1. Energy Metabolism Laboratory H H OH CH 2 OH H OH H The Epidemic of Type-2 Diabetes: Obesity or Physical Inactivity? Barry Braun, Ph.D. Director, Energy Metabolism Laboratory Dept. of Exercise Science University of Massachusetts, Amherst

2. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Obesity is a big problem (and growing) Obesity greatly increases risk for Type-2 diabetes and heart disease, etc. Weight loss helps lower risk Weight loss is key: “war on obesity” we disagree with the basic premise that obesity CAUSES cardiometabolic disease THE POPULAR MODEL

3. Energy Metabolism Laboratory H H OH CH 2 OH H OH H In our model, obesity AND disease are both symptoms of excess energy intake (diet) or low output (physical inactivity) physical inactivity and/or excess energy intake obesity cardiometabolic disease (diabetes, heart disease, etc.) ?

4. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Optimizing design of an exercise drug to enhance metabolic health Regular exercise improves cardiometabolic health and reduces risk for chronic disease. There are few long-term adaptations to exercise that persist in the absence of a continued exercise stimulus (use it or lose it). The “trained” state is maintained only with regular applications of individual exercise bouts. In this context, each individual exercise bout is appropriately viewed as a drug.

5. Energy Metabolism Laboratory H H OH CH 2 OH H OH H When taken at a sufficient dose, a bout of exercise has effects on metabolic function that peak at a specific timepoint and then diminish over time until they are no longer apparent, requiring a subsequent dose to maintain the effects. Viewed in this context, the physiological impact of each individual exercise dose becomes critical: tailoring the dose to achieve the maximal possible benefit is likely to result in the biggest long-term reward in terms of optimizing cardiometabolic health. Exercise as a drug

6. Energy Metabolism Laboratory H H OH CH 2 OH H OH H OVERALL MISSION of the LAB To optimize the use of exercise to minimize insulin resistance and prevent/manage Type-2 diabetes. Specifically, we hope to: 1.understand the mechanism 2.work out the dose-response relationship 3.focus on interactions with other agents * dietary energy intake * pharmacologic agents * meal timing and composition

7. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Completed Studies; 1. mechanism During exercise, obese women with insulin resistance (pre-diabetes; more than 25 million in the U.S.) were able to take up glucose (sugar) from the blood at the same rate as individuals who were insulin sensitive. Implication: The metabolic defect that causes insulin resistance does not impair the ability to clear sugar from the blood during exercise

8. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Completed Studies; 2. energy intake Men and women with pre-diabetes had a dramatic improvement in blood sugar control after only 6 days of exercise training, but only if the energy expended during exercise was not added back to their diet. Implication: Starting an exercise program can generate big improvements very quickly, well before any substantial weight loss. Exercise “effect” may be related to energy balance.

9. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Completed Studies; 3. energy intake Only 3 days of inactivity coupled with energy surplus (overeating) caused lean, fit people to become more insulin-resistant. A single session of exercise reversed the effect, even though the individuals were still overeating. Implication: Beneficial effects of exercise are apparent even when people overeat (so, do take that walk after Thanksgiving dinner!)

10. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Completed Studies; 4. obesity Health risks (e.g. diabetes) were shown to be unaffected by obesity in people who are physically fit. Is it because they are insulin sensitive despite excess body fat? We found that overweight endurance athletes (>30% body fat) were much more insulin-sensitive than sedentary women with the same % body fat and nearly as insulin- sensitive as lean athletes (<18% body fat). Implication: Cardiorespiratory fitness, not body fat, may primarily determine “metabolic health”. Supports the notion that people can be “healthy at any weight”

11. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Other studies in progress The most widely prescribed anti-diabetes drug in the U.S. and Europe is called metformin Metformin or exercise increase sensitivity to insulin and reduce risk for Type-2 diabetes a. Are effects of exercise and metformin additive? b. Does metformin + a little exercise confer the same benefit as a lot of exercise alone? c. Are the effects due to similar cell mechanisms? These question are the focus of a 3-year Junior Faculty Award (Braun) from the American Diabetes Association.

12. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Other studies in progress We are currently studying how timing (immediately post-exercise or delayed for 2-3 hours) and composition (quantity and type of carbohydrate) of post-exercise meals modulates the impact of each exercise “dose” on insulin sensitivity and, ultimately, cardiometabolic health. These results, along with the published data described earlier, will be used as preliminary data for a grant proposal to the National Institutes of Health to be submitted 10-1-05. Metabolic Health

13. Energy Metabolism Laboratory H H OH CH 2 OH H OH H Energy Metabolism Laboratory Steve Black, Ph.D.* Stuart Chipkin M.D. Rebecca HassonLaura Gerson Carrie Sharoff. M.S.Kaila Holtz Liz Mitchell* Todd Hagobian, M.S Francesca Beaudoin M.S.*Allison Gruber Brooke Stephens, M.S. * = graduated Funding from: Glass Charitable Trust American Diabetes Association Baystate/UMASS Biomedical Research Group H H OH CH 2 OH H OH H