Metablic And Endocrine Control During Special Circumstances Flashcards
What are teh fuel sources normally available in blood
Glucose
• Glucose is the preferred fuel source
• Little (~12g) free glucose available
• More glucose (~300g) stored as glycogen
Fatty acids • Can be used as fuel by most cells except red blood cells, brain and CNS • Stored as triacylglycerol (fat) in adipose • 10-15 kg fat in 70kg man (~2 months fuel supply)
What are the fuel sources available under special conditions?
Available under special conditions Amino acids • Some muscle protein (~6kg) can be broken down to provide amino acids for fuel • Converted to glucose or ketone bodies • ~2 weeks supply of energy
Ketone bodies
• Mainly from fatty acids
• Used when glucose is critically short
• Brain can metabolise instead of glucose
Lactate
• Product of anaerobic metabolism in muscle • Liver can convert back to glucose (Cori cycle)
or can be utilised as fuel source for TCA cycle
in other tissues (e.g. heart)
Name some energy stores
Glycogen ~ 400g
Readily available source of glucose Made & stored in liver and muscle Made when glucose is in excess in blood
Fat ~10 -15kg Made from glucose and dietary fats when in excess Stored as triacylglycerol in adipose tissue Source of:
• Fatty acids • Glycerol
Muscle protein ~ 6kg available Used in emergency Amino acids can be: Glucogenic (e.g. Ala & Val) Ketogenic (Lys & Leu) or both (e.g. Tyr & Phe) Store ‘filled’ by normal growth and repair processes
What are the key features of metabolic control
See slide
Name anabolic and catabolic hormoens
Anabolic hormones • Promote fuel storage • Insulin • (Growth Hormone) increases protein synthesis Lack of insulin -> Catabolic state
Catabolic hormones
• Promote release from
stores & utilisation
• Glucagon • Adrenaline • Cortisol • Growth hormone
(increases lipolysis & gluconeogenesis)
• Thyroid hormones
What is the action of insulin
Reduces • Gluconeogenesis • Glycogenolysis • Lipolysis • Ketogenesis • Proteolysis
Increases
• Glucose uptake in
muscle and adipose
(GLUT 4). • Glycolysis • Glycogen synthesis • Protein synthesis
What are the effects of feeding
Effects of feeding insulin. • Increase in blood glucose stimulates pancreas to release insulin • Increases glucose uptake and utilisation by muscle and adipose (GLUT 4) • Promotes storage of glucose as glycogen in liver and muscle. • Promotes amino acid uptake and protein synthesis in liver and muscle. • Promotes lipogenesis and storage of fatty acids as triacylglycerols in adipose tissue.
What are the effects of fasting
Effects of fasting • Blood glucose falls & insulin secretion depressed. • Reduces uptake of glucose by adipose and muscle. • Low blood glucose stimulates glucagon which stimulates: • Glycogenolysis in the liver to maintain blood glucose for brain and other glucose dependent tissues. • Lipolysis in adipose tissue to provide fatty acids for use by tissues. • Gluconeogenesis to maintain supplies of glucose for the brain.
What is energy starvation
• Reduction of blood glucose stimulates release of cortisol from adrenal
cortex & glucagon from pancreas.
• Stimulate gluconeogenesis & breakdown of protein & fat.
• Reduction in insulin & anti-insulin effects of cortisol prevent most
cells from using glucose & fatty acids are preferentially metabolised. • Glycerol from fat provides important substrate for gluconeogenesis,
reducing the need for breakdown of proteins.
• Liver starts to produce ketone bodies & brain starts to utilise these
sparing glucose requirement from protein
• Kidneys begin to contribute to gluconeogenesis
• Once fat stores depleted system must revert to use of protein as fuel
• Death related to loss of muscle mass (respiratory muscle: infection).
Describe the metabolic and endocrine adaptations to pregnancy
• Number of alterations to maternal metabolism and endocrine system • Accommodate increased demands of developing fetus and placenta • Growth of fetus requires lots of energy & raw materials! • 2/3rds of fetal growth occurs over the last 1/3 of pregnancy • From 28 weeks onwards fetus grows from ~1000g to ~3500g
What are the 2 main phases of metabolic adaptation during pregnancy?
Anabolic phase • In early pregnancy, mother is in an anabolic state • Increase in maternal fat stores • Small increase in level of insulin sensitivity. • Nutrients are stored to meet future demands of rapid fetal growth in late gestation and lactation after birth.
Catabolic phase
• Late pregnancy characterised as
catabolic state
• Decreased insulin sensitivity
(increased insulin resistance).
• Increase in insulin resistance results in an increase in maternal glucose and free fatty acid concentration
• Allows for greater substrate availability for fetal growth.
What is placental transfer ?
- Most substances transfer by simple diffusion down concentration gradients (some active transport e.g. amino acid transporters)
- Glucose is principal fuel for fetus and transfer facilitated by transporters (mainly GLUT 1).
How does the foetus affect maternal metabolism?
• Fetus controls maternal metabolism to ensure its own survival
• The placenta, fetal adrenal glands and fetal liver, constitute a new endocrine entity, known as the
fetoplacental unit
• Placenta secretes a wide range of proteins that can control the maternal Hypothalamic pituitary axis
EE slide for table
Important placental steroid hormones include:
Oestriol & progesterone
Describe the maternal metabolic Chang’s during the first half of pregnancy
• Changes to maternal metabolism during first 20 weeks of pregnancy related to a preparatory increase in maternal nutrient stores (mainly adipose tissue).
• In preparation for:
• Rapid growth rate of fetus
• Birth
• Subsequent lactation
• Increasing levels of insulin ( ↑ insulin/anti-insulin ratio) promote an anabolic state in mother that results in
increased nutrient storage.
What are the maternal metabolic changes in the second half of pregnancy?
• Maternal metabolism adapts to meet increasing demands
• Concentration of nutrients in the maternal circulation kept relatively high by:
Maternal metabolic changes during second half of pregnancy
• Reducing maternal utilisation of glucose by switching tissues to use of fatty acids.
• Delaying maternal disposal of nutrients after meals.
• Releasing fatty acids from stores built up during 1st half of pregnancy.
• Maternal insulin levels continue to increase but the production
of anti-insulin hormones by the fetal placental unit increases at an even faster rate and the insulin/anti-insulin ratio therefore falls
What are the anti insulin hordes secresd by the placenta?
• Placenta secretes several hormones that exert an anti-insulin
effect on maternal metabolism
• Corticotropin releasing hormone
• Human placental lactogen
• Progesterone } Also implicated but
mechanism less clear
• Tend to result in transient hyperglycaemia after meals
because of increased insulin resistance • Overall late pregnancy has blood glucose ~10% lower since
insulin levels are ~1.65 x higher in fasting state and ~ 3 x higher in postprandial state.
• Hypoglycaemia can occur between meals and at night because
of the continuous fetal draw of glucose
What is the role of cortotropin releasing hormone in pregnancy?
Increases CRH in maternal blood by >1000 fold. Maternal Anterior Pituitary becomes desensitised resulting in a more modest increase in ACTH & cortisol
Describe insulin secretion in pregnancy
• Increased appetite in pregnancy means more glucose is ingested
• Oestrogens and progesterone increase sensitivity of maternal pancreatic β-cells to blood glucose
• β-cell Hyperplasia (more cells)
• β-cell Hypertrophy (bigger cells)
• Leads to increased insulin synthesis & secretion
• If β-cells do not respond normally, blood glucose may become seriously elevated & Gestatio nal diabetes may
develop
What is gestational diabetes?
Disease in which pancreatic β-cells do not produce sufficient insulin to meet increased requirement in late pregnancy
3 known underlying causes:
1) Autoantibodies similar to those characteristic - <10%
of Type I DM
2) Genetic susceptibility similar to maturity onset diabetes - 1-5% rare
3) β-cell dysfunction in setting of obesity and chronic insulin resistance (i.e. “evolving” type II DM) - vast majority
What are the clinical implications of gestational diabetes
Clinical implications
• Affects 3–10% of pregnancies
• Increased incidence of miscarriage
• Incidence of congenital malformation 4x higher
• Fetal macrosomia (large body - big baby)
• Disproportionate amount of adipose
around shoulders and chest could lead to shoulder dystocia - shoulders get “stuck” during birth
• Associated with hypertensive disorders of pregnancy such as Gestational hypertension and Preeclampsia - high bl protein in urine
• Risk of complications greatly reduced if gestational diabetes is diagnosed and managed.
Describe the insulin existence/age graph
See slide
What are risk factors for gestational diabetes?
Risk factorsq
• Maternal age >25 years • Body mass index >25 kg/m2
• Race/Ethnicity
• More common in Asian, Black and Hispanic ethnic groups
• Personal or family history of Diabetes • Family history of macrosomia
Describe teh management of gestational diabetes
Management
• Initial dietary modification including calorific reduction in obese patients
• Insulin injection if persistent hyperglycaemia is present: (7.5-8 mmol/l postprandial or >5.5-6 mmol/L fasting)
• Regular ultrasound scans to assess fetal growth & well being
Describe the metabolic response to exercise
The switch from rest to exercise involves rapid adaptations in a range of systems:
• Musculo-skeletal system • Cardiovascular system • Respiratory system • Temperature regulation
The metabolic response needs to ensure:
• Increased energy demands of skeletal and cardiac muscle
are met by mobilisation of energy stores.
• Minimal disturbances to metabolic homeostasis by keeping
rate of mobilisation equal to rate of utilisation.
• Glucose supply to brain is maintained.
• End products of metabolism are removed as quickly as
possible.
What does the magnitude/a true of the metabolic response to exercise depend on?
Magnitude and nature of response depends on:
• Type of exercise (muscles used)
• Intensity and duration of exercise
• Physical condition and nutritional state of individual
What are the energy requirements of exercise?
• ATP “stores” in muscle are limited (~5 mmol/kg)
• In theory enough to last ~2 seconds during a sprint - ATP concentration would nto fall by >205 due to rapid regeneration
• ATP must therefore be rapidly resynthesised at a rate that meets the
metabolic demands placed upon cell
• Depending on rate of ATP hydrolysis, cell will employ different metabolic strategies to match re-synthesis rate with hydrolysis rate
Descrie the muscle atp turnover during excerise
Myosin ATPase accounts for ~70% of the ATP usage. Remainder comes from other cellular processes such as maintaining ionic gradients across cell membrane (Na+, K+, Ca2+)
50 fold increase 100m sprint than rest
Whee does the energy for muscle contraction come from
- Muscle creatine phosphate stores (~17mmol/kg muscle) can rapidly replenish ATP to provide immediate energy
- Still only enough for ~5 seconds worth of energy during a 100m sprint
- Beyond initial burst of energy, further ATP must be supplied by:
- Glycolysis - inefficient
- Oxidative phosphorylation - required o2
- Must therefore draw on energy stores to provide substrate for these pathways
How can additional intensive exercise be sustained?
• Additional intensive exercise (anaerobic) for up to ~2 minutes can be
sustained by breakdown of muscle glycogen
• If exercise is low intensity enough O2 can be supplied for complete oxidation of glucose and glycogen stores (from muscle + liver) could theoretically last for ~60 minutes (e.g. jogging)
See slide
Describe bld glucose regualtion and th cori cycle
• Liver is principal organ for regulating blood
glucose
• Exercise results in an increase in hepatic blood glucose production through glycogenolysis
and gluconeogenesis
• Liver recycles lactate produced by anaerobic metabolism (Cori cycle).
• Muscle takes up blood glucose via GLUT4 transporter (insulin promotes translocation to plasma membrane) and GLUT1 (constitutively active)
• Exercising muscle also has insulin independent process of glucose
uptake ( rise in AMP stimulates AMPK resulting in signalling cascade which
increases GLUT4 translocation)
• Rate of glucose production from liver however is insufficient to meet full
demands of exercising muscle
• Essential that blood glucose levels maintained for use by brain
Describe fatty acids as a fuel
• Major store of triacylglycerol in adipose (~15kg) but also some in muscle itself • Theoretically could provide enough energy for ~48 hours of low intensity exercise • Can only be used in aerobic conditions • Slow release from adipose tissue • Limited carrying capacity in blood • Capacity limited by uptake across mitochondrial membrane (carnitine shuttle)
Devirbe wjat happens in 100m sprint
• Short, high intensity exercise • Cannot deliver sufficient oxygen to muscles
in time • Once high energy phosphate stores used
(~5 sec) must create ATP anaerobically
• Inefficient • Incomplete metabolism of glucose
• Produces lactate (lactic acid) with subsequent build up in H+
produces fatigue • Cannot deliver extra glucose to muscle cells fast enough • Need muscle store of glycogen • Helps to spare blood glucose for brain
Describe what happens in a 1500 run
• Medium intensity • Can deliver some extra oxygen to muscles • However, still ~40% anaerobic metabolism • Aerobic metabolism can use fatty acids as
well as glucose • Three phases to race:
• Initial start uses creatine phosphate and anaerobic glycogen
metabolism. • Long middle phase in which ATP is produced aerobically from muscle glycogen (relies on adequate supply of O2 to muscles). • Final finishing sprint relies again on the anaerobic metabolism of
glycogen and produces lactate.
What happens in a marathon
• Low intensity, long duration • 95% aerobic • Use of
• Muscle glycogen • Liver glycogen • Fatty acids
• Muscle glycogen depleted in a few minutes. Glucose from liver
glycogen peaks at ~1 hour then declines steadily • Utilisation of fatty acids rises steadily from 20-30 minutes
See side
Give an overview of energy sources during exercise
See slide
Describe the hormone control of the metabolic response to prolonged exercise
Over the course of running a marathon:
• Insulin levels fall slowly (inhibition of secretion by adrenaline)
• Glucagon levels rise:
• Stimulates glycogenolysis (activates glycogen phosphorylase)
• Stimulates gluconeogenesis (PEPCK & fructose 1,6 bisphosphatase)
• Stimulate lipolysis (Hormone sensitive lipase)
• Adrenaline and growth hormone rise rapidly
• Adrenaline stimulates glycogenolysis & lipolysis
• Growth hormone stimulates lipolysis & gluconeogenesis
• Cortisol rises slowly
• Stimulates lipolysis & gluconeogenesis
What are the benefits of exercise?
• Body composition changes (adipose ↓, muscle ↑). * • Glucose tolerance improves (muscle glycogenesis ↑). * • Insulin sensitivity of tissues increases * • Blood triglycerides decrease (VLDL & LDL ↓, HDL ↑) * • Blood pressure falls. * • Psychological effects Feeling of “well-being” * Especially important for diabetics • Reverses progression of metabolic disease • More successful that pharmacological intervention for treatment of T2DM
