INTELLIGENT DESIGN OF THE EXERCISE

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INTELLIGENT DESIGN OF THE EXERCISE DRUG TO
PREVENT/MANAGE TYPE-2 DIABETES

• Barry Braun, PhD, FACSM
• Dept. of Kinesiology
• University of Massachusetts, Amherst

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OUTLINE

• 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

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Mokdad et al., JAMA, 2003
OBESITY
DIABETES
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Normal insulin action
LIVER
X

FFA
FAT
GLUCOSE
CNS
islet cells
MUSCLE
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Insulin Resistance
Insulin levels ? ? and compensate for cell
resistance
LIVER
X

x
FFA
FAT
GLUCOSE
CNS
islet cells
MUSCLE
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Diabetes Prevention Program, NEJM, 2002
low-fat, low kcal diet, gt150 exercise/wk, lose
7 BW
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Lifestyle change
Pharmacology
Weight loss
beneficial impact on metabolic health
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• Impact of energy deficit, (Ein lt Eout), is clear
• well before clinically relevant weight loss.
• Improvements dissipate during weight
• maintenance when energy balance restored

Assali et al., J Endocrinol 2001
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Is fat removal sufficient to cause metabolic
change? Remove fat (9-11 kg) but no change in
energy balance No effects on insulin action or
other metabolic markers like adipokines, etc.
(Klein et al. NEJM 2004)
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The fit-fat concept
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.
Better to be fit and fat than unfit and lean
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Is the protective effect related to
maintenance of high insulin sensitivity despite
high body fat in people with high
cardiorespiratory fitness?
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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

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OF more like LF than OU
LF OF OU
Relatively subtle differences between OF and LF
despite 2x the body fat in OF
Gerson and Braun, Med Sci Sports Exerc 2006
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Lifestyle change
Pharmacology
exercise training
Weight loss
beneficial impact on metabolic health
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Hayashi et al. Amer. J. Physiol. 1997
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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?

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Subjects
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Experimental Protocol
Exercise at 45VO2peak Glucose isotope infusion
Blood and breath samples Analysis of Ra and Rd
15 30 40 50
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Stable Isotope Dilution
Liver
Infuse stable isotopes ( glucose)
Blood
Brain
Uptake
Muscle
Fat
Measure appearance and disappearance of isotope
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Methods Isotope Dilution
Infusion of labeled Glucose (G)
G
IE
G
G G
G
G
rate F
G
Blood
G
G
G
Blood samples to determine Isotopic Enrichment
(IE)
G
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GC-MS or LC-MS
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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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Glucose metabolism post-exercise

• Chronic exercise training improves insulin
• action. One bout of exercise also effective

Pre-training
Post-training
Holloszy et al., Acta Med Scand, 1986
King et al., JAP, 1995
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Lifestyle change
Pharmacology
exercise training
acute exercise
Weight loss
beneficial impact on metabolic health
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Exercise as a drug

• 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.

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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
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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.

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What we think we know

• Physical 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 gt150/week imp. Key may be total EE

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What about energy deficit?

• 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 (lt7d), before significant weight loss
• Q How much of the exercise effect is actually
• mediated by short-term energy deficit?

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Study Design
Energy Deficit DEF
Weight Maintenance Period
Post- Training Measures Insulin Action, Body
Comp, CVD risk factors
Pre-Training Measures Insulin Action, Body Comp,
CVD risk factors
Recruit subjects at risk
6 DAYS OF EXERCISE
Energy Balance BAL
Black et al. J. Appl Physiol 2005
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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
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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 subjects EE estimated from
RMR, accelerometers, food, activity records
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Quantitative, physiological method to assess
whole-body and hepatic insulin action (CIG-SIT)
90 minute infusion 6,6 2H glucose 5-2H
glycerol isotopes
60 minute CIGSIT (20 glucose 2 6,6 2H
glucose)
Change infusate
Steady-state
Fasted state
0
140 145 150
75 90
Outcomes whole-body glucose uptake and
suppression of liver glucose output
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HYPOTHESIS
Post

• Insulin action will
• improve in both
• groups with
• DEF gt BAL

Post
Pre
Pre
Insulin Action
Energy Deficit (DEF)
Energy Balance (BAL)
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Muscle
DEF BAL
Black et al. J Appl Physiol, 2005
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DEF BAL
Black et al. JAP, 2005
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• 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).

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Lifestyle change
Pharmacology
exercise training
acute exercise
Weight loss
energy balance
meal CHO
beneficial impact on metabolic health
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Energy surplus causes insulin resistance. Can
resistance be reversed with exercise, even if
energy surplus is maintained?

-
Insulin-mediated glucose uptake
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• 3 days energy
• surplus reduced
• insulin action.
• One day with
• exercise restored
• insulin action
• despite continued
• 25 overfeeding

Insulin (µUml-1min)
Hagobian and Braun, Metabolism, 2006
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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?
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Lifestyle change
Pharmacology
exercise training
acute exercise
Weight loss
timing
energy balance
meal CHO
beneficial impact on metabolic health
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Timing of CHO replacement
Holding energy balance and CHO availability
constant, does delaying the provision of CHO
and energy accentuate exercise-induced
improvement in insulin sensitivity?
2.5 days
Detrain Overfeed (TDEE500 kcal)
Meal/Exercise intervention
Whole-body and hepatic insulin action
12-hr fast
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Study Meal
Exercise Running or cycling at 65
VO2max Expend 30 TDEE 10 x 30 sec maximal
sprints on cycle ergometer

• 30 TDEE to replace kcals expended during
  exercise
• Composition
• 63.2 CHO
• 24 FAT
• 12.8 PROTEIN

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4 Study Conditions
CON

PRE

IMM POST

Wait 3 hours
Post 3HR

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Significantly different from control
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Insulin Action

significantly different from control
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Lifestyle change
Pharmacology
exercise training
acute exercise
Weight loss
timing
energy balance
meal CHO
beneficial impact on metabolic health
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Exercise drug and pharmacology

• Exercise 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).

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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

• Steve Black, PhD Stuart Chipkin MD
  Kaila Holtz
• Rebecca Hasson, MS Laura Gerson, MS
  Kirsten Granados
• Carrie Sharoff, MS Tara DEon, Ph.D.
  Steve Malin, MS
• Brooke Stephens, MS Todd Hagobian, MS
• Francesca Beaudoin MD graduated
• American Diabetes Association
  Glass Charitable Trust
• Baystate/UMASS CBR