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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. 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

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  1. INTELLIGENT DESIGN OF THE EXERCISE “DRUG” TO PREVENT/MANAGE TYPE-2 DIABETES • Barry Braun, PhD, FACSM • Dept. of Kinesiology • University of Massachusetts, Amherst

  2. 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. OBESITY Mokdad et al., JAMA, 2003 DIABETES

  4. Normal insulin action LIVER X FFA FAT GLUCOSE CNS islet cells MUSCLE

  5. Insulin levels   and compensate for cell resistance Insulin Resistance LIVER X x FFA FAT GLUCOSE CNS islet cells MUSCLE

  6. Diabetes Prevention Program, NEJM, 2002 low-fat, low kcal diet, >150’ exercise/wk, lose 7% BW

  7. Lifestyle change Pharmacology Weight loss beneficial impact on metabolic health

  8. 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

  9. 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. 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”

  11. Is the protective effect related to maintenance of high insulin sensitivity despite high body fat in people with high cardiorespiratory fitness?

  12. 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

  13. 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

  14. Lifestyle change Pharmacology exercise training Weight loss beneficial impact on metabolic health

  15. Hayashi et al. Amer. J. Physiol. 1997

  16. 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. 0 1 2 3 4 5 6 7 8 9 10 11 12 Insulin ResistantInsulin Sensitive Subjects

  18. 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’

  19. Heart Stable Isotope Dilution Liver Infuse stable isotopes (& glucose) Blood Brain Uptake Muscle Fat Measure appearance and disappearance of isotope

  20. 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

  21. GC-MS or LC-MS

  22. insulin resistance had no impact on uptake of blood glucose during exercise Braun et al. J. Appl. Physiol 2004

  23. 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

  24. Lifestyle change Pharmacology exercise training acute exercise Weight loss beneficial impact on metabolic health

  25. 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.

  26. 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

  27. 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.

  28. 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

  29. 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?

  30. 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

  31. EXERCISE TRAINING

  32. ENERGY BALANCE All food provided for subjects EE estimated from RMR, accelerometers, food, activity records

  33. 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

  34. HYPOTHESIS Post • Insulin action will • improve in both • groups with: • DEF > BAL Post Pre Pre Insulin Action Energy Deficit (DEF) Energy Balance (BAL)

  35. Glucose Muscle DEF BAL Black et al. J Appl Physiol, 2005

  36. Glucose Liver DEF BAL Black et al. JAP, 2005

  37. 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).

  38. Lifestyle change Pharmacology exercise training acute exercise Weight loss energy balance meal CHO beneficial impact on metabolic health

  39. Energy surplus causes insulin resistance. Can resistance be reversed with exercise, even if energy surplus is maintained? + - Insulin-mediated glucose uptake

  40. 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

  41. 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?

  42. Lifestyle change Pharmacology exercise training acute exercise Weight loss timing energy balance meal CHO beneficial impact on metabolic health

  43. 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

  44. 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

  45. 4 Study Conditions CON = PRE = IMM POST = Wait 3 hours Post 3HR =

  46. * * * * * * * Significantly different from control

  47. Insulin Action * * significantly different from control

  48. Lifestyle change Pharmacology exercise training acute exercise Weight loss timing energy balance meal CHO beneficial impact on metabolic health

  49. 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).

  50. 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

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