Metabolic syndrome

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APTA CSM 2014 Las Vegas, NV Effects of Exercise Intervention on Metabolic Abnormalities Associated with Metabolic Syndrome
Abraham D. Lee, Ph.D., P.T.
Associate Professor Dept. of Rehabilitation Sciences The University of Toledo
abraham.lee2@utoledo.edu
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, the heart, and skeletal muscle), which lead to the development of metabolic syndrome.
• Explain the concept of metabolic inflexibility. • Explain how exercise intervention improves metabolic abnormalities associated with metabolic syndrome. 1
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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 include:
–
–
–
–
–
Elevated plasma glucose
Elevated plasma triglyceride
Low high‐density lipoprotein
High blood pressure
Abdominal obesity (increased 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)
• 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 in men
WC≥88 cm 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
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
≥130/85 or HTN Tx
≥130/85 mmHg or HTN Tx
Glucose
IGT, IFG, or T2DM
≥100 mg/dl (include diabetes)
≥110 mg/dl (2001 version)
≥100 mg/dl (includes diabetes)
Other
Microalbuminuria, >30 mg/g creatinine
HDL < 40 mg/dl in men & <50 mg/dl in women or drug Tx for low level
Adapted from Grundy et al., Circulation 2005, 112:2735‐2752 Unified Definition of MetS
Alberti et al., Circulation 2009, 120:1640‐1645 3
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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
Men Women
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
Europids: people of European origin Alberti et al., Circulation 2009, 120:1640‐1645 4
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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)
Relative risk of developing CVD with Metabolic Syndrome
H.N. Ginsberg et al., J. Cardiometabolic Syndrome 2009, 4:113‐119 8
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Relative risk of developing diabetes with Metabolic Syndrome
H.N. Ginsberg et al., J. Cardiometabolic Syndrome 2009, 4:113‐119 Overweight/Obesity
• Why do we develop overweight/obesity? 9
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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? 10
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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 14
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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. 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
<18.5
Normal wt. 18.5‐24.9
Overweight 25‐29.9
Obesity class I
30‐34.9
Obesity class II
35‐39.9
Obesity class III
40
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 or Tx for high glucose
HDL<1.03 mmol/l for males or HDL<1.29 mmol/l for females
TG>1.7 mmol/l
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 18
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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 19
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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 on glucose disposal N=44 obese postmenopausal women w/ BMI 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
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Association of glucose tolerance w/ obesity Oral glucose tolerance test
Healthy premenopopausal white women
Evans et al, Metabolism 33:68‐75, 1984
What causes triglyceride elevated in the presence of MetS? 21
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Visceral Fat Accumulation
Insulin resistance in skeletal muscle & fat tissues
Insulin resistance in the liver
Gluconeogenesis
Hyperglycemia
Hyperinsulinemia
Dyslipidemia
Hepatic portal vein
http://www.biologycorner.com/resources/hepatic.gif
http://www.netterimages.com/images/vpv/000/000/003/3003‐0550x0475.jpg 22
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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
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 23
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Insulin resistance is associated with hypertriglyceridemia
A. Kamagate & H.H. Dong, Cell Cycle 2008, 7:3162‐3170
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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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 25
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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 26
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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
Fasting insulin
Open bar: control
Black bar: high fat fed
*P<0.05; **P<0.001
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
Why is HDL a good guy? • HDL metabolism & its function
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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
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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
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.
D. Rader, J. Clin. Investigation, 2006, 116: 3090‐3100
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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
Function of HDL: Reverse Cholesterol Transport
SR-B1: scavenger receptor class B1
A. R. Tall et al., Cell Metabolism, 2008, 7:365‐375
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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
HDL, mg/dl
Lesion area in aortic arch, %
Control
N=10
15.2
30.3
JTT‐705
N=10
30.0** 9.2**
Simvastin
N=10 19.5
CETP: cholesteryl ester transfer protein
ABCA1: ATP‐binding cassette transporter A1
SR‐B1: scavenger receptor class B1 5.9**
Rabbits were fed cholesterol diets for 6 months. H. Okamoto et al., Nature 2000, 406:203‐207
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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
Other benefits by HDL
Brewer et al., Arterioscler. Thromb. Vasc. Biol. 2004;24:1755‐1760
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Diverse biological actions by HDL
D.J. Hausenloy & D.M. Yellon, Postgrad. Med. J. 2008, 84:590‐598
How does HTN occur in the presence of MetS? Since we know that BP = CO X TPR,
CO
TPR Change(s) has to occur, leading to HTN. 37
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Obesity‐Induced Hypertension
• Increased activity of sympathetic nervous system
• Endothelial dysfunction
• Inflammatory cytokines/adipokines
Inf
NAFLD: non‐alcohol fatty liver disease
NASH: non‐alcohol steatohepatitis
Kenneth Cusi, Curr Diab Rep, 2010, 10:306‐315 38
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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 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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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
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Changes in biomarkers after training
Oberbach et al., Eur J. Endocrinology, 2006, 154:577‐585
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
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How do inflammatory markers cause insulin resistance? 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; it phosphorylates IkB, causing it to be destroyed. This action then activates NF‐kB by releasing it from IkB. IL‐2 gene
TNF gene
GM‐CSF
Li & Verma, Nature Reviews Immunology, 2002, 2:725‐734
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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
Organs involved in Glucose Metabolism http://www.google.com/imgres?imgurl=http://people.eku.edu/ritchisong/301images/
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Blood glucose
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ibCw&ved=0CHQQ9QEwBg&dur=1564
http://www.carlalbert.edu/assets/images/Math%20and%2
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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? 44
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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 45
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Is Exercise/Physical activity Obligatory for Good Health? Physical Inactivity
Overweight/Obesity
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. 46
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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
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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
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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
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. Km. J. Cardiol. 2002, 90:795‐797
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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
Higher fitness level protects from developing MetS
C.E. Finley et al., J. of the American Dietetic Association, 2006, 106:673‐679
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Can exercise ameliorate metabolic syndrome? Randomized Exercised Training K.J. Stewart, Am. J. Prev. Med. 2005, 28:9‐18 51
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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 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 52
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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, ‐25.8, P<0.001
cm2
‐2.9
SBP, mmHg
‐5.3
‐4.5
DBP, mmHg
‐3.7, P<0.02
‐1.5
HDL, mg/dl
3.0, P<0.01
‐0.3
TG, mg/dl
‐13.4
1.2
Glucose, mg/dl
0.2
1.7
MetS, %
43.4
41.2
K.J. Stewart, Am. J. Prev. Med. 2005, 28:9‐18 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 53
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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 + Diet group
N=12
Exercise 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 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 54
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Lipoprotein changes with training
• Changes depends on the intensity of exercise
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 55
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Characteristics of Subjects
Age, yrs
Weight, kg
BMI, kg/m2
 weight, kg
Control
50.5
84.1
29.0
0.95
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
W. E. Kraus et al., New. Engl. Med., 2002, 347: 1483‐1492 Changes in LDL
W. E. Kraus et al., New. Engl. Med., 2002, 347: 1483‐1492 56
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Changes in HDL
W. E. Kraus et al., New. Engl. Med., 2002, 347: 1483‐1492 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
*P
†P
‡P
48.7
50.6*
52.5*†
< 0.001 vs nonrunners;
< 0.01 vs nonrunners and 5 mi/wk;
< 0.01 vs all other groups
Kokkinos PF et al. Arch Intern Med 1995;155:415–420
http://www.lipidsonline.org
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Effect of exercise on HDL metabolic pathway
A. Blazek et al., Am Heart J 2013, 166:392‐400
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 58
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Aerobic Exercise vs. Resistance Exercise 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 59
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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  in
Resistance
Aerobic
Res. + 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
HDL, mg/dl
‐0.63
1.03
1.55
TG, mg/dl
‐5.25
‐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
‐3.32, P<0.044
FPG, mg/dl
‐0.37
‐0.22
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
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 60
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Changes with training L. A. Bateman et al., Am. J. Cardiol. 2011, 108:838‐844 Physical Activity/Exercise
• Insulin resistance • Insulin sensitivity
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The Effect of Exercise on the Liver Fatty Liver
Verna et al., Seminars in liver disease, 2008, 28:407‐426
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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
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 63
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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
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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
Does daily walking count as an exercise? • Twelve healthy volunteers were asked to reduce steps< 5000/day for 3 days. • Glucose and insulin responses during OGTT were investigated. C. Mikus et al., Med. Sci. Sports Exercise, 2012, 44:225‐231
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Glucose and insulin responses during OGTT
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
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References
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•
•
•
•
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•
•
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 fatty acid oxidation in skeletal muscle. Endocrinology, 2008, 149:935‐941
M.A. Guzzardi, Iozzo P, Fatty heart, cardiac damage, and inflammation, the Review of Diabetic Studies, 2011, 8:403‐417 The End
• Any questions? 67