Endocrinology Session 5 CLINICAL Flashcards
What are the fuel sources normally available in blood?
- Glucose
- Fatty acids
What are the fuel sources available in blood under special conditions?
- Amino acids
- Ketone bodies (when glucose critically short)
- Lactate (anaerobic metabolism)
What are the glycogen stores?
- Liver and muscle fuck medicine
- Made when glucose is in excess
What are the fat stores?
- Made from glucose and dietary fats when excess
- Stored as TAG in adipose tissue
What are the muscle protein stores?
- Used in emergenices
- Filled by normal growth and repair
What are the key features of metabolic control?*
- Immediate metabolism supported by glucose
- Making glycogen and fat stores
- If no food for 8-10 hours, gluconeogenesis by using AAs, glycerol, lactate to make glucose for brain
- Maintain blood glucose by using liver glycogen stores
- Glucose preserved for the brain
- Fatty acid metabolism producing ketone bodies which brain can adapt to using in starvation
What are anabolic hormones?
Hormones that promote fuel storage
- Insulin
- Growth hormone
What are catabolic hormones?
Hormones that promote release of fuel from stores and utilisation
- Glucagon
- Adrenaline
- Cortisol
- Growth hormone (lipolysis and gluconeogenesis)
- Thyroid hormones
What does insulin STOP?
- Gluconeogenesis
- Glycogenolysis
- Lipolysis
- Ketogenesis
- Proteolysis
What does insulin START?
- Glucose uptake in muscle and adipose by GLUT4
- Glycolysis
- Glycogen and protein synthesis
What are the effects of FEEDING?
- Increase in blood glucose stimulates insulin release
- Insulin increases uptake and utilisation by muscle and adipose (GLUT4)
- Promotes storage of glucose as glycogen
- Promotes amino acid uptake and protein synthesis
- Promotes lipogenesis and storage of fatty acids
What are the effects of FASTING?
- Blood glucose falls
- Less insulin
- Low blood glucose stimulates glucagon
- Stimulates glycogenolysis to use up glycogen stores and maintain blood glucose
- Lipolysis to provide fatty acids for use by tissues
- Gluconeogenesis to make glucose for the brain
What happens in energy starvation that goes on for a prolonged period of time?
- Reduction of blood glucose stimulates release of cortisol from adrenal cortex and glucagon
- Stimuates gluconeogenesis
- Anti-insulin effects of cortisol and low insulin prevent tissues from using glucose to save it for brain
- Tissues metabolise fatty acids
- Glycerol for fat provides substrate for gluconeogenesis so reduced protein breakdown
- Liver produces ketone bodies that brain starts to use
- Kidneys contribute to gluconeogenesis
- Once all depleted, using protein as fuel
Death due to loss of muscle mass
Why do metabolic and endocrine adaptation happen in pregnancy?*
- Accommodate increased demands of developing fetus and placenta
- Needs much energy and materials
- Mother gains about 8kg
When does most fetal growth occur?*
- 2/3rds over last 1/3 of pregnancy
What state is the mother at in early pregnancy?
ANABOLIC STATE
- Increasing maternal fat stores
- Small increase in insulin sensitivity
- Nutrients stored to meet future demands of rapid growth and lactation after birth or later in pregnancy
What state is the mother at in late pregnancy?
CATABOLIC STATE
- Decreased insulin sensitivity
- Increase in maternal glucose and free FA concentration
- Allows more substrate availability for growing fetus
How does placental transfer occur?*
- Most by simple diffusion down concentration gradients
- Some (AA) by active transport
- Glucose is main fuel and transported via GLUT1
How is fetal growth and survival maintained?
- Fetus controls maternal metabolism
- Placenta, fetal liver create the fetoplacental unit
- Placenta can secrete many hormones that control maternal hypothalamic pituitary axis
What hormones can the placenta secrete?
- GnRH
- TRH
- GHRH
- CRH (MAIN)
- ACTH
- hCG (human chorionic gonadotropin)
- cCT (human chorionic thyrotropin)
- hPL (human placental lactogen)
What are important placental STEROID hormones?
- Oestriol
- Progesterone
What are the first changes in maternal metabolism related to?
- Preparation for rapid growth, birth, lactation
- Increase in maternal nutrient stores
- Increase in insulin levels promotes anabolic state that stores more nutrients
What are the second changes in maternal metabolism related to?
- Adapting to meet demands
- Reduced maternal glucose utilisation
- Delayed disposal after meals
- Releasing fatty acids from stores
- Fetal-placental units produces anti-insulin hormones faster than production of maternal insulin, that cause insulin resistance
What are the main anti-insulin hormones?
- Corticotropin releasing hormone (maternal A. Pituitary desensitised)
- Human placental lactogen
- Progesterone
Why can the anti-insulin hormones cause hypo and hyperglycaemia?
- Hyperglycaemia AFTER MEALS: increased insulin resistance that cannot lower blood glucose well
- Hypoglycaemia BETWEEN MEALS: continuous fetal glucose draw
What do the oestrogens and progesterones do?
- Increase sensitivity of maternal pancreatic B cells to glucose
- Causes hypertrophy and hyperplasia
- Increased insulin secretion and sensitivity
What occurs if the B cells do not respond accordingly?
Blood glucose can be very elevated and gestational diabetes may develop
What is gestational diabetes?
A disease in which pancreatic B cells do not produce sufficient insulin to meet increased requirement in late pregnancy
What are the causes of gestational diabetes?
1) Autoantibody production
2) Genetic susceptibility
3) B cell dysfunction in setting of obesity and chronic insulin resistance (similar to T2 diabetes, most common)
What are the clinical implications for gestational diabetes?*
- 3-10% pregnancies
- Increased miscarriage risk
- 4x higher risk of congenital malformation
- Fetal macrosomia
- More adipose around shoulders = shoulder dystocia (stuck during birth)
- Associated with preeclampsia and gestational hypertension
Reduced if managed
What can determine if the mother will develop gestational diabetes?*
- Starting point of insulin resistance
- High risk women have a higher insulin resistance BEFORE pregnancy
- Often develop type 2 diabetes later in life
What are the risk factors for gestational diabetes?
- Maternal age >25
- BMI >25
- Race/ethnicity - more common in Black, Asian, Hispanic
- Family history of diabetes
How to manage gestational diabetes?
- Dietary modifications at first (initial)
- Insulin injection if persistent hyperglycaemia)
- Regular ultrasounds for fetal wellbeing
What does the change in metabolic response to exercise ensure?
- Enough to meet increase energy demands of skeletal and cardiac muscle (more energy stores mobilised)
- Rate of mobilisation = rate of utilisation
- Maintained glucose supply to brain
- End products removed as fast as possible
What does the magnitude and nature of response depend on?
- Type of exercise (muscles used)
- Intensity and duration
- Physical conditions
- Nutritional state of individual
How is ATP rapidly resynthesised in increased metabolic demands?*
- High muscle ATP turnover
- Myosin ATPase (70%)
- Rest from maintaining ionic gradients across cell membranes
Where does energy to replenish ATP come from?*
- Muscle creatine phosphate stores (immediate energy, only about 5 seconds of a 100m sprint)
- Glycolysis (very low)
- Oxidative phosphorylation (needs oxygen)
= DRAW ON ENERGY STORES TO PROVIDE SUBSTRATE FOR PATHWAYS
What activates muscle glycogen phosphorylase to release glucose?
- Adrenaline
- AMP (allosteric)
- PFK then stimulated by high AMP and pyruvate enters TCA cycle (aerobic) or lactate (anaerobic)
What if the exercise is low intensity?
- Enough O2 supplied for complete oxidation
- Glycogen stores can supply energy
Where is blood glucose regulated?*
Liver (can also recycle lactate in Cori cycle)
What does exercise do to the liver?
Increases hepatic blood glucose production by glycogenolysis and gluconeogenesis
How does muscle take up blood glucose?
- GLUT4
- GLUT1
What is the insulin independent process of glucose uptake in exercising muscle?
- High AMP stimulating AMPK that increases glucose translocation)
Why must blood glucose levels be maintained?
Use by brain
Why can fatty acids only be used for energy in aerobic conditions?
- Slow release from adipose
- Limited carrying capacity in blood
- Limited carnitine shuttle uptake across membrane
Low ATP production but high capacity
What happens in a 100m sprint?
- Short and high intensity so cannot deliver enough O2
- Anaerobic ATP creation so incomplete and inefficient
- Lactate made (fatigue due to acidic condition because of rapid ATP hydrolysis)
- Muscle store of glycogen spares blood glucose for the brain
What happens in a 1500m middle distance run?
- Medium intensity so can deliver some extra O2 (40% anaerobic)
- Uses fatty acids and glucose
- Initially creatine phosphate and anaerobic glycogen
- Moves to aerobic from muscle glycogen
- Final sprint again anaerobic metabolism
What happens in a marathon?**
- Long duration and low intensitiy
- 95% aerobic
- Muscle glycogen, liver glycogen, fatty acids used
- Utilisation of fatty acids at about 20-30 min, muscle glycogen depleted in few mins
What are the benefits of exercise?
- Change of body composition to less fat and more muscle
- Better glucose tolerance
- Better insulin sensitivity of tissues
- Blood TAG decrease (HDL higher)
- Lower BP
- Feeling better psychologically
- Reverses progression of metabolic disease
What happens in prolonged exercise to hormonal control?
- Insulin levels fall slowly
- Glucagon levels rise
- Adrenaline and GH rise rapidly
- Cortisol rises slow
Why do insulin levels fall?
Secretion inhibited by adrenaline
Why do glucagon levels rise?
Must mobilise energy stores
- Activates glycogen phosphorylase (glycogenolysis)
- Activates PEPCK and fructose-1,6-bisphosphate (gluconeogenesis)
- Hormone sensitive lipase (lipolysis)
Why do adrenaline and growth hormone rise?
- Adrenaline to stimulate glycogenolysis and lipolysis
- GH stimulates gluconeogenesis and lipolysis
Why does cortisol rise slowly?
To stimulate lipolysis and gluconeogenesis
