Exercise is Medicine: Translational Research in Obesity and Insulin Resistance

1. Exercise is Medicine: Translational Research in Obesity and Insulin Resistance Alice S. Ryan, Ph.D. Baltimore VA Medical Center University of MD School of Medicine

2. Advice from Newsweek 2010 “basic muscle-strengthening activities twice a week … and find two and a half more hours in your week for moderate aerobic activity.” – Science of Healthy Living

3. Percentage of Adults Who Reported No Leisure-Time Physical Activity by Age in Maryland, 2001-2003

4. % BMI>25 40% 31% % BMI>30 28% 12% Data from CDC National Center for Chronic Disease Prevention & Health Promotion Behavioral Risk Factor Surveillance System

5. Prevalenceof Diabetes by Age and Obesity Percent Diabetic BMI (kg/m2) <22 >35 <22 >35 22-25 26-30 22-25 26-30 31-35 31-35 20 - 54 60 - 74 Age (years)

6. Where is the Fat? Abdominal Fat Mid-thigh

7. Fat Distribution Trends in Postmenopausal Women Visceral and Subcutaneous Adipose Depots Total and Central Obesity Sample: Caucasian N = 50 – 80 per group

8. Increased Fasting Glucose & Insulin across VAT quintiles 1 1 1 1,2,3 1,2,3 1,2,3 1 VAT quintiles (cm2) Numbers signify P<0.05 from quintiles 1, 2, 3 Analyses adjusted for age, fat mass, & race Nicklas et al. Diabetes Care, 2003

9. VAT of ~ 100-110 cm2 is predictive of adverse lipid (HDL, TG) and diabetes risk factors in women. Depres and Lamarche, Nutr Res Rev, 1993 Williams MJ et al, Int J Obes Relat Metab Disord, 1996 Nicklas et al., Diabetes Care, 2003 Visceral Adipose Tissue Risk

10. Exercise Reduces Visceral Fat in Women Athletes * * VAT (cm2) N = 10 – 14 per group * P < 0.01 Ryan et al. Am J of Physiol, 1996

11. Visceral Adipose Tissue Decreases with ↑VO2 max r=-0.47, p<0.01 Lynch et al., J Appl Physiol, 2001

12. BEDSIDE Measurement of Insulin Sensitivity: Hyperinsulinemic-euglycemic clamp Insulin 80mU/min

13. 70 60 50 * . 40 30 20 10 0 Athletes Controls 18-29 40-49 18-29 30-39 50-69 40-50 Chronic Exercise in Older Women Prevents the Decline in Insulin Sensitivity Observed with Aging Glucose Uptake (umol/kgFFM/min) *P < 0.05 Ryan et al. J Appl Physiol, 2001

14. Older Elite Football Players have Reduced Cardiac Risk Factors • Former Colts compared to age, BMI, race and current physical activity level matched men: • 26% lower visceral fat and lower total body fat (p<0.01). • 13% higher muscle mass (p<0.01) • 37% higher HDL-C & 31% lower TG (p<0.05) Suggests that the high levels of exercise in young adulthood conferred benefits later in life Lynch et al. Med Sci Sports Exerc, 2007

15. Can We Modify Obesity and Insulin Resistance with Exercise Training?

16. Study Design Screening Enrollment Metabolic Testing Interventions WL: 1x/wk AEX+WL: 3x/wk 0 m Dietary Stabilization Metabolic Testing • 45 - 80 year old Caucasian or African American women • Postmenopausal (1 year) • BMI: 25 – 50 kg/m2 • Sedentary, Weight stable • Non-smokers (≥ 1 year) • No symptomatic heart disease or medications interfering with muscle metabolism 6 m 12 m Weight Stable 2 wks

17. Study Design • Metabolic Testing • VO2max, Body Composition (DXA, CT) • 3-hr OGTT • 3 hr 80 mU/m2/min Hyperinsulinemic-euglycemic Clamp w/Indirect Calorimetry • Skeletal Muscle Biopsy (basal & @120min) • Gluteal & Abdominal Adipose Tissue Biopsy Interventions 0 m Metabolic Testing 6 m 12 m

18. Study Design Screening N ~ 3000 Enrollment N = 292 Metabolic Testing N = 174 AEX+WL N = 88 Entered WL N = 86 Entered Dropped N = 63 Completed & Noncompliant N=8 AEX+WL N = 53 Completed WL N = 50 Completed

19. Successful Weight Loss with AEX+WL and WL Improvements in Fitness only with AEX+WL Weight VO2max  8%  8% 14% ‡ * * * (l/min) (kg) *P<0.001 *P<0.001 ‡P<0.05 AEX+WL vs. WL

20. Losses of both Fat Mass and FFM with AEX+WL and WL Fat Mass FFM  2%  4% 16%  13% ‡ ‡ * * (kg) (kg) *P<0.001 ‡P<0.05

21. Reductions in Abdominal and Intra-muscular Fat Mid-thigh Intramyocellular Lipid Visceral Fat Area  16%  13%  9% * + + * (cm2) (cm2) *P<0.001

22. Improvements in Insulin Sensitivity  14%  6% * Glucose Uptake (mol/kgFFM/min) *P<0.01 ‡P<0.05

23. Improvements in Insulin Sensitivity are associated with an Increase in Fitness r=0.30,P<0.05 ∆ M (µmol/kgFFM/min) ∆ VO2max (l/min)

24. Mechanisms of Action of Lifestyle Interventions Exercise Training Weight Loss Adipose Muscle  Insulin Sensitivity  Fat stores • Capillarization Insulin Activation of Glycogen Synthase ↑ Enzymes of Fatty Acid Metabolism  Inflammation

25. “BEDSIDE TO BENCH” Skeletal Muscle and Adipose Tissue Mechanisms of Exercise Vastus Lateralis Biopsy Gluteal Adipose Tissue Biopsy

26. Skeletal Muscle Capillarization and Fiber Type Double Stain Myosin ATPase Type I: stain dark brown/black Type IIa: stain light brown/white Type IIx: stain brown CD: Capillary Density (cap/mm2) CFPE: Capillary-to-fiber perimeter exchange index (cap/mm perimeter)

27. VASCULAR and SYSTEMIC MARKERS in NGT (n = 42) and IGT (n = 28) Postmenopausal Women VASCULAR and SYSTEMIC MARKERS in NGT (n = 42) and IGT (n = 28) Postmenopausal Women VASCULAR and SYSTEMIC MARKERS in NGT (n = 42) and IGT (n = 28) Postmenopausal Women † † † a a a * * * a P =0.06, * P<0.01, † P<0.005 IGT women were older, had a higher BMI, and a lower M than NGT. a P =0.06, * P<0.01, † P<0.005 IGT women were older, had a higher BMI, and a lower M than NGT. a P =0.06, * P<0.01, † P<0.005 IGT women were older, had a higher BMI, and a lower M than NGT. Reduced Skeletal Muscle Capillarization is Associated with Glucose Intolerance Prior et al. Microcirculation, 2009

29. Insulin Sensitivity is Reduced In Women with Impaired Glucose Tolerance * Glucose Uptake (mol/kgFFM/min) *P<0.01 n = 64 n = 34

33. M e t a b o l i c I n f l e x i b i l i t y i n O b e s e S u b j e c t s 1 l e a n o b e s e 0 . 9 0 . 8 0 . 7 F a s t i n g I n s u l i n - S t i m u l a t e d Kelly & Mandarino, Diabetes 2000 Metabolic Inflexibility • Ability to switch from fat utilization during fasting to carbohydrate utilization during hyperinsulinemia (Kelley et al. 2000) • Clamp RQ – Fasting RQ

34. Metabolic Flexibility is Associated with Insulin Sensitivity in Postmenopausal Women n = 92, r=0.46, P<0.0001

36. Exercise + Weight Loss Increases Muscle LPL Skeletal Muscle Lipoprotein Lipase P<0.01 =-3%, P=NS =49%, P<0.05 Pre Post WL AEX+WL

37. Exercise + Weight Loss Increases Skeletal Muscle ACS Muscle Acyl-CoA Synthase P<0.05 =-6%, P=NS =45%, P<0.05 Pre Post Pre Post

38. Exercise + Weight Loss Increases Skeletal Muscle CS Muscle Citrate Synthase P<0.08 =-1%, p=NS =32%, P=0.05 Pre Post Pre Post

39. Exercise + Weight Loss Decreases Adipose Tissue LPL Gluteal Lipoprotein Lipase Abdominal Lipoprotein Lipase =-18%, P=0.01 =-26%, P<0.001 =-14%, P=NS =-28%, P<0.001 Pre Post Pre Post Pre Post Pre Post

40. Exercise + Weight Loss Shifts Lipid Partitioning from Storage to Oxidation Ratio of Gluteal to SM-LPL Ratio of Abdominal to SM-LPL P<0.05 P<0.09 =54%, p=NS =-32%, P=0.005 =-24%, p<0.05 Pre Post Pre Post Pre Post Pre Post

42. Insulin Suppresses ACS after Exercise TrainingChange in insulin’s effect on ACS after AEX+WL in postmenopausal women (n = 17, *P<0.05). *

43. Insulin Suppresses -HAD after Exercise TrainingChange in insulin’s effect on -HAD after AEX+WL in postmenopausal women (n = 17, *P<0.05). *

45. “Bench to Bedside” How is this Translated to an Exercise Prescription?

46. Summary of the ACSM/AHA Updated Physical Activity Guidelines for Healthy Adults Under Age 65 • Do moderate-intensity cardiovascular activity for 30 minutes a day, 5 days a week or • Do vigorous cardiovascular activity 20 minutes a day, 3 days a week and • Do 8 – 10 resistance-training exercises, performing 8 – 12 repetitions for each exercise, twice a week • Moderate-intensity physical activity means working hard enough to raise your heart rate and break a sweat, yet still being able to carry on a conversation. It should be noted that to lose weight or maintain weight loss, 60 to 90 minutes of physical activity may be necessary. The 30-minute recommendation is for the average healthy adult to maintain health and reduce the risk for chronic disease. • Med Sci Sports Exercise: 39(8); 1423-1434, 2007

47. Benefits of Aerobic Exercise Improved cardio-respiratory fitness Weight Control Improved Endurance Stress Relief Improved energy Decreased fatigue Improved immune system Improved quality of sleep Psychological benefits

48. Physical Activity Pyramid Inactivity in moderation Flexibility Strength Training Cardiovascular Exercise Leisure Time Activity

49. AcknowledgementsMany Thanks! Investigators: • Andrew Goldberg, M.D. • Heidi Ortmeyer, Ph.D. • Jacob Blumenthal, M.D. • Lyndon Joseph, Ph.D. • Susan Fried, Ph.D. • John McLenithan, Ph.D. • Steve Prior, Ph.D. Exercise Physiologists: • Lynda Robey, M.S. • Gretchen Zietowski, M.S., R.N. • Greig Frietag, M.S. • Nicole Fendrick, M.S.. • Melinda Erbe, M.S. Research Assistants: • Melissa Gray • Keisha Galloway, M.S. • Agnes Kohler, M.S. • Carole St. Clair • Sara Herts • Jonelle George • Linsday Koepper • Urmila Sreenivasan • Tara McDonald • Lisa McFarland • Sumi Khan • Nikki Glynn Clinical Staff: • Joyce Evans, R.N. • Sarah Witten, R.N. • Kathie Brandt, R.N. • Ivey Dorsey, R.N. • Anita Neal, L.P.N. • Cheryl Beasley, L.P.N. • Luz Ortiz-Corral, R.N. • Lynn Stars-Zorn, N.P. • Linda Hatler, N.P. • Peter Normandt, N.P. Dieticians: • Kelly Ort, R.D. • Kathy Simpson, R.D. • Andriane Kozlovsky, R.D • Amy Matson, R.D. • Tara Caulder, R.D. Funding: • VA • NIH