Interactions of exercise and diet in health prevention

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1 Interactions of exercise and diet in health prevention Dr Jason Gill Institute of Cardiovascular and Medical Sciences University of Glasgow

2 Physical activity and health outcomes does one size fit all? Physical activity and postprandial lipoprotein metabolism Physical activity, dietary intake and energy balance

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4 Global burden of physical inactivity Wen and Wu (2012) The Lancet

5 A brief history of physical activity guidelines (for adults) minutes of moderate or 75 minutes of vigorous physical activity per week in bouts of at least 10 minutes Muscle strengthening activities 2 x per week Minimise the amount of time spent sedentary (sitting)

6 Physical activity and health outcomes: does one size fit all?

7 How much physical activity do people need to do? Risk of vascular or metabolic disease High-risk populations Low-risk populations Low absolute disease risk Low Physical activity level High Modified from Gill and Cooper (2008) Sports Med, 38:

8 Moderate exercise and insulin responses in lean and obese men Plasma insulin (µu.ml -1 ) Lean subjects Control Exercise Time (h) Plasma insulin (µu.ml -1 ) Centrally obese subjects 3% 11% Time (h) Gill et al (2004) J Am Coll Cardiol, 44:

9 Vigorous exercise, BMI and diabetes incidence in the Physicians Health Study Incidence of type 2 diabetes (per person-years) Vigorous exercise < once per week Vigorous exercise once per week 1 (Low) (High) BMI Quartile Manson et al (2002) JAMA, 268:63-67

10 Change in insulin sensitivity following a 7- week exercise intervention in women with and without a family history of diabetes 2 Insulin Sensitivity Index Control Offspring Insulin Sensitivity Index Delta aa b 4 Pre-intervention Post-intervention Barwell et al (2008) Diabetologia 51:1912-9

11 Grip-strength, physical activity and risk of mortality in UK Biobank (n = 495,786) Celis-Morales et al (2016) European Heart Journal

12 Fitness, physical activity and risk of mortality in UK Biobank (n = 76,702) Celis-Morales et al (2016) European Heart Journal

13 Five-sixths of the World s population is not of White European origin.

14 Ethnicity and diabetes risk

15 Ethnicity, BMI and diabetes prevalence in UK Biobank Ntuk et al (2014) Diabetes Care 37:2500-7

16 Ethnicity, BMI and diabetes prevalence in UK Biobank Ntuk et al (2014) Diabetes Care 37:2500-7

17 Diabetes risk progression Glycaemia Diabetes IGT ~10% per year Normoglycaemia Age Sattar and Gill (2015) Lancet Diabetes Endocrinol

18 Diabetes risk progression Diabetes Glycaemia IGT Normoglycaemia Lifestyle intervention Age Sattar and Gill (2015) Lancet Diabetes Endocrinol

19 Long-term follow-up in US Diabetes Prevention Program Knowler et al. NEJM 2002; 346: Knowler et al. Lancet 2009; 374:

20 Diabetes risk progression Lifestyle reduces absolute diabetes incidence by ~5-7 cases per 100 in patients with IGT Diabetes Glycaemia IGT Normoglycaemia <5% per year Lifestyle intervention Age Sattar and Gill (2015) Lancet Diabetes Endocrinol

21 Diabetes risk progression Diabetes South Asian Glycaemia IGT European Normoglycaemia Age Sattar and Gill (2015) Lancet Diabetes Endocrinol

22 Diabetes risk progression Diabetes South Asian 10 years Glycaemia IGT European Normoglycaemia Age Sattar and Gill (2015) Lancet Diabetes Endocrinol

23 Diabetes risk progression Diabetes South Asian Glycaemia IGT European ~18% per year Normoglycaemia Age Sattar and Gill (2015) Lancet Diabetes Endocrinol

24 Diabetes risk progression Diabetes South Asian Glycaemia IGT European Normoglycaemia Lifestyle intervention Age Sattar and Gill (2015) Lancet Diabetes Endocrinol

25 The Indian Diabetes Prevention Programme Control Metformin Lifestyle Lifestyle + Metformin Ramachandran et al (2006) Diabetologia, 49:

26 Diabetes risk progression Lifestyle reduces absolute diabetes incidence by ~5 cases per 100 in patients with IGT Diabetes South Asian Glycaemia IGT European Normoglycaemia ~13% per year Lifestyle intervention Age Sattar and Gill (2015) Lancet Diabetes Endocrinol

27 Diabetes risk progression BUT absolute progression rate still much higher. Should we target South Asians for earlier intervention? Diabetes South Asian Glycaemia IGT European ~13% per year Normoglycaemia Age Lifestyle intervention? Sattar and Gill (2015) Lancet Diabetes Endocrinol

28 Hypothesised mechanisms for South Asians increased diabetes risk Genetic factors? Lower brown adipose tissue activity / volume? Higher percentage fat mass Lower capacity for subcutaneous fat storage Greater proportion of deep subcutaneous / visceral fat Greater ectopic fat (e.g. liver) Fetal programming? Epigenetic factors Lifestyle factors (urbanisation, diet, physical activity) Lower percentage lean mass Lower cardiorespiratory fitness Lower capacity for muscle fat oxidation Increased insulin resistance Lifelong compensatory hyperinsulinaemia Lower beta cell capacity? Sattar and Gill (2015) Lancet Diabetes Endocrinol Earlier beta cell insufficiency/failure Increased type 2 diabetes

29 Hypothesised mechanisms for South Asians increased diabetes risk Genetic factors? Lower brown adipose tissue activity / volume? Higher percentage fat mass Lower capacity for subcutaneous fat storage Greater proportion of deep subcutaneous / visceral fat Greater ectopic fat (e.g. liver) Fetal programming? Epigenetic factors Lifestyle factors (urbanisation, diet, physical activity) Lower percentage lean mass Lower cardiorespiratory fitness Lower capacity for muscle fat oxidation Increased insulin resistance Lifelong compensatory hyperinsulinaemia Lower beta cell capacity? Sattar and Gill (2015) Lancet Diabetes Endocrinol Earlier beta cell insufficiency/failure Increased type 2 diabetes

30 Adiposity, fitness and insulin resistance in South Asian and European men South Asians (n = 20) Europeans (n = 19) P (unadjusted) P (adjusted for age, BMI and fat mass) Age (years) 26.9 ± ± BMI (kg.m -2 ) 23.6 ± ± Total fat mass (kg) 18.4 ± ± < VO 2 max (ml.kg -1.min -1 ) 40.6 ± ± 5.7 < VO 2 max (ml.kg -1 fat-free mass.min -1 ) 54.1 ± ± 5.8 < Fasting glucose (mmol.l -1 ) 5.14 ± ± Fasting insulin (mu.l -1 ) 6.56 ± ± hour insulin (mu.l -1 ) 46.6 ± ± Insulin sensitivity index 5.89 ± ± Hall et al (2010) PLoS ONE: 5(12): e14197

31 Fitness, BMI and risk of type 2 diabetes: The Aerobics Center Longitudinal Study Low fitness Moderate fitness High fitness Wei et al (1999) Ann Intern Med, 130:89-96

32 Artificial selection for fitness and insulin sensitivity Breeding rats for low fitness makes them insulin resistant Wisloff et al (2005) Science 307:

33 Does lower fitness in South Asians simply reflect lower physical activity levels?

34 Self-reported vs objective physical activity measurement Celis-Morales et al (2012) PLoS ONE 7:e36345

35 Can lower fitness explain increased insulin resistance in South Asians?

36 Relationship between fitness and HOMA in European and South Asian men VO 2max log HOMA IR log HOMA IR log HOMA IR adjusted for VO 2max VO 2max (ml.kg -1.min -1 ) Ghouri et al (2013) Diabetologia, 56:

37 Relationship between fitness and physical activity in European and South Asian men MVPA 65 VO 2max (ml.kg -1.min -1 ) VO 2max VO 2max adjusted for MVPA MVPA (min/day) Ghouri et al (2013) Diabetologia, 56:

38 Impaired skeletal muscle oxidative capacity as a mechanism for greater insulin resistance in South Asians? Fatty acid uptake IR TG TG MISMATCH LCACoA DAG Ceramide PKC IRS - 1 PI3K INSULIN RESISTANCE Fatty acid oxidation PKB GLUT4

39 Fat oxidation during submaximal exercise in South Asian and European men South Asian man European man

40 Fat oxidation during submaximal exercise in South Asian and European men South Asian man European man Fat oxidation (mg.kg -1.min -1 ) P for ethnicity = (0.014 fully adjusted) European South Asian Percentage VO 2 max Hall et al (2010) PLoS ONE: 5(12): e14197

41 Substrate utilisation during exercise and insulin sensitivity in South Asian and European men Fat 55% VO2max (mg.kg -1.min -1 ) r = p = South Asian European Square-root insulin sensitivity index Fat 55% VO2max (mg.kg -1.min -1 ) r = p = Log PKB serine 473 phosphoryation Hall et al (2010) PLoS ONE: 5(12): e14197

42 Do we need ethnicityspecific public health guidelines to reflect innate ethnic differences in disease risk?

43 A brief history of physical activity guidelines (for adults) minutes of moderate or 75 minutes of vigorous physical activity per week in bouts of at least 10 minutes Muscle strengthening activities 2 x per week Minimise the amount of time spent sedentary (sitting)

44 Ethnicity and physical activity Cardio-metabolic disease risk 150 minutes per week ~ minutes per week South Asians European Low absolute disease risk Low Physical activity level High Modified from Celis-Morales et al (2013) PLOS ONE 8(12):e82568 & Iliodromiti et al (2016) PLOS ONE 11(8): e

45 JBS3 (2014) Heart 100:ii1-ii67.

46 Physical activity and postprandial lipoprotein metabolism

47 Mechanisms behind protective effect of physical activity Gill and Malkova (2006) Clin Sci, 110:

48 HDL cholesterol in runners HDL cholesterol concentration (mmol/l) N = 8283 men >80 Distance run per week (km) Williams (1997), Arch Intern Med, 157:

49 Neutral Lipid Exchange Triglyceride-rich lipoproteins Cholesterol-rich lipoproteins TG CETP Hepatic lipase Low HDL CM Cholesterol TG Small dense LDL Atherogenic Lipoprotein Phenotype

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51 Role of postprandial lipid metabolism in the progression of atherosclerosis Postprandial lipoproteins and their remnants may directly deposit into the arterial wall High postprandial triglyceride concentrations contribute to the atherogenic lipoprotein phenotype Endothelial function is impaired following ingestion of a high fat meal Pro-thrombotic and pro-inflammatory changes are evident postprandially

52 Triglyceride metabolism in the fasted state LIVER VLDL ADIPOSE TISSUE Fatty Acids LPL LPL Fatty Acids SKELETAL MUSCLE remnants

53 Triglyceride metabolism in the postprandial state LIVER SMALL INTESTINE VLDL Chylomicrons ADIPOSE TISSUE Fatty Acids LPL LPL Fatty Acids SKELETAL MUSCLE remnants

54 Postprandial lipaemia in trained and untrained men Merrill et al (1989), Arteriosclerosis, 9:

55 Postprandial lipaemia in trained and untrained men Merrill et al (1989), Arteriosclerosis, 9:

56 Long-term training adaptation or acute effect of recent exercise? exercise lipids

57 Detraining and postprandial lipaemia Hardman et al (1998), JAP, 84:

58 Experimental protocol Day 1 Day 2 Exercise or Rest Oral fat tolerance test Time (hours)

59 Moderate exercise and postprandial TG concentrations in lean and obese men Gill et al (2004) J Am Coll Cardiol, 44:

60 Energy deficit? exercise lipids

61 Exercise, energy intake restriction and postprandial metabolism 2.6 Control Exercise 40 Plasma TG (mmol.l -1 ) Serum insulin (mu.l -1 ) % 15% Time (h) Time (h) Gill et al (2000), Am J Clin Nutr, 71:

62 Exercise, energy intake restriction and postprandial metabolism 2.6 Control Energy intake restriction Exercise 40 Plasma TG (mmol.l -1 ) Serum insulin (mu.l -1 ) 30 7% 20 1% 20% 15% Time (h) Time (h) Gill et al (2000), Am J Clin Nutr, 71:

63 Exercise with and without energy deficit and postprandial metabolism Control Exercise with energy deficit Test meal Plasma TG (mmol.l -1 ) Time (min) 14% Plasma insulin (mu.l -1 ) Time (min) 18% Burton et al (2008) Int J Obes, 32:

64 Exercise with and without energy deficit and postprandial metabolism Plasma TG (mmol.l -1 ) Control Exercise with energy replacement Exercise with energy deficit Time (min) 6% 14% Plasma insulin (mu.l -1 ) Test meal Time (min) 10% 18% Burton et al (2008) Int J Obes, 32:

65 Mechanisms? exercise lipids

66 Triglyceride-rich lipoprotein metabolism LIVER HL VLDL 1 VLDL 2

67 Triglyceride-rich lipoprotein metabolism LIVER HL VLDL 1 VLDL 2 LPL Remnants

68 Triglyceride-rich lipoprotein metabolism HL LIVER CM VLDL 1 VLDL 2 LPL Remnants

69 Moderate exercise and postprandial TG-rich lipoprotein concentrations Chylomicrons Large VLDL (VLDL 1 ) Small VLDL (VLDL 2 ) Chylomicron concentration (mg.dl -1 ) ## ** ## ** ** ** # Control ** Exercise ** Time (h) # ** ** VLDL 1 concentration (mg.dl -1 ) Time (h) VLDL 2 concentration (mg.dl -1 ) Time (h) Gill et al (2006) Atherosclerosis, 185:87-96

70 Effects of exercise on triglyceride-rich lipoprotein metabolism HL LIVER CM VLDL 1 VLDL 2

71 Concentration of VLDL 1

72 Production of VLDL 1 Concentration of VLDL 1

73 Production of VLDL 1 Concentration of VLDL 1 Clearance of VLDL 1

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75 VLDL 1 Metabolism in the Fasted State LIVER VLDL 1 ADIPOSE TISSUE Fatty Acids LP L LP L Fatty Acids SKELETAL MUSCLE remnants

76 Effect of Chylomicrons (CM) & CM-like Particles on VLDL 1 Clearance LIVER Chylomicrons or Intralipid VLDL 1 X ADIPOSE TISSUE Fatty Acids LP L LP L Fatty Acids SKELETAL MUSCLE remnants

77 The Intralipid Method Happy subject Bolus Intralipid dose: 0.1 g.kg -1 body mass 0.1 g.kg -1.h -1 Intralipid infusion for 75 mins Two fasting baseline and multiple EDTA blood samples are drawn before, during and post-infusion Intralipid, VLDL 1 and VLDL 2 fractions are separated by density gradient ultracentrifugation. Al-Shayji et al (2007) J Lipid Res, 48:

78 Kinetic Data Obtained from the Intralipid Method 7000 TG Pool (mg) Plasma Intralipid VLDL 1 VLDL 2 VLDL 1 -TG Pool (mg) y = 35.79x R 2 = VLDL 1 -TG Production Rate Intralipid-TG (mmol.l -1 ) y = e x R 2 = Intralipid-TG Clearance Rate Time (mins) Infusion Time (mins) Post-infusion Time (mins) 70 ApoB Pool (mg) Time (mins) VLDL 1 -ApoB Pool (mg) VLDL ApoB Production Rate y = 0.848x R 2 = Infusion Time (mins) ApoB Al-Shayji et al (2007) J Lipid Res, 48:

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80 Effects of moderate exercise on TRL kinetics Control Exercise Change (%) Fasting plasma TG (mmol/l) 1.54 ± ± 0.15* -21% Fasting VLDL 1 concentration (mg/dl) 94.9 ± ± 11.4* -34% VLDL 1 -TG production rate (mg/h) 1272 ± ± % VLDL 1 -apob production rate (mg/h) 37.2 ± ± % Intralipid-TG FCR (pools/d) 47.6 ± ± 9.7* +43% VLDL 1 -TG FCR (pools/d) 16.0 ± ± 4.4* +82% VLDL 1 -apob FCR (pools/d) 10.4 ± ± 5.1* +146% *p < 0.05 for Control vs Exercise Al-Shayji et al (2012) Am J Physiol 302:E349-E355

81 Effects of moderate exercise on TRL kinetics VLDL1-TG FCR (pools.day -1 ) Control Exercise Intralipid-TG FCR (pools.day -1 ) Exercise y = 0.37x r = 0.82, p = Control y = 0.28x r = 0.91, p < Exercise increases relative affinity for VLDL 1 clearance compared to chylomicronlike particle clearance Al-Shayji et al (2012) Am J Physiol 302:E349-E355

82 Ghafouri et al (2015) J Clin Endocrinol Metab 100:

83 Effects of moderate exercise on affinity of TRL for LPL Fasting VLDL 1 Postprandial VLDL 1 Ghafouri et al (2015) J Clin Endocrinol Metab 100:

84 Effects of moderate exercise on affinity of TRL for LPL Ghafouri et al (2015) J Clin Endocrinol Metab 100:

85 Physical activity, dietary intake and energy balance

86 Weight loss outcomes in clinical trials: Systematic review and meta-analysis 80 studies, n = 26,455 (18,199 completers) Franz et al (2007) J Am Diet Assoc.107:

87 Effects of exercise training, without weight loss, on body fat 60 min moderate exercise, 5 x per week for 13 weeks Lee et al (2005) J Appl Physiol 99:

88 The substrate balance equation Fat intake CHO intake Protein intake Fat expenditure CHO expenditure Protein expenditure Fat balance CHO balance Protein balance

89 Fat oxidation and weight gain in Pima Indians Zurlo et al (1990) Am J Physiol, 259:E650-E657

90 Substrate metabolism and feeding behaviour under high and low energy turnover conditions Burton et al (2010) Br J Nutr 104:

91 Substrate metabolism and feeding behaviour under high and low energy turnover conditions Burton et al (2010) Br J Nutr 104:

92 Substrate metabolism and feeding behaviour under high and low energy turnover conditions Burton et al (2010) Br J Nutr 104:

93 Substrate metabolism and feeding behaviour under high and low energy turnover conditions Burton et al (2010) Br J Nutr 104:

94 Effects of exercise before or after breakfast on energy and fat balance Farah et al (2013) Br J Nutr 109:

95 Effects of exercise before or after breakfast on energy and fat balance Farah et al (2013) Br J Nutr 109:

96 Effects of exercise before or after breakfast on energy and fat balance Farah et al (2013) Br J Nutr 109:

97 Longer-term effects of exercise on body fat

98 Individual variability in weight loss response to exercise Barwell et al (2009) Metabolism 58:

99 Factors influencing individual variability of in weight loss response to exercise Differences in dietary compensation King et al (2008) Int J Obes 32: Differences in physical activity compensation Manthou et al (2010) Med Sci Sports Exerc 42:

100 Individual variability in weight loss response to exercise Barwell et al (2009) Metabolism 58:

101 Individual variability in weight loss response to exercise Barwell et al (2009) Metabolism 58:

102 Acknowledgements Funders Diabetes UK Translational Medicine Research Initiative Chest Heart and Stroke Scotland European Commission MRC Research Team Prof Naveed Sattar Prof Jill Pell Dr Carlos Celis Dr Nazim Ghouri Dr Lesley Hall Dr Colin Moran Ms Uduak Ntuk Dr Dilys Freeman Dr Ian Salt Dr Niall MacFarlane Dr Danny MacKay Dr Alex McConnachie Mr David Purves Mr John Wilson