Integration of Metabolism Flashcards
How can changes in metabolic pattern be achieved? (4)
Variation in amount of available substrate
Allosteric enzyme regulation
Covalent modification of enzymes
Changes in enzyme synthesis
What are the main hormones controlling intermediary metabolism?
Insulin
Glucagon
What type of hormone is insulin? (relating to glucose)
The only hypoglycaemic hormone
What type of hormone is glucagon? (relating to glucose)
Hyperglycaemic
What are some other insulin counter-regulatory hormones other than glucagon?
Adrenaline
Cortisol
Growth hormone
Where is adrenaline produced?
Adrenal medulla
Where is cortisol produced?
Adrenal cortex
Where is growth hormone produced?
Anterior pituitary
What do the islets of Langerhans make up?
Endocrine part of pancreas
What do b-cells secrete?
Insulin
What do a-cells secrete?
Glucagon
What cells secrete insulin?
b-cells
What cells secrete glucagon?
a-cells
How much of the total pancreatic mass is made up of islets of Langerhans?
2%
How many islets are in the average human pancreas?
1 million
Where are islets of Langerhans found?
Pancreas
What percentage of islets are b-cells?
60-70%
What percentage of islets are a-cells?
30-40%
What do δ-cells secrete?
Somatostatin
What stimulates insulin secretion? (4)
Rise in blood glucose
Rise in blood amino acids (weaker influence)
Gut hormones
Glucagon
What gut hormones stimulate insulin secretion?
Secretin and other GI hormones released after food intake, before blood glucose is elevated
Why is it beneficial that glucagon stimulates insulin release?
Allows fine tuning of glucose homeostasis (prevent large fluctuations)
What inhibits insulin secretion?
Adrenaline
What glucose transporter is found on b-cells?
GLUT2
Is the affinity of GLUT2 high or low for glucose?
Low affinity (only takes in glucose when in high concentrations)
How does glucose stimulate insulin secretion?
Glucose enters cell via GLUT2
Metabolised to ATP
K+ channel closed so no K+ in
Voltage-gated Ca2+ channel opens and intracellular Ca2+ concentration increases
Insulin released from vesicles
What polypeptide is insulin derived from?
Proinsulin
What is produced from the processing of proinsulin?
Insulin
C peptide
How many disulfide bridges are in insulin?
3 - two between alpha and beta chains and one on the alpha chain
How many polypeptide chains is insulin made up of?
2
What can we use C peptide for?
Diagnostic purposes to see how much endogenous insulin is produced
What is the ratio of synthesis of C peptide to insulin?
1:1
What stimulates glucagon secretion?
Low blood glucose
High blood amino acid concentration
Adrenaline
Why is it important that high blood amino acid concentration stimulates glucagon secretion?
Prevents hypoglycaemia after a protein meal as brain and red blood cells need glucose
What are the metabolic effects of insulin? (3)
Promotes fuel storage after a meal
- Stimulates glycogenesis
- Stimulates fatty acid synthesis and storage from carbohydrates when glycogen capacity exceeded
Promotes growth
Stimulates amino acid uptake and protein synthesis
Describe the structure of an insulin receptor
Dimer
Two alpha and two beta subunits
Extracellular insulin binding site
Intracellular tyrosine kinase
What are the three functions of the tyrosine kinase of the insulin receptor?
IRS docking site (insulin receptor substrate)
Kinase activation
Growth promoting activity
What does IRS stand for?
Insulin receptor substrate
What happens when insulin binds to its receptor? (IRS pathway)
Autophosphorylation of tyrosine residues on b-subunit
IRS phosphorylated
P13 kinase activated
Phospholipids phosphorylated and kinase cascade leading to protein kinase B activated (phosphorylated)
On which subunit is the insulin binding site found?
Alpha
On which subunit is the tyrosine kinase found?
Beta
Describe how insulin affects glucose transport/storage in a muscle/fat cell (PKB)
Protein kinase B promotes GLUT4 (translocation) so more glucose taken in
Protein kinase B phosphorylates glycogen synthase kinase = inactivated
Glycogen synthase remains active (not inhibited by GSK) so more glycogenesis
Describe how insulin affects lipolysis in adipocytes (PKB)
Protein kinase B phosphorylates phosphodiesterase = active
Phosphodiesterase converts cAMP to 5’AMP
No cAMP available to activate protein kinase A
Hormone sensitive lipase not activated so TAG not hydrolysed
Describe how insulin affects gene expression
Insulin binding and autophosphorylation of tyrosine residues
Protein scaffold results in Ras-GTP being formed (activated)
Kinase phosphorylation cascade results in activation of MAP kinase
MAP kinase alters activity of transcription factors
Which glucose transporter is insulin-dependent?
GLUT4
What are the metabolic effects of glucagon?
(Mobilises fuel and maintains blood glucose during fasting)
Activates glycogenolysis and gluconeogenesis (and amino acid uptake) in liver
Activate fatty acid release from adipose tissue
Activate fatty acid oxidation and ketogenesis in liver
What are the metabolic effects of adrenaline?
Mobilises fuel during stress
Stimulates glycogenolysis in muscle and liver
Stimulates fatty acid release from adipose tissue
What are the metabolic effects of cortisol? (3)
(Provides for long-term requirements)
Stimulates amino acid mobilisation from muscle
Stimulates fatty acid release from adipose tissue
Stimulates gluconeogenesis
What is the fed state?
When your body is digesting food and absorbing nutrients
Lasts 2-4 hours after a meal
How do concentrations of nutrients in the blood change during the fed state?
Increase in blood glucose, amino acids and TAG (as chylomicrons)
Where does the liver get nutrients from?
Hepatic portal vein/supply
When is the liver engaged in gluconeogenesis?
At all times except during the fed state
What glucose transporter is found on liver cells?
GLUT2
What is the difference between glucokinase and hexokinase?
Glucokinase (liver) has a higher Km for glucose
So does not compete with brain when blood glucose concentration is low
Which enzymes must be activated for glycolysis to occur (fed state)?
Glucokinase
Phosphofructokinase
Pyruvate kinase
How are the enzymes involved in glycogen synthesis/breakdown affected in the fed state?
Glycogen synthase activated
Glycogen phosphorylase inhibited
How is fat metabolism in the liver affected in the fed state?
Fatty acid and TAG synthesis activated
Acetyl CoA carboxylase activated (rate-limiting step)
What glucose transporter is present in the brain?
GLUT1
What glucose transporter is present on red blood cells?
GLUT1
Describe GLUT1
Present on brain and red blood cells
Not insulin-dependent
Low Km/high affinity
Always takes up glucose
What occurs in muscle during the fed state?
Increased glucose uptake as increased GLUT4
Glycogenesis (same as liver)
Amino acid uptake activated and increased protein synthesis
Where is glycogen synthesis activated during the fed state?
Liver
Muscle
What occurs in adipose tissue in the fed state?
Lipoprotein lipase activated by insulin allows fatty acids to enter adipocytes
Glucose uptake increased due to increased GLUT4 for glycerol phosphate production
TAG stored
Hormone sensitive lipase inhibited by insulin
How much protein does the average man have?
6kg
How much protein can be lost before you die?
1/3
When do blood glucose levels peak?
1 hour after eating
When do blood glucose levels return to normal?
By 2 hours after eating
What happens to insulin and glucagon levels in the fasting state?
Insulin decreases
Glucagon increases
What is the normal blood glucose concentration?
4mM
What is used in gluconeogenesis?
Lactate
Glycerol
Amino acids
What process generates all blood glucose 24 hours after eating?
Gluconeogenesis
Which tissue supplies the greatest source of energy in the fasting state?
Adipose tissue (TAG)
How are fatty acids transported in the bloodstream?
Bound to albumin
What substances activate hormone sensitive lipase in the fasting state?
Glucagon
Adrenaline
What is the source of energy in muscles during the fasting state?
TAG
No GLUT4 as no insulin
Why is it important that muscles do not use glucose during the fasting state?
So they do not compete with the brain
What happens to fatty acids in the liver during the fasting state?
Degraded to acetyl CoA (beta oxidation)
Acetyl CoA converted to ketone bodies or used in TCA cycle
Why is muscle protein degraded during the fasting state?
Generate amino acids for gluconeogenesis in liver
What hormone activates the link reaction?
Insulin
What hormone inhibits the link reaction?
Glucagon
Why are fatty acids not gluconeogenic precursors?
Acetyl CoA cannot be converted back to pyruvate (to glucose)
Why does glucagon inhibit pyruvate dehydrogenase in the fasting state?
Inhibits the link reaction
Ensures all gluconeogenic substrates are channelled into glucose production NOT acetyl CoA formation
Why does insulin activate pyruvate dehydrogenase in the fed state?
Activates link reaction
Pyruvate –> acetyl CoA for fatty acid synthesis (acetyl CoA carboxylase also activated)
What are two examples of ketone bodies?
Acetoacetate
b-hydroxybutyrate
Why can the brain use ketone bodies but not fatty acids?
Ketone bodies are smaller (and lipid-soluble) so can pass blood-brain barrier
Why is it important that the brain can use ketone bodies?
Results in up to 40% reduction in glucose demand of brain
Less muscle protein degraded as less gluconeogenesis required
Loss of 1/3 of body protein = death
Why can urea excretion be used to measure gluconeogenesis?
Urea excretion is proportional to protein breakdown
What happens during starvation? (5)
More ketone bodies recovered from kidneys
Muscle uses fatty acids
Fatty acid concentrations plateau and ketone bodies rise
Brain uses more ketone bodies and less glucose
Urea production decreases
How do people die from starvation? (3)
Fuel exhaustion
Impairment of immune system - INFECTION
Loss of function from loss of protein
What is a common infection that causes death during starvation and why?
Pneumonia
Intercostal muscles damaged
Cannot clear lungs
Approximately how long does it take to die from starvation?
40 days
How are each of the glucose tolerance curves of diabetics different to normal?
Type I: starts much higher and does not decrease back to ‘normal’ level
Type II: starts higher and takes longer to reach ‘normal’ level
What percentage of the population in the UK is affected by diabetes mellitus?
2-3%
What is Type I diabetes often referred to as and why?
Insulin dependent diabetes mellitus/IDDM
Insulin must be injected in order to survive
What is Type I diabetes?
Autoimmune destruction of b-cells
What are some of the symptoms of Type I diabetes?
HYPERLIPIDAEMIA
KETOACIDOSIS
Polyuria
Polydipsia
Polyphagia
Fatigue
Weight loss
Muscle wasting
Weakness
What is Type II diabetes often referred to as?
Non-insulin dependent diabetes mellitus/NIDDM
What is Type II diabetes?
Insulin resistance
Associated with diet and lifestyle
How does the metabolic pattern in uncontrolled diabetes relate to that of starvation?
Much more exaggerated
No insulin (starvation= low insulin) so glucagon acts unopposed
Muscle protein breakdown and fatty acids release continue and uncontrolled ketogenesis (starvation = ketone bodies stimulate release of insulin to limit these processes)
What is found in the urine of diabetics (uncontrolled)?
Glucose
Ketone bodies
What are the chronic complications of diabetes mellitus? (4)
Microangiopathy (thickening of basement membrane)
Retinopathy (blindness is 25x more common)
Nephropathy (renal failure is 17x more common)
Neuropathy (postural hypotension, impotence, foot ulcers)
How is Type I diabetes treated?
Exogenous insulin injections (must be balanced with food intake to prevent hypoglycaemia)
How is Type II diabetes treated?
Weight reduction
Dietary modification
Oral hypoglycaemic agents
What are the two hypoglycaemic agents used to treat Type II diabetes?
Biguanides
Sulphonylureas
What do biguanides do?
Increase number of GLUT4
What do sulphonylureas do?
Act on b-cells to improve insulin secretion
