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Core
This article is a hybrid article between the Metabolism and Endocrine units, so the topics mentioned in it will relate to both of those units.
In the body there are two types of fuel sources available: those available in normal circumstances, and those available in so called ‘special conditions’, which is any condition in which the body does not have the normal resources available to it (like starvation, or in the middle of a marathon).
Sources of energy normally available in the blood:
- Glucose – this is the preferred fuel, and most is stored as glycogen.
- Fatty Acids – these can be used by most cells in the body, except red blood cells and cells of the CNS (so fatty acids can’t be used by the brain). They are stored in the body as triacylglycerol (TAG) in adipose tissue.
Sources of energy available in ‘special circumstances’:
- Amino acids from muscles:
- Glucose – muscle proteins are broken down into their amino acids, and then glucogenic amino acids (like alanine) are converted into glucose.
- Ketone bodies – again from amino acids released from muscle breakdown. Ketogenic amino acids (like leucine) are converted into ketone bodies. Ketone bodies are the fuel used in the brain when there is not enough glucose in the blood.
- Lactate – in the liver, this can be converted into glucose (through the Cori cycle, see below) or can be used in the Krebs Cycle directly.
Fuel Stores in the Body
- Glycogen – about 400g stored in the liver and muscle, acting as a source of glucose.
- Fat – between 10kg and 15kg in someone who has a ‘healthy’ BMI, acting as a source of fatty acids and glycerol.
- Muscle Protein – about 6kg, acting as a source of glucose or ketone bodies following metabolism depending on whether the amino acid is glucogenic or ketogenic.
Which Stores When?
Feeding
Up to 2 hours – Glucose and fat absorption from the gut fuels metabolism and prompts storage.
2-10 hours – Absorption stopped, the body relies on fatty acid and glycogen stores. Blood glucose is preserved for brain use.
8+ hours – Glycogen stores begin to deplete, gluconeogenesis begins to produce glucose from fatty acids, proteins and lactate.
Starvation (multiple days) – By this point there is no glycogen left, so the body becomes reliant on protein breakdown and fatty acids found in the blood to produce ketone bodies. However, protein metabolism is not sustainable, so the body begins to shut down and rely only on fatty acids found in the blood. The uptake of fatty acids is limited by the carnitine shuttle (mitochondrial uptake of fatty acids), and their metabolism creates a small but sustainable amount of ATP.
Hormonal Influences on Metabolism
Anabolic (promoting fuel storage) – insulin and growth hormone (promotes protein synthesis).
Catabolic (promoting release from stores and utilisation) – glucagon, adrenaline, cortisol and thyroid hormones and growth hormones (promotes increased lipolysis and gluconeogenesis).
Insulin is one of the most important hormones in the body when it comes to metabolism as it has many different effects. It is vital to remember that insulin is released after a meal, when there is plenty of glucose available in the blood, so the body wants to store fuels and not release any more.
- Insulin stops – gluconeogenesis, glycogenolysis, lipolysis, proteolysis and ketogenesis. Insulin wants to store fuel sources, not to break them down.
- Insulin starts – GLUT4-mediated uptake of glucose into adipose and muscle cells for storage, glycogen synthesis, and protein synthesis.
This relates to the Feeding-Fasting Cycle
- Feeding releases insulin – this prompts the storage of many molecules. There is increased GLUT4-mediated glucose uptake into muscle and fat, increased glycogen storage, increased amino acid uptake, increased lipogenesis.
- Fasting releases glucagon – this prompts the release of molecules that can be used as a fuel source. There is decreased uptake of glucose into muscle and fat, increased glycogenolysis in the liver, increased lipolysis, increased gluconeogenesis.
There are many changes that occur during pregnancy relating to metabolism because the metabolism of the mother must account for the needs of the growing fetus. Over pregnancy, around 8kg is gained by the mother, made up of the fetus, placenta, amniotic fluid and stores laid down.
- The first half of the pregnancy can be described as anabolic – increased fat and nutrient stores to allow for supply to grow a fetus and to lactate post-partum (after birth).
- The second half of pregnancy can be described as catabolic – decreased insulin sensitivity to leave glucose and fatty acids in the bloodstream for the metabolism of the fetus.
These changes occur due to the Fetoplacental unit, a system of the fetal adrenal glands, fetal liver and the placenta that team up to secrete proteins (e.g. oestrogen and progesterone precursors) to help alter the maternal hypophyseal-pituitary axis (HPA axis) so it creates conditions in the maternal body that are more favourable for the fetus.
This involves the fetal-released hormones increasing the maternal resistance to insulin to cause hyperglycaemia, so the fetus has a high glucose supply. This leads to hyperglycaemia after meals and hypoglycaemia overnight (because glycogen stores are depleted) and can lead to Gestational Diabetes.
Gestational diabetes is similar to Type Two Diabetes Mellitus (T2DM) in that they both involve episodes of hyperglycaemia relating to insulin resistance. However, gestational diabetes often resolves following birth. It is important to have a baseline for insulin resistance before pregnancy, because some women may be very likely to develop gestational diabetes if they are already resistant to insulin, or unable to produce adequate insulin.
There are three main causes of gestational diabetes:
- Autoantibodies present in the blood (similar to those present in Type One Diabetes Mellitus) that impair function of the pancreas only very mildly. This means that normally the patient had enough insulin to function effectively, but in pregnancy with the mildly increased insulin resistance, the patient develops diabetes.
- Genetic susceptibility to T2DM that would normally lead to onset in maturity, but the pregnancy-related insulin resistance causes it to present earlier.
- In some people, the normal insulin resistance in pregnancy is enough to induce a diabetic state.
Clinical implications of gestational diabetes can be serious:
- Increased incidence of miscarriage.
- Increased risk of congenital malformation (lots of different things affecting CNS, GI tract, heart, joints and skeletal systems).
- Increased incidence of macrosomia (basically a big baby) which can lead to shoulder dystocia (when the shoulders of the baby get stuck in the birth canal, leading to risk of tearing to the mother and risks of fractures or brachial plexus injury (specifically Erb’s Palsy) to the baby).
- Increased risk of gestational hypertension and pre-eclampsia (a condition characterised by proteinuria and hypertension in a mother and thought to be caused by the placenta not being able to provide enough blood supply to the fetus, which can lead to fits and death in the mother if not properly treated).
It is important to note that gestational diabetes is diagnosed with an oral glucose tolerance test and can easily be managed to help reduce the risk of the complications listed above.
Management strategies include:
- Dietary modification – management like any patient recently diagnosed with T2DM (basically eating less sugar).
- Insulin injections
- Regular fetal monitoring – this is important to prepare for macrosomia and to check for congenital malformation.
Risk factors for developing gestational diabetes include:
- Maternal age over 25.
- Maternal BMI over 25 (anyone classified as overweight or obese).
- Family history of diabetes of any sort.
- Family history of macrosomia (as these might have been cases of undiagnosed gestational diabetes).
Metabolic Responses to Exercise
Exercise requires rapid musculoskeletal, cardiovascular, respiratory and temperature changes in the body, which drastically alters the metabolic demand of the body. The body also has to control the homeostasis in the rest of the body, increase the speed of waste removal (like lactate build up), and maintain the glucose supply to the brain.
The Cori Cycle
The liver is important for regulating blood glucose. Exercise increases the glycogenolysis and gluconeogenesis that occur in the liver to maintain the glucose concentration of the blood.
The liver recycles lactate present in the blood through the Cori Cycle (shown in the diagram below), and the muscle takes up this new glucose through GLUT4 transporters.
Exercising muscle also has the ability to increase GLUT4 transporters, which depends only on the concentration of AMP in the cells (so lots of AMP means increased GLUT4 because this is a low energy state, so the cells need more glucose). This process is insulin-independent, meaning that the cells can get more glucose through increasing uptake from the Cori Cycle even if insulin is present in the body. This is useful when the muscles have a high glucose demand (like when running a marathon) because if insulin was present in the blood, glucose from the blood would be stored rather than maintained.
Diagram - The Cori Cycle, where the liver recycles lactate into glucose for the muscle to use
SimpleMed original by Maddie Swannack
Hormonal Changes During Extreme Exercise
During a marathon, there are a number of changes that occur in the hormonal profile of the body. This reflects the need of the body to increase the amount of glucose available in the blood.
- Insulin decreases – prevent storage of glucose in the body.
- Glucagon increases – increased glycogenolysis, lipolysis, and gluconeogenesis.
- Increased adrenaline, growth hormone and cortisol – increased glycogenolysis, lipolysis, and gluconeogenesis.
Edited by: Dr. Thomas Burnell
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