Lecture 9.2 - Control of Metabolism - Exercise and Pregnancy PDF

Exercise: ◦Humans are well adapted to exercise ◦Many physiological and biochemical processes specifically configured ◦What is needed: ‣ Ability to rapidly alter metabolic processes ‣ Consider different 'fuel mixes' to optimise O2 availability and how rapidly ener...

Exercise: ◦Humans are well adapted to exercise ◦Many physiological and biochemical processes specifically configured ◦What is needed: ‣ Ability to rapidly alter metabolic processes ‣ Consider different 'fuel mixes' to optimise O2 availability and how rapidly energy transformation is needed to generate the required amount of power Need to...: ◦Meet the acute oxygen (heart rate and respiratory rate) and metabolic fuel needs of muscles ◦Dispose of carbon dioxide and other waste products of metabolism (e.g. lactate and protons) ◦Minimise disturbances to other physiological systems Whole system response: ◦Exercise involves changes in: ‣ Musculo-skeletal system ‣ Cardiovascular system ‣ Respiratory system ‣ Temperature system ‣ Urinary system ‣ Metabolism Metabolic response to exercise: ◦Need to mobilise stored fuels ‣ At a rate to match increased activity ◦Need to preserve blood glucose levels to protect the brain ◦Magnitude and nature of response depends on: ‣ Type of exercise (muscles used) ‣ Intensity and duration of exercise ‣ Physical condition and nutritional state of individual Energy requirements of exercise: ◦Resting metabolic rate ~4 kJ/min-1 ◦100m sprint ‣ 200 kJ/min-1 ‣ 30kJ total ◦1500m race ‣ 140 kJ/min-1 ‣ 500kJ total ◦Marathon 42km ‣ 800 kJ/min-1 ‣ 10,000 kJ total Where does the energy come from?:  ◦ATP required for muscle contraction ‣ Very short term stores ATP and creatine phosphate Lasts about 5 seconds ‣ ATP must rapidly be recreated by: Oxidative phosphorylation (aerobic) Anaerobic pathways (not challenging waste product of H+) ‣ Must draw on stores Fuel stores: ◦In the circulation: ‣ Glucose (12g - about 2.5 minutes of marathon) ‣ Fatty acids (4g - about 1.5 minutes of a marathon) ◦In tissue stores: ‣ Glycogen: 400-600g - about 60 min marathon (muscle) not available for release as no glucose 6- phosphatase in muscle 100-150g - in liver, supports circulating glucose as glucose 6-phosphatase is available ‣ Triacylglycerols 15kg - about 48 hour marathon Running 100m: ◦Very short, high intensity exercise ◦Cannot deliver extra oxygen to muscles in time ◦Once high energy phosphate stores used, must create ATP anaerobically ‣ Inefficient ‣ Incomplete metabolism of glucose ◦Produces lactate (lactic acid) which includes H+ ◦Cannot deliver extra glucose to muscle cells fast enough (from circulation) ◦Need muscle store of glycogen ◦Helps to spare blood glucose (needed for tissues which are unable to store glucose as glycogen e.g. brain) Muscle glycogen: ◦Available even when blood flow limited ◦No need to cross cell membranes ◦Produces glucose-6-phosphate without using ATP ◦Can be mobilised rapidly ◦Released glucose 6-P can be metabolised anaerobically ◦Lactate can be released into circulation for gluconeogenesis in liver via Cori cycle Running 1500m: ◦Moderately high intensity which is maintained over period 3-6 minutes ◦Can deliver some extra oxygen to muscles ◦Still 40% anaerobic metabolism ◦Aerobic metabolism can use fatty acids as well as glucose  Fuels in exercise: Fatty acids as fuel: ◦High capacity, but: ‣ Slow release from adipose tissue ‣ Limited carrying capacity in blood ‣ Capacity limited uptake across mitochondrial membrane (carnitine shuttle) ‣ Requires more oxygen per mole ATP produced ‣ Only metabolised under anaerobic conditions Aerobic and anaerobic metabolism in exercise: ◦0-30 sec - 95% anaerobic ◦2-4 mins - 40-50% anaerobic ◦> 20 min - 95% aerobic Phases of response: ◦Initial sprint ‣ Muscle ATP and creatine phosphate ◦Long middle phase ‣ Aerobic metabolism of glucose from glycogen and fatty acids ◦Finishing sprint ‣ Anaerobic metabolism of glucose from glycogen ◦This pattern of varying creatine phosphate/anaerobic/aerobic can cycle in intermittent sports e.g. football, hockey etc. Mobilising reserves: ◦Need insulin for glucose to enter muscle (GLUT4) - although exercise may help this (increasing insulin sensitivity) ◦Glucagon stimulates glycogenolysis in liver (glycogen phosphorylase phosphorylation) ‣ Helps to maintain blood glucose ◦Adrenaline stimulates glycogenolysis in muscle (glycogen phosphorylase phosphorylation) Running a marathon: ◦Lower intensity, long duration ◦95% (at least) aerobic ◦Use of fuel molecules and stores ‣ Muscle glycogen ‣ Liver glycogen  ‣ Fatty acids ◦Muscle glycogen depleted in a few minutes ◦Utilisation of glucose from liver glycogen peaks at about 1 hour ‣ Declines steadily thereafter ◦Utilisation of fatty acids rises steadily from 20-30 minutes into exercise Mobilising reserves: ◦Over a marathon: ‣ Insulin levels fall slowly (but are not stopped completely) ‣ Glucagon levels rise ‣ Adrenaline and growth hormone rise rapidly Growth hormone mobilises fatty acids (lipolysis) ‣ Cortisol rises slowly Mobilises fats Stimulates gluconeogenesis if exercise very prolonged (phosphoenolpyruvate carboxylkinase (PEPCK) and fructose 1,6 bisphosphatase) Benefits of exercise: ◦Better balance of lean tissue and fat ◦Lower blood lipids ◦Lower blood pressure ◦Improve glucose tolerance ◦Improve muscle sensitivity to insulin ◦Reduced risk of mortality, especially cardiovascular over 5 years ◦No significant effect on weight, but can aid weight maintenance Training: ◦Regular exercise produces improved exercise capacity ‣ Can lead to adaptations e.g. muscle hypertrophy ‣ Can lead to bone remodelling ◦But most aspects rapidly reversible Response to training: ◦Cardiovascular fitness ‣ Lower heart rate for a given output ◦Skeletal muscle ‣ More and bigger fibres ‣ More capillaries ‣ More myoglobin to store oxygen ‣ Better fatty acid oxidation capacity ‣ Increased glucose transport capacity ‣ Increased glycogen storage Adaptations to pregnancy:  ◦Growth of foetus requires lots of: ‣ Energy ‣ Raw materials ◦Must be supplied from maternal circulation ◦Via placental exchange Placental transfer: ◦For most substances occurs by diffusion ‣ Sometimes facilitated by carrier proteins ◦Diffusion occurs down concentration gradients ◦For molecules to move into foetal blood they are usually at higher concentration in maternal than foetal blood (there is some active transport) ◦Requires reorganisation of maternal metabolism Maternal adaptations: ◦Adjust maternal blood concentrations of nutrients ◦Modify nutrient stores to cope with demands ‣ Highest in late pregnancy and during lactation ◦Affects especially fat stores ◦Increased plasma volume ◦Change in basal metabolic rate, initially increases then slows into 2nd and 3rd trimester Maternal stores: ◦Maternal weight gain 8-10kg ◦About 3kg of which is energy stores ‣ Very variable ◦Stores accumulated mostly in first 20 weeks ◦Under influence of reproductive hormones ‣ Largely from the placenta ‣ Small contribution from ovaries up to 12 weeks The aggressive parasite: ◦The foetus is adapted via the placenta to take over maternal metabolism and ensure its own survival ◦The placenta supersedes the hypothalamus-pituitary axis (HPA) Building stores - the first 20 weeks of gestation: ◦Stimulus to appetite ◦Store more fat and more glycogen ◦Due to increased action of insulin on storage tissues and decreased action of insulin on tissues which use energy ‣ More insulin ‣ But also more anti-insulins Insulin secretion in pregnancy: ◦Reproductive steroids (oestrogens and progesterone) ‣ Increase sensitivity of beta-cell to blood glucose  ‣ Increase appetite, therefore more glucose ingested Specific effect on calorific foods - to support growth Beta cell response to pregnancy: ◦Hyperplasia (more cells) ◦Hypertrophy (bigger cells) ◦Increased insulin synthesis ◦Increases secretion ‣ Basal ‣ Stimulated Anti-insulins in pregnancy: ◦Ovary, then placenta secretes huge amounts of: ‣ Oestrogen (oestriol) ‣ Progesterone ‣ Human placental lactogen (hPL) ◦These are all anti-insulins in action ‣ Make muscle resistant to insulin Blood glucose in pregnancy: ◦Blood glucose levels higher on average ‣ Especially after meals ‣ Despite higher insulin levels ◦Elevated blood glucose ‣ Increases glucose gradient across placenta ‣ Drives glucose into storage tissues Adipose tissue Gestational diabetes: ◦Control of maternal metabolism in presence of ‣ Extra demand ‣ Insulin resistance ◦Depends on increased insulin secretion ◦If beta-cells do not respond normally ◦Blood glucose seriously elevated ◦Gestational diabetes ◦Affects 3-10% of pregnancies Consequences of gestational diabetes: ◦Maternal effects of hyperglycaemia ◦Excess foetal growth ‣ Macrosomia ‣ Fat baby with lots of liver and muscle glycogen ‣ Difficult delivery (shoulder dystocia)  ◦Screening for gestational diabetes after 24 weeks (NICE 24-28 weeks based on risk: BMI > 30kgm-2, previous macrosomia, ethnicity, family history previous history GDM) ‣ Fasting glucose > 5.6 mmol/L or 2 hours > 7.8 mmol/L ‣ Not by HbA1c as altered haemoglobin metabolism in pregnancy, oral glucose challenge (typically in UK 75g OGTT) Testing gestational diabetes: ◦With care: ‣ Diet - dietitian led can include manage weight gain, portion control, controlled carbohydrate intake ‣ Appropriate physical activity ◦Self monitoring of glucose ◦Often use insulin short term although metformin may also be used ◦Normally corrects after delivery ◦Increased lifetime risk of developing type 2 diabetes