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Energy Metabolism Laboratory
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INTELLIGENT DESIGN INTELLIGENT DESIGN OF THE EXERCISE “DRUG” OF THE EXERCISE “DRUG”
TO PREVENT/MANAGE TO PREVENT/MANAGE TYPE-2 DIABETESTYPE-2 DIABETES
Barry Braun, PhD, FACSMDept. of KinesiologyUniversity of Massachusetts, Amherst
Energy Metabolism Laboratory
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OUTLINEOUTLINE
Scope of the problem
Mechanism
Lifestyle change
Is weight loss necessary?
Single bout effect. Exercise as drug
Exercise drug / diet interactions
Exercise drug/pharmacological interactions
Energy Metabolism Laboratory
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OBESITY
DIABETES
Energy Metabolism Laboratory
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Normal insulin actionNormal insulin action
LIVER
MUSCLE
GLUCOSE
FFAX
CNS
FAT
islet cells
Energy Metabolism Laboratory
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Insulin Insulin ResistanceResistance
LIVER
MUSCLE
GLUCOSE
FFAX x
Insulin levels and compensate for cell resistance
FAT
CNSislet cells
Energy Metabolism Laboratory
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Diabetes Prevention Program, NEJM, 2002Diabetes Prevention Program, NEJM, 2002
low-fat, low kcal diet, >150’ exercise/wk, lose 7% BW
Energy Metabolism Laboratory
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Weight loss
beneficial impact on metabolic health
Lifestyle changePharmacology
Energy Metabolism Laboratory
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Impact of energy deficit, (Ein < Eout), is clear well before clinically relevant weight loss. Improvements dissipate during weight maintenance when energy balance restored
Assali et al., J Endocrinol 2001
Energy Metabolism Laboratory
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Is fat removalsufficient to cause metabolic change?
Remove fat (9-11kg) but no change in energy balance
No effects on insulin action or other metabolic markers like adipokines, etc. (Klein et al. NEJM 2004)
Energy Metabolism Laboratory
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A series of studies from the research group headed by Steven Blair have suggested that individuals who are overweight or obese but physically fit have lower risk for chronic disease than individuals who are normal weight but physically unfit.
The “fit-fat” conceptThe “fit-fat” concept
“Better to be fit and fat than unfit and lean”
Energy Metabolism Laboratory
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Is the protective effect related to maintenanceof high insulin sensitivity despite high body fatin people with high cardiorespiratory fitness?
Energy Metabolism Laboratory
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Overweight athletes
Compared a group of 10 lean fit women (LF) (BF = 17%, VO2peak = 73 ml/kgFFM/min)
with group of 10 overweight fit women (OF)(BF = 34%, VO2peak = 74 ml/kgFFM/min)
and group of 10 overweight unfit women (OU)(BF = 36%, VO2peak = 42 ml/kgFFM/min)
Insulin response to glucose, triglycerides
Energy Metabolism Laboratory
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OF more like LF than OU
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Time
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LA OA OS
Relatively subtle differences between OF and LF despite 2x the body fat in OF
LF OF OU
Gerson and Braun, Med Sci Sports Exerc 2006
Energy Metabolism Laboratory
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Weight loss
beneficial impact on metabolic health
Lifestyle change
Pharmacology
exercise training
Energy Metabolism Laboratory
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Hayashi et al. Amer. J. Physiol. 1997
Energy Metabolism Laboratory
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Resistance to the exercise drug?Resistance to the exercise drug?
GLUT4 translocation normal in muscle from humans with T2D (L. Goodyear laboratory)
Are pathways independent in vivo?
Do insulin-resistant humans have “normal”glucose uptake & oxidation during exercise?
Energy Metabolism Laboratory
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SubjectsSubjects
0 1 2 3 4 5 6 7 8 9 10 11 12
Insulin Resistant Insulin Sensitive
Variable IR IS (95%C.I.) p
Age (years) 37.3 ± 6.9 33.3 ± 7.9 (-5.7,13.7) 0.370Weight (kg) 72.4 ± 3.6 77.8 ± 8.9 (-15.0,4.2) 0.220
BMI (kg/m2) 28.5 ± 1.64 27.5 ± 1.87 (-1.30,3.3) 0.350% Body Fat 38.4 ± 3.2 44.6 ± 4.2 (-11.3,-1.3) 0.019*Lean Mass (kg) 42.4 ±1.6 41.5 ± 3.2 (-2.6,4.3) 0.570VO2 peak (mg/kg/min) 29.7 ± 2.5 30.7 ± 6.1 (-7.3,2.6) 0.310
Fasting Glucose (mM) 5.67 ± 0.67 4.38 ± 0.28 (0.56,2.0) 0.004*Fasting Insulin (pM) 74.5 ± 1.7 39.1 ± 10.0 (2.0,68.7) 0.041*OGTT Mean Glucose (mM) 8.13 ± 1.99 6.35 ± 1.35 (-0.48,4.05) 0.110OGTT Mean Insulin (pM) 446 ± 149 198 ± 33 -87,409 0.011*C-ISI score 3.03 ± 0.69 7.65 ± 0.95 (-5.69,-3.53) 0.001*
Energy Metabolism Laboratory
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Experimental Experimental ProtocolProtocol
90 minutes resting infusion
Standard Snack
-90’
45 min exercise infusion
-15’ 0’
2 hours
15’ 30’ 40’ 50’
Exercise at 45%VO2peak
Glucose isotope infusion
Blood and breath samples
Analysis of Ra and Rd
Energy Metabolism Laboratory
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Infuse stable isotopes (&
glucose)
Measure appearance and disappearance of isotope
Bloo
dUptake
Liver
Muscle
Brain
Fat
Heart
Stable Isotope Dilution
Energy Metabolism Laboratory
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Methods: Isotope DilutionMethods: Isotope Dilution
Blood samples to determine Isotopic
Enrichment (IE)
Bloo
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Infusion of labeled Glucose
(G*)
G*
G*
G*
G*
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G* + G= IE
rate = F
Energy Metabolism Laboratory
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GC-MS or LC-MS
Energy Metabolism Laboratory
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insulin resistance had no impact on uptake of blood glucose during exercise
Braun et al. J. Appl. Physiol 2004
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Rest EX30 EX40 EX50
Rd
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Resistant
Sensitive
Energy Metabolism Laboratory
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Glucose metabolism post-exerciseGlucose metabolism post-exercise
Chronic exercise training improves insulin action. One bout of exercise also effective
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Time
Glu
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(m
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Pre-trainingPre-training
Post-trainingPost-training
Holloszy et al., Acta Med Scand, 1986 King et al., JAP, 1995
Energy Metabolism Laboratory
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Weight loss
beneficial impact on metabolic health
Lifestyle change
Pharmacology
exercise training
acute exercise
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Taken at a sufficient dose, a bout of exercise, [coupled with the proximal nutrient intake], impacts metabolic function for some period of time and then wanes, requiring subsequent doses to maintain the effect.
Tailoring the dose to achieve maximal effect is likely to result in the biggest long-term reward in terms of optimizing cardiometabolic health.
Exercise as a drug
Energy Metabolism Laboratory
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Is Exercise Intensity Important?
No-Exercise
LO = 143 min; 50.4%VO2max = 750 kcal
HI = 89 min; 74.4% VO2max = 750 kcal
Braun et al. J Appl. Physiol. 1995
Energy Metabolism Laboratory
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Does duration matter?Does duration matter?low vol/mod int. = (app. 170’/week) = + 80%
low vol/high int. = (app. 115’/week) = + 40%
high vol/high int. = (app. 170’/week) = + 80%
Conditions with duration of 167-171 min/wk. more effective than condition with 115 min/wk
No change in weight (0.6-1.8 kg) Houmard et al. 2003.
Energy Metabolism Laboratory
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What we think we knowWhat we think we knowPhysical activity delays/prevents transition from IR to T2DM
Exercise effects can be independent of wt. loss
Much of the benefit gained from residual effects of recent exercise; lasting 24-72 h
No obvious effects of mode or intensity but duration >150’/week imp. Key may be total EE
Energy Metabolism Laboratory
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In studies of short-term exercise training (1-7 days), extra energy expenditure due to exercise was NOT added back to diet
Energy deficit reduces insulin resistance quickly (<7d), before significant weight loss
Q: How much of the “exercise effect” is actually mediated by short-term energy deficit?
What about energy deficit?What about energy deficit?
Energy Metabolism Laboratory
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Recruit subjects at risk
Energy Deficit “DEF”
Energy Balance “BAL”
6 DAYS OF
EXERCISE
Weig
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Main
ten
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Peri
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Pre-Training Measures: Insulin Action, Body
Comp, CVD risk factors
Post- Training
Measures: Insulin Action, Body
Comp, CVD risk factors
Study DesignStudy Design
Black et al. J. Appl Physiol 2005
Energy Metabolism Laboratory
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EXERCISE TRAINING
DEF BAL
Exercise EE (kcals)
481.1 32.6 507.5 39.9
Minutes on Treadmill
65.6 4.7 61.6 7.8
VO2 (ml/kg/min)
19.0 1.9 19.5 3.4
HR last 20’ (bpm)
135.4 1.6 136.3 0.9
RPE 13.4 ± 0.1 13.1 ± 0.2
Steps 8053 225 7934 437
Energy Metabolism Laboratory
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ENERGY BALANCE
DEF BAL
Energy Ingested (kcals) 2246 ± 97 2925 ± 159
Estimated Energy Expenditure (kcal)
2727 ± 182 2917 ± 169
Energy Balance (kcal) -481 ± 24 +8 ± 20
Weight Change (kg) -0.62 ± 0.2 +0.03 ± 0.2
All food provided for subjectsEE estimated from RMR, accelerometers, food, activity records
Energy Metabolism Laboratory
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90 minute infusion [6,6 2H] glucose +
[5-2H] glycerolisotopes
60 minute CIGSIT(20% glucose
+ 2% [6,6 2H] glucose)
Changeinfusate
140 145 15075 90
Fasted state
0
Steady-state
Quantitative, “physiological” method to assess whole-body and hepatic insulin action (CIG-SIT)
Outcomes: whole-body glucose uptake and suppression of liver glucose output
Energy Metabolism Laboratory
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HYPOTHESIS
Insulin action will improve in both groups with: DEF > BALInsulin
Action
Pre
Post
Pre
Post
Energy Deficit (DEF) Energy Balance (BAL)
Energy Metabolism Laboratory
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Glucose
Muscle
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NEG BAL
Rd
(u
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FM
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S In
s
Pre
Pre
Post
Post
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Black et al. J Appl Physiol, 2005
DEF BAL
Energy Metabolism Laboratory
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Suppression of Hepatic Glucose Production
(SS HGP/Basal HGP)
0%
20%
40%
60%
80%
100%
120%
Pre-Train Post-Train Pre-Train Post-Train
SS
HG
P/B
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HG
P *
Liver
Glucose
Black et al. JAP, 2005
DEF BAL
Energy Metabolism Laboratory
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Is energy deficit the only explanation?Is energy deficit the only explanation?
No, CHO content of diet was not identical.DEF = 330 g/day; BAL = 410g CHO/day
“Extra” CHO could have upregulated glycogen synthesis pathways (altered GSK, GS activity).
Energy Metabolism Laboratory
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Weight loss
beneficial impact on metabolic health
Lifestyle change
Pharmacology
exercise training
acute exercise
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energy balance
meal CHO
Energy Metabolism Laboratory
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Insulin-m
ediated
glucose uptake
+
-
Energy surpluscauses insulin resistance.
Can resistance be reversed withexercise, even if energy surplus is maintained?
Energy Metabolism Laboratory
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3 days energy surplus reduced insulin action.
One day with exercise restored insulin action despite continued 25% overfeeding 0
2000
4000
6000
8000
10000
12000
Baseline OF OF+EX
Insu
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Hagobian and Braun, Metabolism, 2006
Energy Metabolism Laboratory
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Timing of post-exercise intake?
Differences may be related to timing of energy/ CHO intake relative to energy expenditure. In Black et al., the BAL group had energy (60% CHO) fed immediately post-exercise.
Big stimulation of glycogen synthesis pathway?Glycogen supercompensation?
Energy Metabolism Laboratory
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Weight loss
beneficial impact on metabolic health
Lifestyle change
Pharmacology
exercise training
acute exercise
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energy balance
meal CHO
timing
Energy Metabolism Laboratory
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Detrain +Overfeed
(TDEE+500 kcal)
Meal/Exercise intervention
Whole-body and hepatic
insulin action
2.5 days
12-hr fast
Holding energy balance and CHO availability constant, does delaying the provision of CHO and energy accentuate exercise-induced improvement in insulin sensitivity?
Timing of CHO replacement
Energy Metabolism Laboratory
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Study Meal
30% TDEE to replace kcals expended during exercise
Composition
63.2% CHO
24% FAT
12.8% PROTEIN
Exercise
Running or cycling
at 65% VO2max
Expend 30% TDEE
10 x 30 sec maximal sprints on cycle ergometer
Energy Metabolism Laboratory
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4 Study Conditions
Wait 3 hours
=
=
=
=
CON
PRE
IMM POST
Post 3HR
Energy Metabolism Laboratory
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Plasma Triglyceride Concentration
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Con Pre ImmPost Post 3HR
Meal Condition
mg
/dL Basal
CIGSIT
Plasma Insulin Concentration
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5.0
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35.0
Con Pre ImmPost Post 3HR
Meal conditionµ
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Basal
CIGSIT
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** *
* Significantly different from control
Energy Metabolism Laboratory
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Insulin ActionGlucose Rd/SSPI
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Meal Condition
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SS
PI *
* significantly different from control
Energy Metabolism Laboratory
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Weight loss
beneficial impact on metabolic health
Lifestyle change Pharmacology
exercise training
acute exercise
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energy balance
meal CHO
timing
Energy Metabolism Laboratory
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Exercise drug and pharmacologyExercise + metformin better than either one alone? Hypothesis being tested at 3 physiological levels:
Skeletal muscle (activity of AMPK, GS, GSK-3, Akt, AS160, etc.)
Whole-body insulin action (blood glucose uptake during a glucose clamp)
From a clinical perspective (glucose profile assessed by continuous glucose monitoring).
Energy Metabolism Laboratory
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Lab Mission Statement
To understand how physical activity and food/pharmacology can be optimally integrated to reverse insulin resistance and prevent Type-2 Diabetes
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Energy Metabolism Laboratory
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Energy Metabolism LaboratorySteve Black, PhD* Stuart Chipkin MD Kaila Holtz Rebecca Hasson, MS Laura Gerson, MS* Kirsten GranadosCarrie Sharoff, MS Tara D’Eon, Ph.D. Steve Malin,
MSBrooke Stephens, MS Todd Hagobian, MSFrancesca Beaudoin MD* *= graduated
American Diabetes Association Glass Charitable TrustBaystate/UMASS CBR