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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. OUTLINE. Scope of the problem Mechanism Lifestyle change Is weight loss necessary? Single bout effect. Exercise as drug

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intelligent design of the exercise drug to prevent manage type 2 diabetes
INTELLIGENT DESIGN OF THE EXERCISE “DRUG” TO PREVENT/MANAGE TYPE-2 DIABETES
  • Barry Braun, PhD, FACSM
  • Dept. of Kinesiology
  • University of Massachusetts, Amherst
outline
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
normal insulin action
Normal insulin action

LIVER

X

FFA

FAT

GLUCOSE

CNS

islet cells

MUSCLE

slide6

Diabetes Prevention Program, NEJM, 2002

low-fat, low kcal diet, >150’ exercise/wk, lose 7% BW

slide7

Lifestyle change

Pharmacology

Weight loss

beneficial impact on metabolic health

slide8
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

slide9

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)

slide10

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”

slide11

Is the protective effect

related to maintenance

of high insulin sensitivity

despite high body fat

in people with high

cardiorespiratory fitness?

overweight athletes
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
of more like lf than ou
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

slide14

Lifestyle change

Pharmacology

exercise training

Weight loss

beneficial impact on metabolic health

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?
subjects

0 1 2 3 4 5 6 7 8 9 10 11 12

Insulin ResistantInsulin Sensitive

Subjects
slide18

2 hours

90 minutes resting infusion

45 min exercise infusion

Standard Snack

-90’

-15’ 0’

Experimental

Protocol

Exercise at 45%VO2peak

Glucose isotope infusion

Blood and breath samples

Analysis of Ra and Rd

15’ 30’ 40’ 50’

stable isotope dilution

Heart

Stable Isotope Dilution

Liver

Infuse stable isotopes (& glucose)

Blood

Brain

Uptake

Muscle

Fat

Measure appearance and disappearance of isotope

slide20

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

slide22

insulin resistance had no impact on uptake of blood glucose during exercise

Braun et al. J. Appl. Physiol 2004

glucose metabolism post exercise
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

slide24

Lifestyle change

Pharmacology

exercise

training

acute exercise

Weight

loss

beneficial impact on metabolic health

exercise as a drug
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.
is exercise intensity important
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

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.
what we think we know
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 >150’/week imp. Key may be total EE
slide29

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 (<7d), before significant weight loss
  • Q: How much of the “exercise effect” is actually
  • mediated by short-term energy deficit?
slide30

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

6DAYS OF

EXERCISE

Energy Balance “BAL”

Black et al. J. Appl Physiol 2005

energy balance
ENERGY BALANCE

All food provided for subjects

EE estimated from RMR, accelerometers, food, activity records

slide33

Quantitative, “physiological”method to assess whole-body and hepatic insulin action (CIG-SIT)

90 minute infusion

[6,6 2H] glucose +

[5-2H]glycerol

isotopes

Change

infusate

60 minute CIGSIT

(20% glucose

+ 2% [6,6 2H] glucose)

Steady-state

Fasted state

0

75 90

140 145 150

  • Outcomes: whole-body glucose uptake and
  • suppression of liver glucose output
hypothesis
HYPOTHESIS

Post

  • Insulin action will
  • improve in both
  • groups with:
  • DEF > BAL

Post

Pre

Pre

Insulin Action

Energy Deficit (DEF)

Energy Balance (BAL)

slide35

Glucose

Muscle

DEF BAL

Black et al. J Appl Physiol, 2005

slide36

Glucose

Liver

DEF BAL

Black et al. JAP, 2005

slide37
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).
slide38

Lifestyle change

Pharmacology

exercise

training

acute exercise

Weight

loss

energy

balance

meal

CHO

beneficial impact on metabolic health

slide39

Energy surplus

causes insulin

resistance.

Can resistance be reversed with

exercise, even if

energy surplus is maintained?

+

-

Insulin-mediated glucose uptake

slide40
3 days energy
  • surplus reduced
  • insulin action.
  • One day with
  • exercise restored
  • insulin action
  • despite continued
  • 25% overfeeding

Insulin (µU∙ml-1*min)

Hagobian and Braun, Metabolism, 2006

timing of post exercise intake
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?

slide42

Lifestyle change

Pharmacology

exercise

training

acute exercise

Weight

loss

timing

energy

balance

meal

CHO

beneficial impact on metabolic health

slide43

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

(TDEE+500 kcal)

Meal/Exercise

intervention

12-hr

fast

Whole-body

and hepatic

insulin action

study meal
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
4 study conditions
4 Study Conditions

CON

=

PRE

=

IMM POST

=

Wait

3 hours

Post 3HR

=

slide46

*

*

*

*

*

*

* Significantly different from control

insulin action
Insulin Action

*

* significantly different from control

slide48

Lifestyle change

Pharmacology

exercise

training

acute exercise

Weight

loss

timing

energy

balance

meal

CHO

beneficial impact on metabolic health

exercise drug and pharmacology
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).
slide50

CH2OH

H

H

OH

H

OH

OH

OH

H

  • Lab Mission Statement
  • To understand how physical activity
  • and food/pharmacology can be
  • optimally integrated to reverse insulin
  • resistance and prevent Type-2 Diabetes
energy metabolism laboratory
Energy Metabolism Laboratory
  • Steve Black, PhD* Stuart Chipkin MD Kaila Holtz
  • Rebecca Hasson, MS Laura Gerson, MS* Kirsten Granados
  • Carrie Sharoff, MS Tara D’Eon, Ph.D. Steve Malin, MS
  • Brooke Stephens, MS Todd Hagobian, MS
  • Francesca Beaudoin MD* *= graduated
  • American Diabetes Association Glass Charitable Trust
  • Baystate/UMASS CBR