9.2 Metabolic and endocrine control during special circumstances Flashcards
what fuel sources are usually available in blood?
glucose
fatty acids
How much glucose is usually freely available?
roughly 12g
why is glucose the preferred fuel source over fatty acids?
fatty acids cannot be used by RBCs, Brain and CNS
Ketone bodies are produced as a by product of fatty acid metabolism
what fuel sources are used under special circumstances?
amino acids
ketone bodies
lactate
apart from glucose, what other fuel sources can the brain metabolise?
ketone bodies
how is lactate produced?
As a product of anaerobic metabolism in muscle
what is the function of lactate in the body?
Liver can convert back to glucose (Cori cycle) or can be utilised as fuel source for TCA cycle in other tissues (e.g. heart)
what are the 3 major energy stores?
glycogen
fat
muscle protein
how much glycogen is available in the body?
roughly 400g
where is glycogen made and stored?
liver and muscle
when is glycogen produced?
when glucose is in excess in the blood
when is fat produced as an energy store?
Made from glucose and dietary fats when in excess
Stored as triacylglycerol in
adipose tissue
when is muscle protein used as a fuel source?
in emergency, not used in healthy people.
why is it important to have energy stores in the body?
- Food is consumed episodically leading to intermittent supply
- Absorbed nutrients are sometimes available in excess and sometimes unavailable (feed/fasting cycle, starvation)
- Body needs to be able to draw upon long and short term energy stores to maintain energy supply to tissues
what sources of energy are first utilised after feeding?
2 hours after feeding glucose and fat available from the gut.
• Immediate metabolism supported by glucose
• Speed up growth and repair processes
• Make glycogen as rapidly as possible
• Increase fat stores
After 2 hours after feeding, glucose and fats are no longer being absorbed from the gut. what is the next source of energy?
• Maintain blood glucose by drawing on glycogen stores
• Support other metabolic activity with fatty acids
released from stores
• Preserve blood glucose for brain
After glycogen stores in liver have been depleted ( 8 to 10 hours after feeding ) what energy sources are used?
Need to make more glucose for brain from amino acids, glycerol & lactate by gluconeogenesis
Continue to support other metabolism with fatty acids
what energy stores are mobilised during starvation?
- Fatty acid metabolism produces ketone bodies
* Brain becomes able to metabolise ketone bodies (reduces need or glucose)
what are anabolic hormones?
hormones that promote fuel storage such as insulin and growth hormone
what are catabolic hormones?
Hormones that promote release from stores & utilisation • Glucagon • Adrenaline • Cortisol • Growth hormone (increases lipolysis & gluconeogenesis) • Thyroid hormones
what metabolic processes does insulin inhibit?
- Gluconeogenesis
- Glycogenolysis
- Lipolysis
- Ketogenesis
- Proteolysis
what metabolic processes does insulin stimulate?
- Glucose uptake in muscle and adipose (GLUT 4).
- Glycolysis
- Glycogen synthesis
- Protein synthesis
what effect does feeding have on 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 is the effect of fasting on glucose metabolism?
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 hormones are produced when blood glucose levels are low?
cortisol from the adrenal cortex
glucagon from pancreas
what do most cells not use glucose during energy starvation?
Reduction in insulin & anti-insulin effects of cortisol prevent most cells from using glucose & fatty acids are preferentially metabolised. This allows the depleting glucose levels to be used by cells that cannot use fatty acids as a fuel source such as the brain, CNS and RBCs.
what energy fuels are use instead of protein from muscle in starvation.
- glycogenolysis
- fatty acids
- Gluconeogenesis occurs in kidneys (Glycerol from fat provides important substrate for gluconeogenesis)
- Liver starts to produce ketone bodies & brain starts to utilise these sparing glucose requirement from protein
why is protein not preferentially used as an energy source during starvation?
In long term starvation death is usually related to loss of muscle mass (respiratory muscle : infection)
Why is there a number of alterations to maternal metabolism and endocrine system in pregnancy?
Accommodate increased demands of developing fetus and placenta
why is the mother said to be in an anabolic state in early pregnancy?
in early pregnancy there is an increase in maternal fat stores and a small increase in insulin sensitivity.
Nutrients are stored to meet future demands of rapid fetal growth in late gestation and lactation after birth.
why is 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 the role of GLUT 1 channels?
To facilitate glucose transfusion from maternal blood supply to fatal blood supply in the placenta
how so substances transfer across the placenta?
Most substances transfer by simple diffusion down concentration gradients (some active transport e.g. amino acid transporters)
what is the fetoplacental unit?
Comprised of the placenta, fetal adrenal glands and fetal liver, together they form a functional compartment responsible for synthesizing hormones that maintain pregnancy.
what hypothalamic like releasing hormones does the placenta secrete?
CRH
GnRH
TRH
GHRH
what pituitary like hormones does the placenta release?
ACTH
hCG (human chorionic gonadotropin)
cCT (human chorionic thyrotropin)
hPL (Human placental lactogen)
what steroid hormones does the placenta secrete?
testosterone and oestrogen
what are the maternal metabolic changes
during first half of pregnancy ( 20 weeks )?
preparatory increase in maternal nutrient stores (mainly adipose tissue).
In preparation for:
• Rapid growth rate of fetus
• Birth
• Subsequent lactation
Increasing levels of insulin promote an anabolic state in mother that results in
increased nutrient storage.
what are the maternal changes during the second half of pregnancy?
Concentration of nutrients in the maternal circulation kept
relatively high by:
• 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 hormones does the placenta secrete that have an anti-insulin effect on the maternal metabolism?
anti-insulin hormones include:
Corticotropin releasing hormone
Human placental lactose
Progesterone
Why do pregnant patients occasionally exhibit hyperglycaemia?
Corticotropin releasing hormone secreted by the placenta acts on the anterior pituitary gland to release ACTH.
ACTH levels are increased and more cortisol is secreted from the adrenal glands.
Cortisol blocks insulin, along with estraogen and human placental lactose (also secreted by the placenta)and causes transient hyperglycaemia after meals due to insulin resistance
Why is hypoglycaemia common in late pregnancy?
due to continuous fetal draw of glucose in rapid growth phase
why does insulin secretion in late stage pregnancy increase?
- as more glucose is ingested in pregnancy due to increased appetite
- Oestrogens and progesterone increase sensitivity of maternal pancreatic beta-cells to blood glucose (hyperplasia and hypertrophy). Leads to increased insulin synthesis & secretion
What is gestational diabetes?
Disease in which pancreatic beta-cells do not produce sufficient insulin to meet increased requirement in late pregnancy
What are the 3 underlying cause of gestational diabetes?
1) Autoantibodies similar to those characteristic of Type I DM
2) Genetic susceptibility similar to maturity onset diabetes
3) Beta-cell dysfunction in setting of obesity and chronic insulin resistance (i.e. “evolving” type II DM) - most common
what are the clinical implications of gestational diabetes?
• Increased incidence of miscarriage
• Incidence of congenital malformation 4x higher
• Fetal macrosomia (big baby)
• Disproportionate amount of adipose around shoulders and chest could lead to shoulder dystocia
• Associated with hypertensive disorders of
pregnancy such as Gestational hypertension and Preeclampsia
• Risk of complications greatly reduced if gestational diabetes is diagnosed and managed.
what women have a high risk of developing gestational diabetes?
women that already have a higher insulin resistance before pregnancy.Many women who develop gestational diabetes will go on to develop Type 2 diabetes later in life.
What are risk factors for developing gestational diabetes?
• 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
How is gestational diabetes managed?
• 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
what factors determine the degree of metabolic response to exercise?
- Type of exercise (muscles used)
- Intensity and duration of exercise
- Physical condition and nutritional state of individual
During exercise, how is ATP used?
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+)
what are the order of energy stores used in exercise?
- ATP ‘stores’ in muscle (2 secs)
- Muscle creatine phosphate stores (~17mmol/kg muscle) can rapidly replenish ATP to provide immediate energy
- Muscle glycogen breakdown
- Further ATP supplied by glycolysis and oxidative phosphorylation of energy stores
How long do glycogen stores last during exercise?
In intense anaerobic conditions, muscle glycogen can be broken down in 2 minutes.
In low intensity aerobic exercise, both muscle and liver glycogen and glucose can be fully oxidised and glycogen stores may last for 60 minutes.
describe the process of glycogenolysis in energy supply during exercise
Muscle contains roughly 300g of glycogen. Muscle Glycogen phosphorylase activity is raised by adrenaline (phosphorylation) and raised by AMP (allosteric modulator). glycogen phosphorylase releases glucose-6-P from glycogen storage.
Glucose-6-P enters glycolysis. Phosphofructokinase (key regulator) is stimulated by high AMP and inhibited by high ATP. Pyruvate is the end product of glycolysis and may enter the TCA cycle in aerobic conditions. Under anaerobic conditions lactate is the end product.
what is the principal organ for regulating blood?
liver
how does the liver increase blood glucose levels?
gluconeogenesis
glycogenolysis
what is the cori cycle?
a metabolic process that occurs in the liver. 2 lactate molecules are converted into a glucose molecule.
how does muscle take up blood glucose?
Muscle takes up blood glucose via GLUT4 transporter (insulin promotes translocation to plasma membrane) and GLUT1 (constitutively active)
what process of glucose uptake is insulin independent in exercising muscle?
increase in AMP stimulates AMPK resulting in signalling cascade which increases GLUT4 translocation
why is glucose production in the liver essential during exercise?
during exercise, the glucose blood levels are depleted. The liver replenishes these, maintaining the blood glucose levels for use by the brain.
what are the benefits of using triglycerides as an energy source?
major store of energy (15kg)
high capacity for sustained production of energy (48 hours of low intensity exercise)
what are the negatives of using triglycerides (fatty acids) as an energy source?
can only be used in aerobic conditions
slow release from adipose tissue
limited carrying capacity in the blood
capacity limited by uptake across mitochondrial membrane (carnitine shuttle)
describe energy supply to muscles during 100m sprint.
high energy phosphate stores (creatine phosphate) used and then ATPm must be created anaerobically.
Lactate produces with subsequent build up in H+ produces fatigue.
Cannot deliver extra glucose to muscle cells fast enough. Need muscle store of glycogen which helps to spare blood glucose for brain
describe the energy supply to muscles in 1500m middle distance.
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.
describe the energy supply of marathon runners?
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
Over the course of a marathon, how does the hormonal control change in response to prolonged exercise?
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 decrease, muscle increase). Glucose tolerance improves Insulin sensitivity of tissues increases Blood triglycerides decrease (VLDL & LDL p, HDL n) Blood pressure falls. Psychological effects Feeling of “well-being” Successful treatment of T2DM
