energy metabolism laboratory h h oh ch 2 oh h oh h intelligent design of the exercise “drug” to...

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


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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


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OBESITY

DIABETES


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Normal insulin actionNormal insulin action

LIVER

MUSCLE

GLUCOSE

FFAX

CNS

FAT

islet cells


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Insulin Insulin ResistanceResistance

LIVER

MUSCLE

GLUCOSE

FFAX x

Insulin levels and compensate for cell resistance

FAT

CNSislet cells


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Diabetes Prevention Program, NEJM, 2002Diabetes Prevention Program, NEJM, 2002

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


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Weight loss

beneficial impact on metabolic health

Lifestyle changePharmacology


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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


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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)


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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”


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Is the protective effect related to maintenanceof high insulin sensitivity despite high body fatin 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

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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


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Weight loss


Lifestyle change

Pharmacology

exercise training


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Hayashi et al. Amer. J. Physiol. 1997


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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?


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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*


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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


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Infuse stable isotopes (&

glucose)

Measure appearance and disappearance of isotope

Bloo

dUptake

Liver

Muscle

Brain

Fat

Heart

Stable Isotope Dilution


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Methods: Isotope DilutionMethods: Isotope Dilution

Blood samples to determine Isotopic

Enrichment (IE)

Bloo

d

Infusion of labeled Glucose

(G*)

G*

G*

G*

G*

G

G

G

G

G*

G* + G= IE

rate = F


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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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Rest EX30 EX40 EX50

Rd

(m

g/k

g/m

in)

Resistant

Sensitive


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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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Glu

cose

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l)

Pre-trainingPre-training

Post-trainingPost-training

Holloszy et al., Acta Med Scand, 1986 King et al., JAP, 1995


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Weight loss


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


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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?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 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


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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?


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Recruit subjects at risk

Energy Deficit “DEF”

Energy Balance “BAL”

6 DAYS OF

EXERCISE

Weig

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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


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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 subjectsEE estimated from RMR, accelerometers, food, activity records


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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


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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)


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Glucose

Muscle

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NEG BAL

Rd

(u

M/k

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FM

/min

)/S

S In

s

Pre

Pre

Post

Post

*

Black et al. J Appl Physiol, 2005

DEF BAL


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Suppression of Hepatic Glucose Production

(SS HGP/Basal HGP)

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120%

Pre-Train Post-Train Pre-Train Post-Train

SS

HG

P/B

asal

HG

P *

Liver

Glucose

Black et al. JAP, 2005

DEF BAL


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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).


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Weight loss


Lifestyle change

Pharmacology

exercise training

acute exercise

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energy balance

meal CHO


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Insulin-m

ediated

glucose uptake

+

-

Energy surpluscauses insulin resistance.

Can resistance be reversed withexercise, even if energy surplus is maintained?


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3 days energy surplus reduced insulin action.

One day with exercise restored insulin action despite continued 25% overfeeding 0

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12000

Baseline OF OF+EX

Insu

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(µ

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l-1*m

in)

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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Weight loss


Lifestyle change

Pharmacology

exercise training

acute exercise

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energy balance

meal CHO

timing


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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


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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


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4 Study Conditions

Wait 3 hours

=

=

=

=

CON

PRE

IMM POST

Post 3HR


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Plasma Triglyceride Concentration

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Meal Condition

mg

/dL Basal

CIGSIT

Plasma Insulin Concentration

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30.0

35.0


Meal conditionµ

U/m

l

Basal

CIGSIT

* **

** *

* Significantly different from control


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Insulin ActionGlucose Rd/SSPI

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Meal Condition

Rd

(u

mo

l/kg

FF

M/m

in)/

SS

PI *

* significantly different from control


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Weight loss


Lifestyle change Pharmacology

exercise training

acute exercise

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energy balance

meal CHO

timing


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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).


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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 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

energy metabolism laboratory h h oh ch 2 oh h oh h intelligent design of the exercise “drug” to...

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