistance decrease: 16%(P<0.001) in obese group; 12% (P<0.001) in lean group
Van der Heijden et al., Obesity 2010, 18: 384 390
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Exercise training on hepatic insulin sensitivity
Whole body insulin sensitivity
Hepatic insulin sensitivity
• 11 male/3 female, 64 yrs with BMI 31.9 kg/m2
• Fasting plasma glucose >100 mg/dl & 2 hr plasma glucose with OGTT>200 mg/dl
• Treadmill walking & stationary cycling at 80 85% max HR, 50 60 min/session for
7 consecutive days
J. Kirwan et al., Am. J. Physiol. Endocrinal. Metab. 2009, 297: E151 E156
Low Density Lipoprotein (LDL)
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Composition of Lipoproteins
•Size of diameter
HDL<LDL<IDL<VLDL< Chylomicron
•Core element
HDL: 20-30% TC
LDL: 60-70% TC
VLDL: TG & 10-15% TC
Chylomicron: largest TG among all
•Apoproteins
HDL: 64% Apo A-I & 20% Apo A-II
LDL: 95% Apo B-100
VLDL: 36% Apo B-100 & 40% Apo C-III
Chylomicron: A-I,II,IV, B-48 & E
Overview of Lipoprotein Metabolism
K. Jain et al., Bioorganic & Medicinal Chem., 2007, 15:4674 4699
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LDL Subclasses
D. Mikhailidis et al., Curr. Vascular Pharmacol., 2011, 9:533 571
How does LDL become smaller?
J. Huuskonen, et al., Atherosclerosis 2001, 155:269 281
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LDL particle size with insulin resistance
M. Taskinen, Diabetes Res & Clin Pract. 2003, 61:S19 S26
Original data from R. Gray et al., Arterioscler. Thromb. Vasc. Biol; 1997, 17:2713 2720
Why is HDL a good guy?
• HDL metabolism & its function
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Heterogeneity of human HDL
Diameter, nm
Density, g/ml
HDL2b
HDL2a
HDL3a
HDL3b
HDL3c
10.6
9.2
8.4
8.0
7.6
1.063<d<1.125
1.125<d<1.21
P.J. Barter, Atherosclerosis Supplements, 2002, 3:39 47
Association between HDL particle size cardiometabolic risks
r= 0.39, P<0.001
r= 0.36, P<0.001
• Prospective population study
• N = 25,663 M & F (45 79 yrs) living in
Norfolk, UK
• Cardiometabolic risks
– Elevated WC ( 90 cm for M & 85 for F)
– Elevated SBP (SBP 140 mmHg)
– Elevated TG ( 176.99 mg/dl ( 2 mmol/l) for
M; 132.74 mg/dl ( 1.5 mmol/l) for F)
– Elevated CRP ( 1.5 mg/l for M & F)
– Elevated ApoB ( 120 mg/dl for M & F)
– Decreased LDL particle size (<255 for M &
<260 Angstrom for F)
– Low HDL (<42.47 for M & 50 mg/dl for F)
B. Arsenault et al., Atherosclerosis, 2009, 206:276 281
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Relationship between HDL subclasses & the components of
metabolic syndrome
• Korean Metabolic Syndrome Research
Initiatives Seoul Cohort Study
• N = 541 M & F (older than 30 yrs)
living in Seoul, Korea
• Metabolic syndrome criteria
–
–
–
–
–
WC 90 cm for M & 85 for F
Glucose 100 mg/dl
BP, SBP 130 or DBP 85 mmHg
TG 150 mg/dl
HDL <40 for M & <50 mg/dl for F
M. Lee et al., Atherosclerosis, 2010, 213:288 293
What makes HDL heterogeneous?
• HDL undergoes remodeling in the blood.
• Factors involved in HDL remodeling
– ATP binding casette A1 (ABCA1)
– Lecithin:cholesterol acyltransferase (LCAT)
– Cholesteryl ester transfer protein (CETP)
– Hepatic lipase (HL)
– Lipoprotein lipase (LPL)
– Phospholipid transfer protein (PLTP)
46
2/6/2014
HDL Synthesis
ABCA1: ATP-binding cassette protein A 1
apoA-I or -II: apolipoprotein A-1 or A-II: both are required for HDL biosynthesis (ApoA-I (70%)
>apoA-II)
PL: phospholipids; FC = free cholesterol
CE = cholesteryl ester;
LCAT: lecithin:cholesterol acyltransferase, which esterifies FC by transferring fatty acid from PL.
LPL: lipoprotein lipase, which transports surface lipids (FC & phospholipid) & apolipoproteins to HDL
PLTP: phospholipid transfer protein, which transfers surface phospholipid to HDL.
D. Rader, J. Clin. Investigation, 2006, 116: 3090 3100
HDL catabolism
•
•
•
•
SR-B1: scavenger receptor class B type I
CETP: cholesteryl ester transfer protein
LDLR: LDL receptor
BA: bile acid
D. Rader, J. Clin. Investigation, 2006, 116: 3090 3100
47
2/6/2014
Function of HDL: Reverse Cholesterol Transport
SR-B1: scavenger receptor class B1
A. R. Tall et al., Cell Metabolism, 2008, 7:365 375
Cholesterol Efflux
R. Rosenson et al., Circulation, 2012, 125:1905 1919
48
2/6/2014
Exercise training on ABC A I
ABC A I expression after acute
resistance exercise
20 female participants
5 Control
No exercise
5 exercise
40% 1 RM
5 exercise
60% 1 RM
5 exercise
80% 1 RM
Circuit resistance exercise for 26 min
Blood samples obtained before and after exercise for determinations of lipoproteins
& ABC A I expression on lymphocytes
49
2/6/2014
Lymphocyte ABC A I mRNA expression
All exercise groups showed significant increases (P<0.001)
No changes in HDL after exercise.
A. Ghanbari Niaki et al., Regulatory Peptides, 2011, 166:42 47
Exercise training on ABC A I using animal model
ABC A I mRNA expression in the liver
Exercise Training
• Treadmill running using Wistar male
rats (5 for control & 5 for training).
• 25 m/min, 0% grade, for 90 min/day,
5days/wk for 6 weeks.
• Dependent variables
– ABC A I mRNA in the liver
– Plasma LCAT
– HDL
A. Ghanbari Niaki, Biochemical & Biophysical Res. Commun. 2007, 361:841 846
50
2/6/2014
Exercise training on HDL
• Treadmill running using Wistar male
rats (5 for control & 5 for training).
• 25 m/min, 0% grade, for 90 min/day,
5days/wk for 6 weeks.
• Dependent variables
– ABC A I mRNA in the liver
– Plasma LCAT
– HDL
A. Ghanbari Niaki, Biochemical & Biophysical Res. Commun. 2007, 361:841 846
HDL metabolism: CETP inhibition
Lipid poor A 1:
• efflux of cholesterol
Mature HDL:
• carry cholesterol to liver
• More efflux of cholesterol
CETP:
• Distributes cholesterol & TG b/n
lipoproteins
• Inhibition of CETP by drug
can lead to an increase in
HDL, resulting in a
decrease in
atherosclerosis.
Nissen et al., NEJM 2007, 356:1304 1316
CETP: cholesteryl ester transfer protein
ABCA1: ATP binding cassette transporter A1
SR B1: scavenger receptor class B1
51
2/6/2014
HDL,
mg/dl
Lesion area
in aortic arch, %
Control
N=10
15.2
30.3
JTT 705
N=10
30.0*
*
9.2**
Simvasti
n
N=10
19.5
5.9**
•
•
Rabbits were fed cholesterol diets
for 6 months.
JTT 705 is CETP inhibitor.
H. Okamoto et al., Nature 2000, 406:203 207
CETP inhibition: Human trial
• 1188 pts assigned into
– Statin medicine (control) or
– Statin medicine + CETP inhibitor (Torcetrapib)
– 24 months
• Monitored progression of coronary atherosclerosis
• Results:
–
–
–
–
61% increase in HDL
20% decrease in LDL
No significant favorable effect of CETP inhibitor on atherroma volume
Side effect: an increase in SBP by 4.6 mmHg
• Conclusion
– Side effect of the drug may counterbalance favorable effect or causes
other unknown unfavorable effect on the disease.
Nissen et al., NEJM 2007, 356:1304 1316
52
2/6/2014
Other benefits by HDL
Brewer et al., Arterioscler. Thromb. Vasc. Biol. 2004;24:1755 1760
Diverse biological actions by HDL
D.J. Hausenloy & D.M. Yellon, Postgrad. Med. J. 2008, 84:590 598
53
2/6/2014
Incidence of CHD
HDL’s protection from CHD
W. B. Kannel et al., Am. J. Cardiol. 1983, 52: 9B 12B
HDL is an independent factor in preventing CHD
HDL at high level
mitigates LDL’s negative
effect on CHD.
W. B. Kannel et al., Am. J. Cardiol. 1983, 52: 9B 12B
54
2/6/2014
Obesity or Insulin resistance associated changes in
blood lipid
•
•
•
•
Low HDL (<40 mg/dl for M & <50 mg/dl for F)
High TG (150 25 mg/dl)
Small LDL particles
Borderline high LDL (130 159 mg/dl)
Athrogenic dyslipidemia
Does visceral obesity causes a decrease in HDL?
Lipid levels in obese women
Caucasians, n=183
African Americans, n=50
BMI, kg/m2
31
35
% body fat
46
46
LDL, mg/dl
130.5
118.9
HDL, mg/dl
50.9
51.3
TG, mg/dl
130.0
100.0
Total cholesterol,
mg/dl
198.8
187.2
N = 233 obese pre & post menopausal women
– 183 Caucasians
– 50 African Americans
B. Nicklas et al., Diabetes Care, 2003, 26:1413 1420
55
2/6/2014
Effect of Visceral Adiposity on HDL
•
•
Both HDL & HDL2 subclass decrease with an
increase in visceral adiposity.
Relative risk (RR) of HDL <40 mg/dl
VA area, cm2
105
RR, HDL<40 mg/dl
1
106 139
2.5
140 162
2.3
163 192
5.5
193
5.5
WC, cm
<88
1
89 95
2.3
96
2.1
B. Nicklas et al., Diabetes Care, 2003, 26:1413 1420
Effect of Visceral Adiposity on TG
•
•
TG increases with an increase in visceral
adiposity.
Relative risk (RR) of TG > 150 mg/dl
VA area, cm2
105
RR, TG>150 mg/dl
1
106 139
1.7
140 162
1.7
163 192
1.7
193
3.3
WC, cm
<88
1
89 95
0.6
96
1.4
B. Nicklas et al., Diabetes Care, 2003, 26:1413 1420
56
2/6/2014
Relationship between HDL & TG
Quebec CardiovascularStudy
2103 men were studied for 5 years
J. P. Despres et al., Atherosclerosis 2000, 153:263 272
HDL metabolism in hypertriglyceridemic state
B. Lamarche et al., Clinica Chimica Acta, 1999, 286:145 161
57
2/6/2014
Effect of exercise on HDL metabolic pathway
A. Blazek et al., Am Heart J 2013, 166:392 400
Training effect on HDL metabolism in humans
58
2/6/2014
Effects of Exercise on HDL C Level
• Regular exercise increases HDL C level.
• A clear dose response relationship between aerobic exercise (running) and HDL
C levels in healthy men:
HDL C (mg/dL)
Nonrunner
5 mi/wk
9 mi/wk
12 mi/wk
17 mi/wk
31 mi/wk
(n = 685)
(n = 335)
(n = 512)
(n = 376)
(n = 602)
(n = 396)
53.0*†
56.3*‡
47.3
50.6*
48.7
52.5*†
*P
< 0.001 vs nonrunners;
< 0.01 vs nonrunners and 5 mi/wk;
‡P < 0.01 vs all other groups
†P
Kokkinos PF et al. Arch Intern Med 1995;155:415–420
http://www.lipidsonline.org
HDL in athletes
•
•
•
Controls
Athletes
VO2max,
ml/kg/min
38.8
53.4
P<0.001
BMI, kg/m2
23.2
23.9
NS
LDL, mmol/l
2.9
3.2
NS
HDL, mmol/l
1.4 (54.1 mg/dl)
1.7 (65.6 mg/dl)
P<0.001
ApoA I, mg/dl
128
145
P<0.001
Pre HDL
37
54
P<0.001
LCAT, ug/ml
7.0
6.6
NS
LCAT activity,
nmol/ul/hr
24.2
29.8
P<0.005
Cholesterol efflux, %
16.2
18.8
P<0.02
TG, mmol/l
1.1
0.9
NS
25 male athletes (33.6 yrs, tri & bi athlon, running, & swimming teams)
33 normal active males (30.8 yrs)
Mouse macrophage cells loaded w/ 3H cholesterol incubated with 2% plasma from subjects
B. Olchawa et al., Arterioscler. Thromb. Vasc. Biol., 2004, 24:1087 1091
59
2/6/2014
Longitudinal Studies on Lipoproteins
Lipoprotein changes with training
• Changes depends on the intensity of exercise
60
2/6/2014
Randomized Trial for training induced
changes in lipoproteins
• Group 1: Control group
• Group 2: Low amt/moderate exercise
– 12 miles (19 km)/wk at 40 55% VO2 peak
• Group 3: Low amt/vigorous exercise
– 14 kcal/kg/wk
– 12 miles (19 km)/wk, walking/jogging at 65 80% VO2 peak
• Group 4: High amt/vigorous exercise
– 23 kcal/kg/wk
– 20 miles (32 km)/wk, walking/jogging at 65 80% VO2 peak
Exercise machines: cycle ergometer, treadmill, & elliptical trainers
W. E. Kraus et al., New. Engl. Med., 2002, 347: 1483 1492
Characteristics of Subjects
Age, yrs
Weight, kg
BMI, kg/m2
Control
50.5
84.1
29.0
Low amt
moderate
intensity
54.3
89.8
29.2
0.55
Low amt High 51.8
intensity
87.1
29.6
0.17
High amt
53.0
High intensity
87.3
29.4
1.52
weight, kg
0.95
W. E. Kraus et al., New. Engl. Med., 2002, 347: 1483 1492
61
2/6/2014
Changes in LDL: exercise dose dependent
Change in [small LDL]
Change in size of LDL particles
Change in [IDL]
W. E. Kraus et al., New. Engl. Med., 2002, 347: 1483 1492
Changes in HDL: exercise dose dependent
Change in [HDL]
Change in [ large HDL]
Change in size of HDL particles
W. E. Kraus et al., New. Engl. Med., 2002, 347: 1483 1492
62
2/6/2014
Changes in triglyceride with training
Pre training
Post training
Control
132.1
155.8
Low amt moderate
intensity
196.8
145.2, 26%, P<0.001
Low amt high intensity 130.2
117.1, 10.0%, P<0.07
High amt high
intensity
138.5, 17%, P<0.006
166.9
Unit: mg/dl
W. E. Kraus et al., New. Engl. Med., 2002, 347: 1483 1492
Aerobic Exercise vs. Resistance Exercise
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L. A. Bateman et al., Am. J. Cardiol. 2011, 108:838 844
Baseline characteristics of subjects
Age, yrs
Resistance
Aerobic
Res. + Aerobic
51.8
51.1
45.8
BMI, kg/m2
30.3
30.8
30.4
Gender
F=15; M=16
F=14; M=16
F=12; M=13
White, %
87
83
84
Body mass, kg
89.2
89.3
90.1
HDL, mg/dl
46.8
41.5
45
TG, mg/dl
140
154
152
FBG, mg/dl
99.8
96.3
90.3
SBP, mmHg
120
122
118
DBP, mmHg
78.8
80.6
77.8
L. A. Bateman et al., Am. J. Cardiol. 2011, 108:838 844
64
2/6/2014
Training Protocol
Resistance training (RT)
• 3x/wk, progressive exercise
• 72 sets/wk (actual 60.4
sets/wk)
• 135 180 min/wk
• Adherence:
Aerobic training (AT)
• 130 min/wk, progressive
exercise
• 65 80% of peak VO2
• 14 kcal/kg/wk
• Adherence:
– 77.9% for AT+RT
– 91% for AT
– 77.6% for AT
– 83.8% for RT
• For 8 months
• For 8 months
RT + AT group doubled exercise time by performing both RT &
AT.
MetS was determined by criteria by NCEP ATP (III)
Changes with training
Resistance
Aerobic
Body mass, kg/m2
0.70
1.54, P<0.003
1.90, P<0.014
Peak VO2,
ml/kg/min
1.23, P<0.037
3.33, P<0.0001
3.67, P<0.0001
1.03
1.55
in
HDL, mg/dl
TG, mg/dl
0.63
5.25
Res. + Aerobic
21.0, P<0.049
30.1, 0.006
WC, cm
0.25
1.12, P<0.064
2.48, P<0.003
SBP, mmHg
2.32
0.57
3.08
DBP, mmHg
0.16
0.87
FPG, mg/dl
0.37
0.22
3.32, P<0.044
1.86
# of MetS risk
factor
0.36
0.03
0.64, P<0.005
MetS Z score
0.13
0.76, P<0.067
1.10, P<0.005
More changes occurs with aerobic exercise.
MetS Z score for W = ([50 HDL]/14.1)+([TG 150]/81)+([FPG 100]/11.3)+([WC 88]/9)+([MAP 100]/9.1)
MetS Z score for M = ([40 HDL]/9.0)+([TG 150]/81)+([FPG 100]/11.3)+([WC 102]/7.7)+([MAP 100]/9.1)
L. A. Bateman et al., Am. J. Cardiol. 2011, 108:838 844
65
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Changes with training
Combination of aerobic and resistance exercise yields more benefits.
L. A. Bateman et al., Am. J. Cardiol. 2011, 108:838 844
Metabolic Syndrome: Hypertension
How does it occur?
66
2/6/2014
How does HTN occur in the presence of MetS?
BP = CO X TPR
CO
TPR
Change(s) has to occur, leading to HTN.
Obesity Induced Hypertension
•
•
•
•
Increased activity of sympathetic nervous system
Endothelial dysfunction
Insulin resistance
Inflammatory cytokines/adipokines
Peripheral vascular resistance
HTN
67
2/6/2014
Crosstalk between perivascular adipose tissue
& blood vessel
S. Rajsheker et al., Curr. Opin. In Pharmacol., 2010, 10:191 196
J.M. Rutkowski et al., FEBS J., 2009, 276:5738 5746
Regulation of vascular smooth muscle tone by insulin
•
•
•
Nitric oxide (NO): Powerful vasodilator
Endothelin 1 (ET 1): powerful vasoconstrictor
Endothelial nitric oxide synthase (eNOS)
A. Jonk et al., Physiology, 2007, 22:252 260
68
2/6/2014
Exercise Training on BP
Control Group
Exercise Group
Age, yrs
55.3
51.7
Body mass, kg
80.4
75.4, P=0.032
BMI, kg/m2
26.00
25.02
METS
11.4
11.0
• Exercise Group: stationary cycling, 3x/wk at 60 80% of
HRmax obtained during GXT for 16 wks.
• Control group: no exercise training.
• Dependent variables
– BP responses during exercise test
– Left ventricular mass
C. Pitsavos et al., Hellenic J. Cardiol., 2011, 52:6 14
SBP response
Pre Control ,
Post Control
Pre Training
Post training
Rest, upright
133.50
133.50
133.00
121.25*
Stage 1
162.0
163.6
156.76
134.50*
Stage 2
181.05
181.05
176.85
147.70*
Stage 3
190.00
190.74
186.00
164.2*
Stage 4
191.66
191.66
190.18
171.10*
Stage 5, max.
192.50
193.60
192.60
173.10*
*P<0.05 within group between pre & post training
C. Pitsavos et al., Hellenic J. Cardiol., 2011, 52:6 14
69
2/6/2014
DBP response
Pre Control ,
Post Control
Pre Training
Post training
Rest, upright
83.75
82.75
84.50
77.35*
Stage 1
85.50
84.00
85.50
78.25*
Stage 2
84.50
83.50
86.50
79.00*
Stage 3
83.68
84.74
88.25
80.60*
Stage 4
81.66
81.67
90.90
82.25*
Stage 5, max.
84.50
85.25
88.75
82.25*
*P<0.05 within group between pre & post training
C. Pitsavos et al., Hellenic J. Cardiol., 2011, 52:6 14
Changes in Left Ventricular Structure & Function
Pre Control ,
Post Control
Pre Training
Post training
1.090
1.093
1.110
1.007*
LVED diameter, 4.785
cm
4.865*
4.725
4.531*
LVES diameter,
cm
2.795
2.780
2.880
2.595*
LV mass, g
227.73
231.13*
225.10
181.87*
LV mass index,
kg/m2
115.94
117.52
118.80
96.10*
LVED wall
thickness, cm
LV mass index = LVM/BSA; LVMI of 116 kg/m2 is an indication of moderate hypertrophy.
*P<0.05 within group between pre & post training
C. Pitsavos et al., Hellenic J. Cardiol., 2011, 52:6 14
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2/6/2014
BP Reduction with Exercise Training
J. Hagberg et al., Sports Med., 2000, 30:193 206
Inflammatory Biomarkers
71
2/6/2014
Inf
NAFLD: non alcohol fatty liver disease
NASH: non alcohol steatohepatitis
Kenneth Cusi, Curr Diab Rep, 2010, 10:306 315
Inflammatory biomarkers
NGT, n=45
IGT, n=71
T2DM, n=26
BMI, kg/m2
24.2±1.6
29.5±6.0
31.6±3.3
% body fat
24.1±3.4
34.7±11.9
39.5±8.5
GIR, ml/min
74±15
21±10
22±8
Adiponectin, ug/ml
8.6±2.6
4.3±2.3
3.2±1.7
IL 6, pg/ml
1.0±0.9
3.8±1.9
7.8±1.9
IL 10, pg/ml
2.8±1.4
1.1±1.0
0.78±0.9
CRP, mg/dl
0.11±0.10
0.29±0.13
0.76±0.29
All variables in NGT are different (<0.05) from those in IGT & T2DM.
GIR: glucose infusion rate during euglycemic hyperinsulinemic clamp with r=
Adiponectin:0.47 (P<0.0); IL 6: 0.49 (P<0.0); IL 10: 0.41 (P<0.0); CRP: 0.28(P<0.001)
Bluher et al., Exp. Clin. Endocrinol. Diabetes, 2005, 113:534 537
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2/6/2014
Inflammatory biomarkers with exercise training
• 60 white Caucasian men and women(45.2±3.9 yrs)
– 20 NGT, 20 IGT, & 20 T2DM
• Supervised exercise training
– with 100% compliance
– 3x/wk for 4 wks, 60 min/session (20 min warm up and cool down, 20
running or biking + 20 min power training)
– 60 min swimming on a separate day
– Intensive exercise
Oberbach et al., Eur J. Endocrinology, 2006, 154:577 585
Improvement with training
NGT
IGT
T2DM
BM, kg
2.0%*
3.6%*
1.6%*
BMI, kg/m2
24.2, 1%*
29.8, 3%*
31.3, 3%*
VO2max (ml/kg/min)
6%*
6%*
5%*
GIR (umol/kg/min)
12%
89%*
52%*
*P<0.05 vs. baseline
Body mass index (BMI)
Glucose infusion rate (GIR) during euglycemic hyperinsulinemic clamp
Oberbach et al., Eur J. Endocrinology, 2006, 154:577 585
73
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Changes in biomarkers after training
Oberbach et al., Eur J. Endocrinology, 2006, 154:577 585
Obesity induced Insulin resistance in
other insulin target organs
• Causes
• Consequences
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If adipokines/cytokines are not
controlled…
• They will cause the development of insulin
resistance in insulin target tissues.
– Skeletal muscle
– The liver
– Adipose tissues
– The heart
How do inflammatory markers cause
insulin resistance?
75
2/6/2014
IKK/NF kB signaling pathway
NF kB: nuclear factor kB; transcription
factor that regulates the transcription of
proinflammatory cytokine genes
*IL 2 gene: activating immune cells (T cells & B cells)
*TNF gene : the production of TNF
*GM CSF (granulocyte macrophage colony stimulating factor)
gene: the growth of WBC & monocytes
IkB: Inhibitor of NF kB; regulatory proteins
of NF kB by retaining NF kB in cytoplasm
IKK: Inhibitor kB kinase (IKB); it
phosphorylates IkB, causing it to be
destroyed. This action then activates NF
kB by releasing it from IkB.
TNF
IL 2 gene
TNF gene
GM CSF
+
Inflammation
IKK
IkB
Li & Verma, Nature Reviews Immunology, 2002, 2:725 734
NF kB
Many inflammatory cytokines inhibit insulin action
MCP-1: monocyte chemoattractant
protein-1
IKK: Inhibitor of NF-kB kinase
JNK: JUN N-terminal kinase
IRS1: insulin receptor substrate 1
Heilbronn & Campbell, Curr. Pharmaceut. Design 2008, 14:1225 1230
76
2/6/2014
Organs involved in Glucose Metabolism
Insulin resistance in these organs
Hyperglycemia
http://www.google.com/imgres?imgurl=http://people.eku.edu/ritchisong/301images/
muscle_structure.jpg&imgrefurl=http://people.eku.edu/ritchisong/301notes3.htm&h=
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epsAKk3s3TCw&sqi=2&ved=0CFkQ9QEwAA&dur=1869
http://library.med.utah.edu/WebPath/LIVEHTML/LI
VER002.html
Blood glucose
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http://www.carlalbert.edu/assets/images/Math%20and%2
0Science/adipose%20tissue.jpg
Ectopic Fat Accumulation
A. Tchernof & J P. Despres, Physol. Rev. 2013, 93:359 404
77
2/6/2014
Sequence of the development of metabolic syndrome
Physical inactivity:
initial trigger
Genetic predisposition
Abdominal obesity
Endothelial
dysfunction
Insulin resistance
Dyslipidemia
Hypertension
Metabolic
syndrome
Impaired glucose tolerance
Diabetes
What causes metabolic inflexibility?
• Metabolic inflexibility refers to the inability
of a insulin target tissue to utilize available
energy substrate.
78
2/6/2014
Obesity induced metabolic inflexibility
J. Galgani et al., Am J Physiol Endocrinol Metab 2008, 295:E1009 E1017
Exercise increases Metabolic Flexibility
N. Osler et al., Endocrinology 2008, 149:935 941
79
2/6/2014
How can we restore metabolic
flexibility?
Sequence of the development of metabolic syndrome
Physical inactivity:
initial trigger
Genetic predisposition
Abdominal obesity
Endothelial
dysfunction
Insulin resistance
Dyslipidemia
Hypertension
Metabolic
syndrome
Impaired glucose tolerance
Diabetes
80
2/6/2014
The Effect of Exercise on Skeletal Muscle
Insulin stimulated glucose transport by skeletal muscle
Muscle
Blood vessel
GLUT4
Glucose
Glucose
Glucose
Glucose
AS160
Akt
Insulin
IR
IRS
PI 3 kinase
81
2/6/2014
Effect of a bout of exercise on insulin sensitivity
•This is very important
clinical application.
• Recommendation for
a decrease insulin-sensitizing
Medicine.
Mechanisms
•Glycogen depletion
•AMPK activation
•Other unknown factors
Wojtaszewski et al., A Appl. Physiol. 93:384-392, 2002
Exercise Training
Aerobic capacity
Fitness level
Aerobic capacity
Fitness level
Insulin
sensitivity
Insulin
sensitivity
% MetS
% MetS
Physical Inactivity
82
2/6/2014
Inverse relationship b/n MetS & fitness level
I, n=85
II, n=91
III, n=84
IV, n=100
Treadmill
time, min
8.7
10.5
12.1
14.2
P<0.0001
MetS
component
2.1
1.6
1.2
0.9
P<0.0001
MetS, %
39
24
13
4
P<0.0001
BMI, kg/m2
31
30
28
26
P<0.0001
Age, yrs
51
49
46
46
P<0.0001
• Middle aged male executives who
visited Mayo Clinic b/n Jan., 2000 and
May 2001 for health check up
• Fitness Quartile (I IV) based on
Treadmill Time per Bruce Protocol
MetS criteria
• HDL<40 mg/dl
• TG 150 mg/dl
• Fasting blood glucose 110 mg/dl
• SBP 130 mmHg or DBP 85 mmHg
• Waist to hip ratio>0.95
I. J. Kullo, Am. J. Cardiol. 2002, 90:795 797
Inverse relationship b/n the prevalence of MetS & fitness level
Low Fitness
Moderate
Fitness
High Fitness
n=
3,872
3,982
3,979
Age, yrs
46.6
45.4
45.8
Treadmill
time, min
12.8
17.7
23.0
P<0.001
Prevalence
of MetS, %
30.9
11.6
3.2
P<0.001
• Men and women (n=11,833)
participated in the Aerobic center
Longitudinal Study (1987 1999)
MetS criteria
• HDL<40 mg/dl for M; <50 mg/dl for F
• TG 150 mg/dl
• Fasting blood glucose 110 mg/dl
• SBP 130 mmHg or DBP 85 mmHg
• WC>102 for M or WC>88 cm
C.E. Finley et al., J. Am. Diet Assoc. 2006, 106:673 679
83
2/6/2014
Higher fitness level protects from developing MetS
C.E. Finley et al., J. of the American Dietetic Association, 2006, 106:673 679
Can exercise ameliorate metabolic
syndrome?
• Longitudinal data
84
2/6/2014
Randomized Exercised Training
K.J. Stewart, Am. J. Prev. Med. 2005, 28:9 18
Characteristics of Subjects
Training
Control
Age, yrs
63.0
64.1
VO2 peak, ml/kg/min
24.4
24.2
BMI, kg/m2
29.4
29.7
WC, cm
94.0
95.0
Abdominal visceral fat, cm2
146.5
142.7
SBP, mmHg
140.3
141.7
DBP, mmHg
76.8
76.4
HDL, mg/dl
56.8
53.1
TG, mg/dl
146.5
125
Glucose, mg/dl
100.8
102.1
MetS, %
43.4
41.2
MetS is determined per NCEP, Adult Treatment Panel (III)
K.J. Stewart, Am. J. Prev. Med. 2005, 28:9 18
85
2/6/2014
Exercised Training
Control group:
• Maintain calorie intake.
• Check BP 2x/month.
Training group
• 3x/wk, 78 sessions (=3 days
x 26 wks) for ~6 months
• Resistance exercise: 2x10
15 reps w/ 7 different
exercises
• Aerobic exercise: 45
min/session using treadmill
& leg cycle ergometer, at
60 90% Hrmax.
• Maintain calorie intake.
• Check BP 2x/month.
K.J. Stewart, Am. J. Prev. Med. 2005, 28:9 18
Changes with training
Training
Control
VO2 peak, ml/kg/min
4.0, P<0.001
0.1
BMI, kg/m2
0.8, P<0.001
0.2
WC, cm
2.9, P<0.01
0.8
Abdominal visceral fat, cm2
26.7, P<0.001
3.8
Abdominal total fat, cm2
52.5, P<0.001
6.5
Abdominal subcutaneous fat,
cm2
25.8, P<0.001
2.9
SBP, mmHg
5.3
4.5
DBP, mmHg
3.7, P<0.02
1.5
HDL, mg/dl
TG, mg/dl
Glucose, mg/dl
3.0, P<0.01
13.4
0.2
0.3
1.2
1.7
K.J. Stewart, Am. J. Prev. Med. 2005, 28:9 18
86
2/6/2014
Exercise Training on MetS
Number of individual MetS risk factors
Pre
Post
Control
2.3
2.0
0.3
Training
2.3
1.7
0.6, p=0.06
Number of individuals with different status
• 9 exercisers became free of MetS
• 8 controls became free of MetS
• 4 controls developed MetS.
K.J. Stewart, Am. J. Prev. Med. 2005, 28:9 18
Intensity and Duration of Exercise?
• How do these parameters influence of
improvement of metabolic syndrome?
87
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Exercise Intensity and Duration
11 miles
11 miles
17 miles
Subjects are overweight or obese (25 35 kg/m2. 40 65 yrs).
J. Johnson et al., Am. J. Cardiol. 2007, 100:1759 1766
Changes # of people with MetS
N=50
N=61
N=55
N=61
J. Johnson et al., Am. J. Cardiol. 2007, 100:1759 1766
88
2/6/2014
Improvement in %MetS among all exercisers
J. Johnson et al., Am. J. Cardiol. 2007, 100:1759 1766
Exercise on metabolic risk factors in
obese adults
N=24 older adults (65.5 5, 9 M & 15 F)
Sedentary obese people with BMI in 30 40 kg/m2
Exercise group
N=12
Exercise + Diet group
N=12
Exercise training program
• Walking on a treadmill or pedaling cycle ergometer
•
50 60 min/day, 5x/wk at 60 85% HRmax for 12 weeks
Results: no difference between the two groups except for
more decrease in BMI & Subcutaneous fat with Exerc. + Diet than with
Exerc. alone
Yassine et al., J Gerontology A Biol Sci Med Sci 2009, 64A: 90 95
89
2/6/2014
Changes in metabolic risk factors in obese adults after exercise
Pre
Post
Significance
Waist circum. cm
118.3 12.7
112.7 11.9
P<0.001
Visceral fat, cm2
192.3 104.3
158.4 87.0
P<0.001
Subcutaneous
fat, cm2
383.4 106.4
347.8 94.2
P<0.001
SBP, mmHg
135.6 11.2
121.1 11.2
P<0.001
DBP, mmHg
81.6 11.2
71.6 9.6
P<0.001
FPG, mg/dl
106.6 10.8
71.6 9.6
P<0.001
TG, mg/dl
169.2 62.5
134.1 37.5
P<0.001
HDL, mg/dl
36.9 8.3
37.5 7.6
P=0.9
Data from the Exercise Group
Yassine et al., J Gerontology A Biol Sci Med Sci 2009, 64A: 90 95
•
•
•
Individualized exercise program at intensity of 14 23 kcal/kg/wk (40 60%
VO2max reserve), 3x/wk for 14 weeks.
Participants (male = 142 & female = 190; 20 80 yrs old) did brisk walking, water
aerobic, stationary cycling, & cross training.
They measured:
•
•
•
•
•
•
•
Energy expenditure
BM, WC
BP
HDL
LDL
TG
Total cholesterol
• Blood glucose
• VO2 max
• Prevalence of metabolic
syndrome
• 10 yr CV risk score
Preventive Medicine, 2013, 57:392 395
90
2/6/2014
Results of the Study
Preventive Medicine, 2013, 57:392 395
Distribution of # of MetS Risk Factors
Men
Women
• Greater decrease in # of people with 2 3 risk factors
• Metabolic prevalence: from 22.3% to 13.5% after training
• MetS factor free: from 19.6% to 30.7% after training
L. Dalleck et al., Preventive Medicine, 2013, 57:392 395
91
2/6/2014
Which factor(s) likely changes with training?
Men
Black bar: before
White bar: after
Women
Baseline
After training
53.6%
49.7%
3.9
Blood glucose 45.2%
30.1%
15.1
HDL
29.8%
21.4%
8.4
TG
25.3%
20.2%
5.1
BP
6.6%
2.1%
4.5
WC
All post training values
Are significantly lower
(P<0.05) except BP in
women.
L. Dalleck et al., Preventive Medicine, 2013, 57:392 395
General Exercise Guideline for Tx of MetS
• Moderate aerobic exercise
– 12 13 RPE (6 20 scales) or 40 60% HRR
– 30 60 min/session
– 15000 2000 kcal/week
– 3 5x/week
• Combined resistance training
• Positive results in 12 16 weeks
• How long in your life?
– Commitment to life time
92
2/6/2014
Is Exercise/Physical activity Obligatory
for Good Health?
Physical Inactivity
Overweight/Obesity
Insulin resistance
Metabolic Syndrome
HTN
WC
Hyperglycemia
TG
HDL
Evolutional perspective of human life
• Without physical works, humans are
supposed to face troubles.
• As long as they worked physically, they could
maintain the homeostasis of human genome.
93
2/6/2014
Humans are designed to do physical works
• What evidence do I have?
– One of the oldest records support this notion.
“The Lord God took the man and put him in the
Garden of Eden to
(Genesis 2:15).”
work it and take care of it
How do exercise & inactivity affect genes?
Human gene pool
Disease resistant gene
Disease susceptible gene
Exercise
Inactivity
Disease resistant genes are activated.
Disease susceptible genes are suppressed.
Good health
Disease resistant genes are suppressed. Disease
susceptible genes are activated.
Diseases
Modified from Booth et al., Physiol. Genomics 2007, 28:146 157
94
2/6/2014
Can exercise prevent the
development of metabolic syndrome?
My answer is resounding, “YES.”
Physical Activity
http://worldphotocollections.blogspot.com/2010/04/sum
o wrestlers amazing photos.html
http://www.zimbio.com/pictures/5hbbWEwrxJY/Bulgarian+Sumo+Wrestler+
Kotooshu+Wins+Tournament/ U6yuDFe0x3/Mahlyanov+Kaloyan+Stefanov
95
2/6/2014
Sumo wrestlers can remain metabolically healthy
Sumo wrestlers
consume high energy
diet (7000 10,000 kcal)
per day with strenuous
physical training
But very little visceral
fat accumulation
Normal lipid and
glucose levels are
within normal limit.
Y. Matsuzawa, Int J Obesity 2008, 32: S83 S92
Physical Activity/Exercise
• Insulin resistance
• Insulin sensitivity
96
2/6/2014
Glucose and insulin responses during OGTT
Active people
~15,000 steps/day
Inactive for 3 days
~5000 steps/day
C. Mikus et al., Med. Sci. Sports Exercise, 2012, 44:225 231
Greater insulin secretion was required
C. Mikus et al., Med. Sci. Sports Exercise, 2012, 44:225 231
97
2/6/2014
References
•
•
•
•
•
•
•
•
R.B. Ervin, Prevalence of metabolic syndrome among adults 20 years of age and over, by
sex, age, race and ethnicity, and body mass index: United States, 2003 2006. National
Health Statistics Reports 2009, 13:1 7
K.G. Alberti et al., Harmonizing the metabolic syndrome: a joint interim statement of the
International Diabetes Federation Task Force on Epidemiology and Prevention; National
Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation;
International Atherosclerosis Society; and International Association for the Study of
Obesity, Circulation 2009, 120: 1640 1645
Y. Okauchi, Nishzawa H, Funahashi T, Ogawa T, Noguchi M, Ryo M, Kihara S, Iwahashi H,
Reduction of visceral fat is associated with decrease in the number of metabolic risk
factors in Japanese men, Diabetes Care 2007 30: 2392 2394
Morris DL, Rui L, Recent advances in understanding leptin signaling and leptin resistance.
AmJ Physiol Endocrinol Metab 2009, 297: E1247 E1259
S.E. Hussey, McGee SL, Garnham A, Wentworth JM, Jeukendrup AE, Hargreaves M,
Exercise training increases adipose tissue GLUT4 expression in patients with type 2
diabetes., Diabetes Obes Metab, 2011, 13:959 62.
J.J. Dube, Amati F, Stefanovic Racic M, Toledo FG, Sauers SE, Goodpaster BH, Exercise
induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox
revisited. Am J Physiol Endocrinol Metab, 2008 May;294(5):E882 E888
M.E. Osler, Zierath JR, Adenosine 5' monophosphate activated protein kinase regulation of
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M.A. Guzzardi, Iozzo P, Fatty heart, cardiac damage, and inflammation, the Review of
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