1st Annual CVD Prevention Conference
26 April 2014
William E. Kraus, M.D.
Exercise	
  and	
  Energy	
  Balance	
  for	
  
...
Ø Effects	
  of	
  Exercise	
  on	
  Lipids	
  and	
  Metabolic	
  
Syndrome	
  
Ø Effects	
  of	
  Caloric	
  Restric�on	...
Ø Effects	
  of	
  Exercise	
  on	
  Lipids	
  and	
  Metabolic	
  
Syndrome	
  
Ø Effects	
  of	
  Caloric	
  Restric�on	...
STRRIDE
Studies of a Targeted Risk Reduction Intervention
with Defined Exercise
STRRIDE	
  I	
   	
  NHLBI:	
  HL-­‐57453	...
STRRIDE: Eligibility Criteria
Age: 40 - 65
Body Composition: 25 ≤ BMI ≤ 35
Lipids: 130 ≤ LDL ≤ 190 or HDL ≤ 40 M and ≤ 45 ...
STRRIDE - Training Protocols
Intensity Amount Time/wk
(peak VO2) (kcal/wk) (min per wk)
Brisk Walking 13 miles/week 170
Jo...
STRRIDE - Study Design
Months 0 3 6 9 10 12 	

Screening
Ramp up	

Detraining
Retraining
(optional)
Training
0	

5	

10	

15	

20	

*	

δδ	

Group	

*	

PercentChangePeakVO2	

Inac�ve	
   Low	
  Dose	
  
Moderate	
  
Low	
  Dose	
 ...
-­‐2	

-­‐1	

0	

1	

2	

*	

Group	

αα	

PercentChangeBodyMass
Inac�ve	
   Low	
  Dose	
  
Moderate	
  
Low	
  Dose	
  
...
Responses	
  of	
  Tradi�onal	
  Lipid	
  Panel	
  to	
  
Various	
  Exercise	
  Regimens	

HDL-­‐C	
  (mmol/L)	
  
-­‐0.1...
-­‐1.2	
  
-­‐0.8	
  
-­‐0.4	
  
0.0	
  
0.4	
  
0.8	
  
Inac�ve	
   Low	
  Dose	
  
Moderate	
  
Low	
  Dose	
  
Vigorous...
“In general, both HDL cholesterol and serum
TG reproducibly and favorably respond to
changes in habitual physical activity...
 
Effects	
  of	
  Exercise	
  Amount	
  
and	
  Intensity	
  on	
  
Lipoprotein	
  Par�cle	
  Size	
  	
  
and	
  Number	
...
  	
  	
  
1.20
1.10
1.06
1.02
1.006
0.95
5 10 20 40 60 80 1000
Chylomicron
Remnants
VLDL
IDL
LDL
HDL2
HDL3
Diameter (nm)
...
A
0.00
0.05
0.10
0.15
0.20
0.25
B
-0.2
-0.1
0.0
0.1
0.2
0.3
C
-0.10
-0.05
0.00
0.05
0.10
0.15
Control Low dose
moderate
Lo...
A
0.00
0.05
0.10
0.15
0.20
0.25
B
-0.2
-0.1
0.0
0.1
0.2
0.3
C
-0.10
-0.05
0.00
0.05
0.10
0.15
Control Low dose
moderate
Lo...
A
-0.05
0.00
0.05
0.10
0.15
0.20
*
C
-0.15
-0.05
0.05
0.15
Control Low dose moderate Low dose vigorous High dose vigorous
...
C
-0.4
-0.2
0.0
0.2
0.4
Control Low dose
moderate
Low dose
vigorous
High dose
vigorous
***
* **
D
-0.10
-0.08
-0.05
-0.03
...
-­‐100	
  
-­‐60	
  
-­‐20	
  
20	
  
	
  Triglycerides	
  (mg/dl)	
  
***	
  
**	
  
Inac�ve	
   Low	
  Dose	
  
Moderate...
ATP III Score
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
Score
Control Mild Moderate High
All
Men
Women
Ø Effects	
  of	
  Exercise	
  on	
  Lipids	
  and	
  Metabolic	
  
Syndrome	
  
Ø Effects	
  of	
  Caloric	
  Restric�on	...
The	
  CALERIE	
  Study	
  Group	
  
DCRI	
  
William	
  E.	
  Kraus	
  
Manju	
  Bhapkar	
  
James	
  Rochon,	
  PI	
  
P...
Specific	
  Ques�ons	
  Being	
  Addressed	
  /	
  Hypotheses	
  of	
  Interest	
  
  Time	
  course	
  effects	
  of	
  CR	...
%CR
-20
-15
-10
-5
0
5
BL M6 M12 M18 M24
Weightchange(kg)
-10
-8
-6
-4
-2
0
2
*
*
*
*
	
   AL	
  (n=75) CR	
  (n=143) p
Ba...
%CR
-20
-15
-10
-5
0
5
BL M6 M12 M18 M24
Weightchange(kg)
-10
-8
-6
-4
-2
0
2
*
*
*
*
	
   AL	
  (n=75) CR	
  (n=143) p
Ba...
Systolic	
  Blood	
  Pressure	
  
-­‐4.0	
  
-­‐3.0	
  
-­‐2.0	
  
-­‐1.0	
  
0.0	
  
1.0	
  
2.0	
  
3.0	
  
4.0	
  
0	
 ...
-­‐12.0	
  
-­‐10.0	
  
-­‐8.0	
  
-­‐6.0	
  
-­‐4.0	
  
-­‐2.0	
  
0.0	
  
2.0	
  
4.0	
  
6.0	
  
0	
   12	
   24	
  
ΔΔ...
-­‐35.0	
  
-­‐30.0	
  
-­‐25.0	
  
-­‐20.0	
  
-­‐15.0	
  
-­‐10.0	
  
-­‐5.0	
  
0.0	
  
5.0	
  
0	
   12	
   24	
  
	
 ...
0.0	
  
1.0	
  
2.0	
  
3.0	
  
4.0	
  
5.0	
  
6.0	
  
0	
   12	
   24	
  
ΔΔ	
  HDL-­‐C	
  (mg/dL)	
  
Follow-­‐up	
  Mo...
Fas�ng	
  Insulin	
  
-­‐2.0	
  
-­‐1.5	
  
-­‐1.0	
  
-­‐0.5	
  
0.0	
  
0.5	
  
0	
   12	
   24	
  
	
  Fas�ng	
  Insuli...
-­‐35.0	
  
-­‐30.0	
  
-­‐25.0	
  
-­‐20.0	
  
-­‐15.0	
  
-­‐10.0	
  
-­‐5.0	
  
0.0	
  
5.0	
  
10.0	
  
15.0	
  
20.0	...
-­‐1.0	
  
-­‐0.5	
  
0.0	
  
0.5	
  
1.0	
  
0	
   12	
   24	
  
	
  hsCRP	
  (µg/mL)	
  
Follow-­‐up	
  Month	
  
AL	
  ...
Metabolic	
  syndrome	
  score	
  (Z-­‐score	
  developed	
  from	
  baseline	
  values	
  
of	
  study	
  subjects	
  for...
Metabolic	
  Syndrome	
  Score	
  
-­‐3.5	
  
-­‐3.0	
  
-­‐2.5	
  
-­‐2.0	
  
-­‐1.5	
  
-­‐1.0	
  
-­‐0.5	
  
0.0	
  
0....
Conclusions	
  
  Significant	
  CR	
  effect,	
  despite	
  normal	
  body	
  
mass,	
  on:	
  
– Systolic	
  and	
  diasto...
Ø Effects	
  of	
  Exercise	
  on	
  Lipids	
  and	
  Metabolic	
  
Syndrome	
  
Ø Effects	
  of	
  Caloric	
  Restric�on	...
Exercise	
  Energy	
  Deficit	
  
Nutri�on	
  Energy	
  Deficit	
  
Nutri�on	
  
Recovery	
  &	
  	
  
Resupply	
  
	
  
Nut...
Hunter-­‐gatherer	
   Agrarian	
   Industrial	
   Digital	
  
Popula�on	
  
Individual	
  
Cellular	
  
Sub-­‐cellular	
  ...
Prescrip�on	
  for	
  Metabolic	
  Health	
  
  Obtain	
  a	
  minimum	
  of	
  one	
  10-­‐hour	
  fast	
  per	
  
day.	
...
Conclusions	
  
  Exercise	
  training,	
  depending	
  on	
  the	
  intensity	
  
and	
  amount	
  of	
  the	
  exposure,...
Conclusions	
  -­‐2-­‐	
  
  Chronic	
  caloric	
  restric�on,	
  of	
  up	
  to	
  15%,	
  with	
  
an	
  8%	
  weight	
 ...
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Prevention 2014: Exercise and Energy Balance for Cardiovascular Health

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William E. Kraus, MD

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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  • 3. Johnson JL, et al. Am J Cardiol, 20074. Bateman LA, et al. Am J Cardiol, 2011
  • Prevention 2014: Exercise and Energy Balance for Cardiovascular Health

    1. 1. 1st Annual CVD Prevention Conference 26 April 2014 William E. Kraus, M.D. Exercise  and  Energy  Balance  for   Cardiovascular  Disease  Preven�on  
    2. 2. Ø Effects  of  Exercise  on  Lipids  and  Metabolic   Syndrome   Ø Effects  of  Caloric  Restric�on  on  Lipids  and   Metabolic  Syndrome   Ø Concept  of  Energy  Cycling  for  Health   Today’s  Discussion  
    3. 3. Ø Effects  of  Exercise  on  Lipids  and  Metabolic   Syndrome   Ø Effects  of  Caloric  Restric�on  on  Lipids  and   Metabolic  Syndrome   Ø Concept  of  Energy  Cycling  for  Health   Today’s  Discussion  
    4. 4. STRRIDE Studies of a Targeted Risk Reduction Intervention with Defined Exercise STRRIDE  I    NHLBI:  HL-­‐57453     STRRIDE  AT/RT    NHLBI:  HL-­‐57453       STRRIDE-­‐PD    NIDDK:  DK-­‐081559   NCT00200993     NCT00275145   NCT00962962  
    5. 5. STRRIDE: Eligibility Criteria Age: 40 - 65 Body Composition: 25 ≤ BMI ≤ 35 Lipids: 130 ≤ LDL ≤ 190 or HDL ≤ 40 M and ≤ 45 W Glucose: fasting ≤ 140 mg%; fasting insulin ≥ 10 IU/ml Blood pressure: ≤ 160/90 mmHg Menstrual status: postmenopausal (FSH ≥ 40) ± HRT ≥ 6 months Demographics: equal genders, 30% minority Activity: sedentary, peak VO2 ≤ 40 ml/kg/min (11 METS) Medications: nothing that is known to influence skeletal muscle or exercise training responses (e.g. ACE inhibitors, β-blockers) and stable for 6 months
    6. 6. STRRIDE - Training Protocols Intensity Amount Time/wk (peak VO2) (kcal/wk) (min per wk) Brisk Walking 13 miles/week 170 Jogging 13 miles/week 120 Jogging 22 miles/week 170 Inactive None None
    7. 7. STRRIDE - Study Design Months 0 3 6 9 10 12 Screening Ramp up Detraining Retraining (optional) Training
    8. 8. 0 5 10 15 20 * δδ Group * PercentChangePeakVO2 Inac�ve   Low  Dose   Moderate   Low  Dose   Vigorous   High  Dose   Vigorous  
    9. 9. -­‐2 -­‐1 0 1 2 * Group αα PercentChangeBodyMass Inac�ve   Low  Dose   Moderate   Low  Dose   Vigorous   High  Dose   Vigorous  
    10. 10. Responses  of  Tradi�onal  Lipid  Panel  to   Various  Exercise  Regimens HDL-­‐C  (mmol/L)   -­‐0.10   -­‐0.05   0.00   0.05   0.10   0.15   Inac�ve   Low  Dose   Moderate   Low  Dose   Vigorous   High  Dose   Vigorous   *** Group
    11. 11. -­‐1.2   -­‐0.8   -­‐0.4   0.0   0.4   0.8   Inac�ve   Low  Dose   Moderate   Low  Dose   Vigorous   High  Dose   Vigorous   Responses  of  Triglycerides  to  Various   Exercise  Regimens Triglycerides(mmol/L)
    12. 12. “In general, both HDL cholesterol and serum TG reproducibly and favorably respond to changes in habitual physical activity, with increases in HDL cholesterol and decreases in serum TG, mostly related to the volume of exercise training and responding with threshold volumes in the range of 7 to 15 miles per week of regular exercise (equating to an approximate 600 to 800 MET-minutes).” Physical Activity Guidelines Advisory Committee Science Report, DHHS, 2008
    13. 13.   Effects  of  Exercise  Amount   and  Intensity  on   Lipoprotein  Par�cle  Size     and  Number  
    14. 14.       1.20 1.10 1.06 1.02 1.006 0.95 5 10 20 40 60 80 1000 Chylomicron Remnants VLDL IDL LDL HDL2 HDL3 Diameter (nm) Density(g/ml) Chylo- microns Lipoprotein  (Sub)Classes   Lp(a)
    15. 15. A 0.00 0.05 0.10 0.15 0.20 0.25 B -0.2 -0.1 0.0 0.1 0.2 0.3 C -0.10 -0.05 0.00 0.05 0.10 0.15 Control Low dose moderate Low dose vigorous High dose vigorous ** D -1.2 -0.8 -0.4 0.0 0.4 0.8 Control Low dose moderate Low dose vigorous High dose vigorous *** ** Responses of Traditional Lipid Panel to Various Exercise Regimens
    16. 16. A 0.00 0.05 0.10 0.15 0.20 0.25 B -0.2 -0.1 0.0 0.1 0.2 0.3 C -0.10 -0.05 0.00 0.05 0.10 0.15 Control Low dose moderate Low dose vigorous High dose vigorous ** D -1.2 -0.8 -0.4 0.0 0.4 0.8 Control Low dose moderate Low dose vigorous High dose vigorous *** ** Responses of Traditional Lipid Panel to Various Exercise Regimens
    17. 17. A -0.05 0.00 0.05 0.10 0.15 0.20 * C -0.15 -0.05 0.05 0.15 Control Low dose moderate Low dose vigorous High dose vigorous * B -1.0 -0.6 -0.2 0.2 *** D -14 -9 -4 1 6 Control Low dose moderate Low dose vigorous High dose vigorous *** *** Responses of HDL and VLDL to Various Exercise Regimens
    18. 18. C -0.4 -0.2 0.0 0.2 0.4 Control Low dose moderate Low dose vigorous High dose vigorous *** * ** D -0.10 -0.08 -0.05 -0.03 0.00 Control Low dose moderate Low dose vigorous High dose vigorous A -0.4 -0.2 0.0 0.2 0.4 0.6 ** B -150 -75 0 75 150 225 * Responses of LDL Particle Parameters to Various Exercise Regimens
    19. 19. -­‐100   -­‐60   -­‐20   20    Triglycerides  (mg/dl)   ***   **   Inac�ve   Low  Dose   Moderate   Low  Dose   Vigorous   High  Dose   Vigorous   -­‐20   0   20   40   60   80   100   120   *   Group   δ   PercentChangeSi
    20. 20. ATP III Score -0.6 -0.4 -0.2 0 0.2 0.4 0.6 Score Control Mild Moderate High All Men Women
    21. 21. Ø Effects  of  Exercise  on  Lipids  and  Metabolic   Syndrome   Ø Effects  of  Caloric  Restric�on  on  Lipids  and   Metabolic  Syndrome   Ø Concept  of  Energy  Cycling  for  Health   Today’s  Discussion  
    22. 22. The  CALERIE  Study  Group   DCRI   William  E.  Kraus   Manju  Bhapkar   James  Rochon,  PI   PBRC   Corby  Mar�n   Leanne  Redman   Don  Williamson   Eric  Ravussin,  PI   TUFTS   Sai  Das   Tammy  Sco�   Ed  Saltzman   Susan  Roberts,  PI   Washington  U   Luigi  Fontana   Samuel  Klein   Dennis  Villareal   John  O.  Holloszy,  PI   U01AG022132   U01AG020478   U01AG020487   U01AG020480   NIA   Sergei  Romashkan   Evan  Hadley    
    23. 23. Specific  Ques�ons  Being  Addressed  /  Hypotheses  of  Interest     Time  course  effects  of  CR  on  cardiometabolic  risk  factors  (i.e.,  BP,   cholesterol,  glucose  control,  Insulin  sensi�vity)  by  group?     Difference  between  the  weight  loss  phase  (first  12  months)  and   the  weight  maintenance  (metabolic  adapta�on)  phase  (12-­‐  to  24-­‐ months)  despite  the  same  degree  of  CR.               Rela�on  between  the  degree  of  CR  actually  achieved  (ITT)  and  the   magnitude  of  the  improvement  in  cardiometabolic  risk.                                                               200  individuals,  randomized  to  CR:AL  in  2:1  ra�o  ,  young,  recruited  in   two  BMI  strata  of  22-­‐24.9  and  25-­‐27.9,  followed  for  two  years.     CALERIE  
    24. 24. %CR -20 -15 -10 -5 0 5 BL M6 M12 M18 M24 Weightchange(kg) -10 -8 -6 -4 -2 0 2 * * * *   AL  (n=75) CR  (n=143) p Baseline 2422  (50) 2409  (38) .88 BL-­‐M12 -­‐22  (25) -­‐341  (19) <.0001 BL-­‐M24 -­‐14  (23) -­‐258  (18) <.0001 M12-­‐M24 -­‐8  (11) -­‐83  (18) <.0001 Energy  Intake  (kcal/d)     AL CR ≥5%  18  91 ≥10%  3  56 ≥15% - 14 %  Weight  Loss:  BL-­‐M24   Ad Lib CR Longitudinal EI and % Weight Loss
    25. 25. %CR -20 -15 -10 -5 0 5 BL M6 M12 M18 M24 Weightchange(kg) -10 -8 -6 -4 -2 0 2 * * * *   AL  (n=75) CR  (n=143) p Baseline 2422  (50) 2409  (38) .88 BL-­‐M12 -­‐22  (25) -­‐341  (19) <.0001 BL-­‐M24 -­‐14  (23) -­‐258  (18) <.0001 M12-­‐M24 -­‐8  (11) -­‐83  (18) <.0001 Energy  Intake  (kcal/d)     AL CR ≥5%  18  91 ≥10%  3  56 ≥15% - 14 %  Weight  Loss:  BL-­‐M24   Ad Lib CR Longitudinal EI and % Weight Loss Weight  Maintenance  Phase  
    26. 26. Systolic  Blood  Pressure   -­‐4.0   -­‐3.0   -­‐2.0   -­‐1.0   0.0   1.0   2.0   3.0   4.0   0   6   12   18   24    Systolic  Blood  Pressure  (mmHg)   Follow-­‐up  Month   AL   CR  -­‐  ITT   *   **  **  
    27. 27. -­‐12.0   -­‐10.0   -­‐8.0   -­‐6.0   -­‐4.0   -­‐2.0   0.0   2.0   4.0   6.0   0   12   24   ΔΔ  LDL-­‐C  (mg/dL)   Follow-­‐up  Month   AL   CR  -­‐  ITT   LDL-­‐Cholesterol   **   ***  
    28. 28. -­‐35.0   -­‐30.0   -­‐25.0   -­‐20.0   -­‐15.0   -­‐10.0   -­‐5.0   0.0   5.0   0   12   24      ΔΔ  Triglycerides  (mg/dL)   Follow-­‐up  Month   AL   CR  -­‐  ITT   Triglycerides   ***   ***  
    29. 29. 0.0   1.0   2.0   3.0   4.0   5.0   6.0   0   12   24   ΔΔ  HDL-­‐C  (mg/dL)   Follow-­‐up  Month   AL   CR  -­‐  ITT   HDL-­‐Cholesterol   *  
    30. 30. Fas�ng  Insulin   -­‐2.0   -­‐1.5   -­‐1.0   -­‐0.5   0.0   0.5   0   12   24    Fas�ng  Insulin  (µIU/mL)   Follow-­‐up  Month   AL   CR  -­‐  ITT   ****   ****  
    31. 31. -­‐35.0   -­‐30.0   -­‐25.0   -­‐20.0   -­‐15.0   -­‐10.0   -­‐5.0   0.0   5.0   10.0   15.0   20.0   0   12   24    AUC  Insulin  (µIU-­‐h/mL)   Follow-­‐up  Month   AL   CR  -­‐  ITT   AUC  Insulin  (OGTT)   ****   ****  
    32. 32. -­‐1.0   -­‐0.5   0.0   0.5   1.0   0   12   24    hsCRP  (µg/mL)   Follow-­‐up  Month   AL   CR  -­‐  ITT   hs-­‐CRP   *  
    33. 33. Metabolic  syndrome  score  (Z-­‐score  developed  from  baseline  values   of  study  subjects  for:  mean  BP,  HDL,  TG,  WC  and  fas�ng  blood   glucose  (refer  to  Kraus  papers  on  this  [refs  3,4])       For  a  popula�on:       Women:  MSS  =  [45-­‐HDL]/SDHDLW+  [TG-­‐150]/SDTG  +  [WC-­‐88]/SDWCW  +                    [FBG-­‐100]/SDFBG  +    [mean  BP-­‐100]/SDMBP       Men:  MSS  =  [40-­‐HDL]/SDHDLM+  [TG-­‐150]/SDTG  +  [WC-­‐102]/SDWCM  +                    [FBG-­‐100]/SDFBG  +  [mean  BP-­‐100]/SDMBP       Note:  WC  is  natural  WC;  SD  derived  from  study  popula�ons.  
    34. 34. Metabolic  Syndrome  Score   -­‐3.5   -­‐3.0   -­‐2.5   -­‐2.0   -­‐1.5   -­‐1.0   -­‐0.5   0.0   0.5   0   12   24    Met  Syndrome  Z-­‐score   Follow-­‐up  Month   AL   CR  -­‐  ITT   ****   ****  
    35. 35. Conclusions     Significant  CR  effect,  despite  normal  body   mass,  on:   – Systolic  and  diastolic  BP   – LDL-­‐C,  HDL-­‐C,  and  TG   – Fas�ng  insulin,  HOMA,  AUC  insulin,  insulin   sensi�vity,  and  insulin  response  (not  on  glucose   measures).   – Metabolic  syndrome  score  (via  BP,  HDL-­‐C,  TG  and   WC)  
    36. 36. Ø Effects  of  Exercise  on  Lipids  and  Metabolic   Syndrome   Ø Effects  of  Caloric  Restric�on  on  Lipids  and   Metabolic  Syndrome   Ø Concept  of  Energy  Cycling  for  Health   Today’s  Discussion  
    37. 37. Exercise  Energy  Deficit   Nutri�on  Energy  Deficit   Nutri�on   Recovery  &     Resupply     Nutri�on   Recovery  &     Resupply    
    38. 38. Hunter-­‐gatherer   Agrarian   Industrial   Digital   Popula�on   Individual   Cellular   Sub-­‐cellular   WWII   Extreme  Training   Michael  Phelps   Macro-­‐autophagy   vs.  Death   Aging,  Chronic  Disease   Cancer,  HIV   Autophagy   vs.  Apoptosis   Mt  Nutri�on  Stress   Incr  Incomplete  Oxida�on   ER  Stress   Hyperacetyla�on   Lifespan   Healthspan   Energy  Stress  across  the  Ages  of  Man  
    39. 39. Prescrip�on  for  Metabolic  Health     Obtain  a  minimum  of  one  10-­‐hour  fast  per   day.     Obtain  at  least  10,000  steps  per  day.     Have  at  least  one  30-­‐minute  period  of  self-­‐ reflec�on  per  day.     Obtain  at  least  30  hours  of  deep  sleep  per   week.     If  you  do  not  measure  it,  you  cannot  change  it.  
    40. 40. Conclusions     Exercise  training,  depending  on  the  intensity   and  amount  of  the  exposure,  has  significant   effects  on  serum  triglycerides,  less  so  on  HDL-­‐ cholesterol  and  almost  no  effect  on  LDL-­‐ cholesterol.     The  effects  on  metabolic  syndrome  in  general   are  similar  to  those  on  serum  triglycerides  
    41. 41. Conclusions  -­‐2-­‐     Chronic  caloric  restric�on,  of  up  to  15%,  with   an  8%  weight  loss,  has  significant  effects  on   serum  TG,  HDL-­‐C,  LDL-­‐C  and  metabolic   syndrome,  even  in  originally  normal,  young   and  modestly  overweight  individuals.     Perhaps  a  combina�on  of  the  two  approaches   has  the  best  poten�al  for  controlling  the   metabolic  crisis  in  the  US.  

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