As part of the mini-symposium entitled  Divergent Impacts of Physical Activity and Sedentary Behavior on Glucose Intolerance and Vascular Function: From Laboratory to Clinic,  this presentation shares data on the role of increased physical activity and sedentary behavior in mediating Type 2 diabetes

Braun, Barry

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University of Massachusetts Medical School eScholarship@UMMS UMass Center for Clinical and Translational Science Research Retreat 2014 UMass Center for Clinical and Translational Science Research Retreat May 20th, 2:30 PM Optimizing the Exercise Drug to Oppose Glucose Intolerance/T2D Barry Braun University of Massachusetts Amherst Let us know how access to this document benefits you. Follow this and additional works at: https://escholarship.umassmed.edu/cts_retreat  Part of the Biochemical Phenomena, Metabolism, and Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Exercise Science Commons, Nutritional and Metabolic Diseases Commons, and the Translational Medical Research Commons Braun B. (2014). Optimizing the Exercise Drug to Oppose Glucose Intolerance/T2D. UMass Center for Clinical and Translational Science Research Retreat. Retrieved from https://escholarship.umassmed.edu/cts_retreat/2014/presentations/3 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in UMass Center for Clinical and Translational Science Research Retreat by an authorized administrator of eScholarship@UMMS. For more information, please contact Lisa.Palmer@umassmed.edu. 1 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Optimizing the Exercise Drug to Oppose Glucose Intolerance/T2D   Barry Braun, PhD Dept. of Kinesiology University of Massachusetts Amherst 2 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Lab mission:  Metabolic rehabilitation  Understand how physical activity, diet and  pharmacology can be optimally integrated to  reverse insulin resistance and prevent T2D  H H OH OH CH2OH H OH OH H 3 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H 4 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H  79 million with prediabetes=   everyone in U.S. that is left-handed (30) +  everyone who is Jewish (6) +  all households in U.S. that own dogs (43).  Insulin resistance is an underlying theme for  Type-2 diabetes (as well as CVD)  5 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Insulin Resistance LIVER MUSCLE GLUCOSE FFA X    x FAT CNS islet cells 6 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Diabetes Prevention Program, NEJM, 2001 >150’ exercise/wk. goal to lose 7% BW.  7 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Weight loss beneficial impact on metabolic health Lifestyle change Metformin 8 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Mean weight loss: 3.3 kg   Activity maintained at about 150’/wk 9 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Weight loss beneficial impact on metabolic health Lifestyle change Metformin habitual activity 10 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H King et al., JAP, 1995 Single dose 11 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Weight  loss beneficial impact on metabolic health Lifestyle change Metformin exercise  training acute exercise HHOHOHCH2OHHOHOH H12 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H At sufficient dose, exercise improves metabolic  function for a period of time but the effect wanes, requiring subsequent doses.   Tailoring dose to achieve maximal effect is  likely to result in biggest long-term reward    Exercise as drug 13 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H What do we need to know? Dose:   Threshold (≈ 150 min/week)  Frequency (3+ d/wk)  Intensity/Duration (HIIT, sedentary time?)  Interactions with diet  Interactions with other medications 14 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H No-Exercise  LO = 3 bouts at 50% VO2max,= 750 kcal  HI = 3 bouts at 75%  VO2max,= 750 kcal  Braun et al. J Appl. Physiol. 1995  15 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H 16 men and women Energy Deficit “DEF” Energy Balance “BAL” 6 DAYS OF   EXERCISE Weight Maintenance Period Interactions with diet: Energy balance? 16 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H 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,  EE derived from RMR, accelerometers, food, activity records 17 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H 90 min  [6,6 2H] glucose   60 min (20% glucose + 2% [6,6 2H] glucose)  Change infusate 140 145 150 75  90 Fasted state 0 Steady-state  Whole-body and hepatic insulin action (CIG-SIT)  Outcomes: whole-body glucose uptake and                      suppression of liver glucose output 18 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Glucose Muscle Black et al. J Appl Physiol, 2005        DEF                        BAL 19 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Energy balance the only difference?  CHO content of diets in 2 groups different.   DEF = 330 g CHO/day; BAL = 410g/day.  Meal (60% CHO) immediately post-exercise    20 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Weight  loss beneficial impact on metabolic health Lifestyle change Pharmacology exercise  training acute exercise HHOHOHCH2OHHOHOH Henergy  balance meal  CHO timing 21 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Diabetes Prevention Program, NEJM, 2001 Lifestyle + metformin = even better? 22 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Exercise and metformin Purpose: Combined effect of metformin  and acute exercise on insulin sensitivity and AMPK α2  Hypothesis: 1 + 1 = 2  23 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Overnight Fast 40 min rest or exercise BIOPSY 90 min. stable isotope [6,6-2H] glucose  infusion euglycemic hyperinsulinemic clamp Metformin group:  pre-Met, Met + rest, post Met + Ex Placebo group:  rest, exercise         Blood sampling Percutaneous biopsy of vastus lateralis  Goodyear lab for analyses  of  AMPK activity, glycogen, and western blots. 24 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Sharoff et al., Am J Phys, 2010 25 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Sharoff et al., Am J Phys, 2010 26 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Does metformin blunt beneficial  effects of training?  32 men and women with prediabetes    12 wks training with or w/o metformin,  metformin only and control  Insulin sensitivity using clamp and tracers    27 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Insulin sensitivity enhanced more with exercise  alone than when combined with metformin 0.02.04.06.08.010.012.014.0P M EP EMNOGD (mg/kg-FFM/min)PrePost  *^Malin et al. Diabetes Care, 2011 28 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Non glycemic outcomes SBP:  C= +6.5%, M= -7.3%, EP= -6.3%, EM= 0.0%  hs-CRP: C= +6.4%, M= -20.1%, EP= -27.4%, EM=-8.4%  TAG: C= +3.1% M= -13.8%, EP= -13.5%, EM= -12.0% Malin et al. Obesity, 2012 29 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Why?  Wt?  Only M and E+M lost weight Fat?  M = nc, E+M and E+P= -2% Central fat? M= nc, E+M and E+P= -1.5%  CRF? M = nc,  E+M ≈ +10%, E+P ≈ +20%  ∆VO2peak and ∆insulin sensitivity: r= .70   30 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Weight  loss beneficial impact on metabolic health Lifestyle change metformin exercise  training acute exercise HHOHOHCH2OHHOHOH Henergy  balance meal  CHO timing 31 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Role of “sedentary behavior” in mediating efficacy of the exercise drug??    32 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H 14 normally active men and women 3 conditions, balanced order  Active, energy bal (no sit 15 hr.)  Inactive (sit 15 hr, no diet change )  Inactive, (sit 15 hr, cut kcals )  33 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H 34 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H -39% -18% Stephens et al. Metabolism 2010 35 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Kozey Keadle et al. Sedentary subjects Control, 12 wks training (EX), reduced  sedentary time (rST) OR both (EX+rST).  EX+rST accentuated impact of EX alone C-ISI up by 24% vs. 17.5% (but TG same)  Little impact of rST alone 36 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Weight  loss beneficial impact on metabolic health Lifestyle change metformin exercise  training acute exercise HHOHOHCH2OHHOHOH Henergy  balance meal  CHO timing 37 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H Conclusions At sufficient dose, exercise/physical activity potent countermeasure  Less sedentary behavior useful but not sufficient  Interxns between exercise and nutritional context  Interactions with other meds NOT predictable 38 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H HHOHOHCH2OHHOHOH Hbeneficial impact on metabolic health 39 Energy Metabolism Laboratory H H OH OH CH2OH H OH OH H NIH  5 R56 DK081038  American Diabetes Assoc. 7-04-JF-10               Glass Charitable Trust Baystate/UMass CBRP ACSM Student grants Tara D’Eon, PhD Steve Black PhD Carrie Sharoff PhD Brooke Stephens PhD Kaila Holtz MS Todd Hagobian PhD Rebecca Hasson PhD Steve Malin, PhD Rob Gerber MS Kirsten Thomson MS Cameron Carter, MS Rich Viskochil MS Jen Blankenship, MS Hannah Masse, BS Patty Freedson, PhD Stuart Chipkin MD Laurie Goodyear PhD John Staudenmayer PhD Sarah Kozey Keadle, PhD Kate Lyden, PhD 

Optimizing the Exercise Drug to Oppose Glucose Intolerance/T2D

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Optimizing the Exercise Drug to Oppose Glucose Intolerance/T2D

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