Control of Metabolism Flashcards
What are the two methods of ATP generation?
- Glycolysis of glucose into pyruvate (net yield of 2 ATP) anaerobically
- Acetyl CoA in Krebs cycle converted into 30+ ATP molecules aerobically
What in the Krebs cycle drives the production of ATP?
Electron Transport Chain
What types of molecules can be used in the Krebs cycle to drive ATP production?
Carbohydrates, Fats, Amino Acids
How are fatty acids broken down into Acetyl CoA?
Via β-oxidation
What happens to excess glucose and why?
It is stored as glycogen for release between meals
What are the circulating nutrients?
Glucose, fatty acids, amino acids, keto bodies, lactate
What are the stored nutrients?
Glycogen, triglycerides, body proteins
What is the normal plasma glucose concentration?
5 mmol L-1
What is hypoglycaemia?
Low blood glucose can lead to coma and death
< 2.5 mmol L-1 is critically low
What is hyperglycaemia?
Very raised blood glucose leading to protein damage and non-enzymatic glycation
How much glucose can we gain from our food per day?
3000 mmol day-1
What are the two metabolic states?
o Absorptive
o Fasting
What occurs during the absorptive state?
Nutrients are being absorbed from the gut and entering circulation
What occurs during the fasting state?
There are no nutrients to absorb from the gut and we live off stored nutrients
Which hormones regulate the switch between these two states to maintain blood sugar levels?
Insulin: dominates absorptive state
Released as blood glucose rises and promotes storage of glycogen
Glucagon: dominates post-absorptive state
Causes nutrient release to raise blood glucose levels after they drop
Cortisol, growth hormone (somatotropin),
Adrenaline: releases nutrients raising blood sugar levels
Which four tissues does insulin promote the uptake of glucose in?
- Adipose Tissue (fat)
- Skeletal Muscle
- Cardiac Muscle
- Liver
Which processes does insulin inhibit?
Gluconeogenesis, glycogenolysis, lipolysis, proteolysis
What are the different metabolic pathways?
1. Glycogenolysis: Release of glucose from glycogen stores 2. Gluconeogenesis: De novo synthesis of glucose from non-carbohydrate substances 3. Lipolysis: Release of fatty acids from TG breakdown 4. β-oxidation: Fatty acids to Acetyl CoA 5. Ketogenesis Production of ketone bodies from Acetyl CoA
What effect does insulin have on free fatty acids and amino acids?
Promotes uptake into adipose tissue and muscle tissue
What are the short-term defences against hypoglycaemia?
o Glucagon
o Epinephrine
o Sympathetic NS
What about medium and long term defences against hypoglycaemia?
o Ketogenesis: fat reserves can provide a partial substitute for glucose, sparing muscle tissue from destruction that would otherwise be needed to provide amino acid substrates for gluconeogenesis
o Cortisol promotes proteolysis to supply amino acids
What are the major effects of glucagon?
Stimulates hepatic glucose production in the liver
What are the major effects of adrenaline (and sympathetic NS)?
o Stimulates hepatic glucose production
o Stimulates lipolysis: release of FA from adipose tissue
What are the major effects of growth hormone?
Stimulates hepatic glucose production and lipolysis
What are the defences against hyperglycaemia?
Insulin which stimulates glucose uptake by tissues and inhibits hepatic glucose production
What does lack of insulin action lead to?
Hyperglaecemia and diabetes mellitus
What is the difference between type I and type II diabetes mellitus?
o Type I is insulin deficiency
o Type II is insulin insufficiency combined with insulin resistance
In the absorptive state, how does blood glucose rise in the cells?
o Glucose enters cells via GLUT protein channels (expression stimulated by insulin)
o It is immediately phosphorylated to maintain diffusion gradient so glucose keeps entering cell
Is glucagon an agonist or antagonistic hormone?
Antagonist
o Causes nutrient releasing pathways to stop blood glucose falling too slow when it is released.
Give an example of gluconeogenesis?
o Amino acids being converted to glucose via pyruvate
o Synthesis of glucose from a non-carbohydrate compound
Why is blood glucose maintenance important?
o The brain is entirely dependent on aerobic metabolism and doesn’t have ability to oxidise fatty acids
o Needs constant uninterrupted supply of glucose via circulation
What does insulin cause in the liver?
o Glycogenesis
o Glycolysis
o Lipogenesis
What does insulin cause in the muscle?
o Glucose uptake
o Amino acid uptake
o Glycogenesis
What does insulin cause in the adipose tissue?
o Glucose uptake
o Free fatty acid uptake
o Lipogenesis
What does glucagon cause in the liver?
o Glycogenolysis
o Gluconeogenesis
o Ketogenesis
What GLUT transporter is responsible for glucose uptake in muscle?
o GLUT4 stimulated by insulin
o Increase their expression on cell membrane to increase glucose permeability
How else does insulin effect the muscles?
o Stimulates amino acid uptake
o Stimulates glycogenesis
What is the function of white adipose tissue?
o Synthesis of TAG from fatty acids and glucose
o Release fatty acids from storage
o Fatty acids are transported to tissues in lipoproteins
How does insulin effect the white adipose tissue?
o Stimulates glucose uptake via GLUT 4 transporters
o Stimulates FA uptake by stimulating lipoprotein lipase
o Lipogenesis
Why are lipids transported as lipoproteins?
They are insoluble in water
What are chylomicrons?
o They carry absorbed fat from the gut to liver/adipose tissue
o Only present in absorptive state
What enzyme breaks down TAGs?
Lipoprotein lipase
What happens to fatty acids after being taken up by adipocytes?
Converted to TAGs and stored for release later
What are VLDL?
o Some of the chylomicrons pass by liver and the FAs get released as VLDLs
o Very-low-density-lipoprotein supplying blood with fatty acids
o In fasting state, TAGs transported in the VLDL particles so that FA released at tissues
What methods of glucose metabolism occur in the liver?
Glycogen formation, glycogenolysis, gluconeogenesis
What about amino acid formation?
Lipogenesis, ketogenesis, gluconeogenesis
What about fatty acid metabolism?
o Lipogenesis
o Ketogenesis
Why are gluconeogenesis and fatty acid oxidation in competition in the liver?
Both require oxaloacetate
Oxidation of Acetyl CoA to enter Krebs cycle
Oxaloacetate to phosphoenol pyruvate for gluconeogenesis
How do we get around a build-up of ACoA if oxaloacetate gets used for gluconeogenesis instead?
o ACoA is metabolised into ketone bodies (acetoacetate, 3-hydroxybutyrate and acetone) so less amino acid demand so less protein breakdown
o Ketone bodies enter circulation and used in muscles where its reconverted into AcoA and enters krebs to produce ATP
o Used in times of starvation and when limited glucose is being conserved.
Why does the body think its starving in type I diabetes?
o No insulin released (dominant in absorptive state) so no indication of absorptive state
o Lack of insulin
Why does diabetic ketoacidosis occur?
o Ketone bodies build up because lots of gluconeogenesis occurs (due to lack of insulin) meaning there is lots of ACoA that undergo ketogenesis
o Ketone bodies are mildly acidic and the blood doesn’t have enough buffering as it gets overwhelmed so you get diabetic ketoacidosis
How does diabetes all start?
o Begin hyperglycaemic as glucose absorbed from gut isn’t taken up by the tissues (no insulin)
o Body making more glucose via gluconeogenesis as not inhibited by insulin = raised blood sugar
o Causes osmotic problems and glycosuria
What is glycosuria?
o Glucose in urea as glucose filtrated from blood into tubule instead of being reabsorbed
o Causes osmotic diuresis as high osmolarity in tubule = less water reabsorption = dehydration = thirsty
o Impairs kidneys as won’t be as good excreting H+ so = acidosis = ketoacidosis
