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Energy Metabolism Laboratory H H OH CH 2 OH H OH H INTELLIGENT DESIGN OF THE EXERCISE DRUG TO PREVENT/MANAGE TYPE-2 DIABETES Barry Braun, PhD, FACSM Dept.

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Presentation on theme: "Energy Metabolism Laboratory H H OH CH 2 OH H OH H INTELLIGENT DESIGN OF THE EXERCISE DRUG TO PREVENT/MANAGE TYPE-2 DIABETES Barry Braun, PhD, FACSM Dept."— Presentation transcript:

1 Energy Metabolism Laboratory H H OH CH 2 OH H OH H INTELLIGENT DESIGN OF THE EXERCISE DRUG TO PREVENT/MANAGE TYPE-2 DIABETES Barry Braun, PhD, FACSM Dept. of Kinesiology University of Massachusetts, Amherst

2 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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

3 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Mokdad et al., JAMA, 2003 OBESITY DIABETES

4 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Normal insulin action LIVER MUSCLE GLUCOSE FFA X CNS FAT islet cells

5 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Insulin Resistance LIVER MUSCLE GLUCOSE FFA X x Insulin levels and compensate for cell resistance FAT CNS islet cells

6 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Diabetes Prevention Program, NEJM, 2001 low-fat, low kcal diet, >150 exercise/wk, lose 7% BW

7 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Weight loss beneficial impact on metabolic health Lifestyle change Pharmacology

8 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Impact of energy deficit, (E in < E out ), is clear well before clinically relevant weight loss. Improvements dissipate during weight maintenance when energy balance restored Assali et al., J Endocrinol 2001

9 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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)

10 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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 concept Better to be fit and fat than unfit and lean

11 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Is the protective effect related to maintenance of high insulin sensitivity despite high body fat in people with high cardiorespiratory fitness?

12 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Overweight athletes Compared a group of 10 lean fit women (LF) (BF = 17%, VO 2 peak = 73 ml/kgFFM/min) with group of 10 overweight fit women (OF) (BF = 34%, VO 2 peak = 74 ml/kgFFM/min) and group of 10 overweight unfit women (OU) (BF = 36%, VO 2 peak = 42 ml/kgFFM/min) Insulin response to glucose, triglycerides

13 Energy Metabolism Laboratory H H OH CH 2 OH H OH H OF more like LF than OU 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

14 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Weight loss beneficial impact on metabolic health Lifestyle change Pharmacology exercise training

15 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Hayashi et al. Amer. J. Physiol. 1997

16 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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?

17 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Subjects Insulin Resistant Insulin Sensitive

18 Energy Metabolism Laboratory H H OH CH 2 OH H OH H ExperimentalProtocol 90 minutes resting infusion Standard Snack min exercise infusion hours Exercise at 45%VO 2 peak Glucose isotope infusion Blood and breath samples Analysis of Ra and Rd

19 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Isotope dilution

20 Energy Metabolism Laboratory H H OH CH 2 OH H OH H insulin resistance had no impact on uptake of blood glucose during exercise Braun et al. J. Appl. Physiol 2004

21 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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, 1986King et al., JAP, 1995

22 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Weight loss beneficial impact on metabolic health Lifestyle change Pharmacology exercise training acute exercise

23 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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

24 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Is Exercise Intensity Important? No-Exercise LO = 143 min; 50.4% VO 2 max = 750 kcal HI = 89 min; 74.4% VO 2 max = 750 kcal Braun et al. J Appl. Physiol. 1995

25 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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 min/wk. more effective than condition with 115 min/wk No change in weight ( kg) Houmard et al

26 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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 h No obvious effects of mode or intensity but duration >150/week imp. Key may be total EE

27 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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?

28 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Recruit subjects at risk Energy Deficit DEF Energy Balance BAL 6 D AYS OF E XERCISE Weight Maintenance Period Pre- Training Measures: Insulin Action, Body Comp, CVD risk factors Post- Training Measures: Insulin Action, Body Comp, CVD risk factors Study Design Black et al. J. Appl Physiol 2005

29 Energy Metabolism Laboratory H H OH CH 2 OH H OH H EXERCISE TRAINING DEFBAL Exercise EE (kcals) Minutes on Treadmill VO2 (ml/kg/min) HR last 20 (bpm) RPE13.4 ± ± 0.2 Steps

30 Energy Metabolism Laboratory H H OH CH 2 OH H OH H ENERGY BALANCE DEFBAL Energy Ingested (kcals)2246 ± ± 159 Estimated Energy Expenditure (kcal) 2727 ± ± 169 Energy Balance (kcal)-481 ± 24+8 ± 20 Weight Change (kg)-0.62 ± ± 0.2 All food provided for subjects EE estimated from RMR, accelerometers, food, activity records

31 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 90 minute infusion [6,6 2 H] glucose + [5- 2 H] glycerol isotopes 60 minute CIGSIT (20% glucose + 2% [6,6 2 H] glucose) Change infusate 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

32 Energy Metabolism Laboratory H H OH CH 2 OH H OH H HYPOTHESIS Insulin action will improve in both groups with: DEF > BAL InsulinAction Pre Post Pre Post Energy Deficit (DEF)Energy Balance (BAL)

33 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Glucose Muscle Black et al. J Appl Physiol, 2005 DEF BAL

34 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Liver Glucose Black et al. JAP, 2005 DEF BAL

35 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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).

36 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Weight loss beneficial impact on metabolic health Lifestyle change Pharmacology exercise training acute exercise energy balance meal CHO

37 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Insulin-mediated glucose uptake + - Energy surplus causes insulin resistance. Can resistance be reversed with exercise, even if energy surplus is maintained?

38 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 3 days energy surplus reduced insulin action. One day with exercise restored insulin action despite continued 25% overfeeding Insulin (µUml -1 *min) Hagobian and Braun, Metabolism, 2006

39 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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?

40 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Weight loss beneficial impact on metabolic health Lifestyle change Pharmacology exercise training acute exercise energy balance meal CHO timing

41 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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

42 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 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% VO 2max Expend 30% TDEE 10 x 30 sec maximal sprints on cycle ergometer

43 Energy Metabolism Laboratory H H OH CH 2 OH H OH H 4 Study Conditions Wait 3 hours = = = = CON PRE IMM POST Post 3HR

44 Energy Metabolism Laboratory H H OH CH 2 OH H OH H * ** ** * * Significantly different from control

45 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Insulin Action * * significantly different from control

46 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Weight loss beneficial impact on metabolic health Lifestyle change Pharmacology exercise training acute exercise energy balance meal CHO timing

47 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Exercise drug and pharmacology Exercise + metformin better than either one alone? Hypothesis being tested at 3 physiological levels: Skeletal muscle (activity of AMP-kinase; a key regulator of muscle glucose uptake) Whole-body insulin action (blood glucose uptake during a glucose clamp) From a clinical perspective (glucose profile assessed by continuous glucose monitoring).

48 Energy Metabolism Laboratory H H OH CH 2 OH H 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 H H OH CH 2 OH H OH H

49 Energy Metabolism Laboratory H H OH CH 2 OH H OH H Energy Metabolism Laboratory Steve Black, PhD* Stuart Chipkin MD Kaila Holtz, MS* Rebecca Hasson, MS Laura Gerson, MS* Kirsten Granados Carrie Sharoff, MS Tara DEon, PhD Steve Malin, MS Brooke Stephens, MS Todd Hagobian, PhD Francesca Beaudoin MS, MD* *= graduated American Diabetes Assoc. Baystate/UMASS CBR Glass Charitable Trust


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