Integration Of Metabolism Flashcards
Definition of hypoglycaemic hormone
Hormones that lower blood glucose such as insulin
Definition of hyperglycaemic hormone
Hormones that raise blood glucose such as glucagon, adrenaline
Describe the supply and demand for fuel
Demand=constant
Supply=intermittent
Changes in circulating [hormones] allows body to
-store fuel when available
-mobilise in starvation, injury and stress
Ways to change metabolic patterns
Variation in amount of substrate available
Allosteric effects
Covalent modification
Enzyme synthesis changes
How does variation in the amount of substrate available change metabolic patterns
What happens when there isn’t enough glucose
FA used in starvation when there is not enough glucose
How do allosteric effects change metabolic patterns
What molecule stimulates glycolysis in skeletal muscle, what enzyme is stimulated
Increase in AMP activates phosphofructokinase in muscle for more ATP production in glycolysis
How does covalent modification change metabolic patterns
How is the enzyme glycogen phosphorylase modified so that it is active
Phosphorylation of glycogen, phosphorylase, synthesise
How does a change in enzyme synthesis affect metabolic patterns
How does the amount of dietary cholesterol alter the enzymes activity
Glucokinase and dietary CHO
If you eat more CHO, increase in glucokinase, increase in HMG CoA reductase, cholesterol synthesis
Hormones involved in intermediary metabolism control
What 3 hormones inhibit insulin
Insulin, hypoglycaemic hormone
Glucagon, hyperglycaemic hormone
Adrenaline (adrenal medulla)
Cortisol (adrenal cortex)
GH (anterior pituitary), all counter regulatory of insulin
Describe the structure of the Islets of Langerhans
What are the 3 main endocrine cells
Endocrine pancreas (2%) a cells (30-40%) secrete glucagon b cells (60-70%) secrete insulin d cells secrete somatostatin
When is insulin released and what happens when it is?
What inhibits insulin
Increase in [glucose], [AA] in the blood
Gut hormones
-secretin, GI hormones released after food intake before [glucose] increases
Glucagon
-released to fine tune [glucose]
Insulin inhibited by adrenaline
Describe the process that causes the beta cells to release insulin
Glucose enters via GLUT2, AA enter cell via channels into B cell
Glucokinase acts on glucose, respires it, ATP synthesised
AA transaminated, ATP synthesised
Increasing ATP conc causes K channels to close, changes polarity of membrane
This opens the Ca channels
Increasing [Ca] in the cell causes insulin release
Processing of pro insulin
Proinsulin has a square spiral shape with 3 disulphides bonds and a C peptide
Proteolysis separates insulin from C peptide
Function of C peptide unknown
What happens when glucagon is released
Released when [glucose] decreases, [AA] increases in blood to prevent hypoglycaemia after protein meal
Adrenaline released regardless of [glucose]
5 main metabolic effects of insulin on the body
Promotes fuel storage after a meal
Promotes growth
Stimulates glycogen synthesis and storage
Stimulates FA synthesis and storage from CHO when intake exceeds glycogen storing capacity
Stimulates AA uptake and protein synthesis
Describe the structure of the insulin receptors
Transmembrane
2 alpha subunits on extracellular side
2 transmembrane b subunits
Cytosidic part has 3 Pi attached to each subunit
First Pi, docking site for insulin receptor substrate
Second Pi, used in kinase activation, attached to tyrosine kinase
Third Pi, growth promoting activity
Describe the metabolic pathway of insulin after it has bound to the insulin receptor
Once insulin has bound to the receptor
Tyrosine kinase is activated (auto phosphorylation)
Secondary messenger signalling via a chain of phosphorylation reactions occur which activates Akt protein kinase
Describe the effects of insulin on glucose transport
What are the enzymes involved
How are they activated
How do we increase the amount of glycogen formed
Glycogen synthase kinase =(Akt/PKB)=> glycogen synthase kinasePi
Glycogen synthase kinasePi inactivated so cannot phosphorylate GS
glycogen synthase => activated
Active Akt/PKB => GLUT 4 containing vesicles fuse with membrane => more glucose can be converted to glycogen
In the liver, GLUT2 is used instead of GLUT4
Describe the effects of insulin on the inhibition of lipolysis in adipocytes
What enzymes are involved
What enzymes are inhibited as a result
Describe the effects of glucagon on hormone sensitive lipase
PDE =(Akt/PKB + Pi)=> PDE(Pi)
PDE inhibits PKA
cAMP =(PDE)=> AMP
Hormone sensitive lipase is inhibited so TAGs cannot be hydrolysed to glycerol and FA
Glucagon activates hormone sensitive lipase
Describe the effect of insulin on gene expression through Ras and MAPK
SHC is phosphorylated and phosphorylates Ras
Ras GTP =>Ras GDP, activates Raf
Raf causes the phosphorylation of Mek
Phosphorylated Mek phosphorylates Erk
Erk (MAPK) acts on the transcription factors and alters gene expression
1 main function of insulin
Effects of insulin, long term and short term
What happens to the sensitivity of the insulin receptors when insulin is high
Promotes appearance of GLUT4 in muscle and adipose
Brain, liver, RBCs, pancreas have GLUT2, not insulin dependent
Increase in [insulin], down regulation of its receptors
Short term action, glucose transport and enzyme activation
Long term action, enzyme synthesis
Functions of glucagon
What 5 processes does it activate
Mobilises fuel
Maintains blood glucose during fasting
Activates
Glycogenolysis
Gluconeogenesis
Uptake of AA by liver for gluconeogenesis
FA release from adipose
FA oxidation and ketone body formation in the liver
3 main functions of adrenaline
Mobilises fuel during stress
Increases glycogenolysis in muscle and liver
Increases FA release from adipose tissue
3 main functions of cortisol
Long term requirements
Increases AA mobilisation for muscle,
increased gluconeogenesis
increase FA release from adipose
Describe the fed state
2-4 hours after a meal
Increase in [glucose], AA, TAGs as chylomicrons
Synthesis/storage of glycogen, TAG and proteins
Liver receives nutrients before other tissues via hepatic portal vein
Excess glucose in liver => acetyl CoA => VLDL
Describe the liver when it metabolises carbohydrate
What are the main processes active in
-the fed state
-the fasting state
How is the Km different in the liver compared to the brain
Fasting
-Gluconeogenesis
Fed
- Glycolysis activated through PFK and pyruvate kinase
- Glycogen synthase (active when dephosphorylated)
- Gluconeogenesis inhibited
High Km, no competition with brain when [glucose] is low
Describe the metabolism of fat in the liver
How are TAGS made from excess glucose
Dihydroxyacetone-3-phosphate => glycerol phosphate
Acetyl CoA + Oxaloacetate =(citrate synthase)=> citrate
Citrate =(citrate ATP lyase)=> oxaloacetate + acetyl CoA
Acetyl CoA + CO2 =(Acetyl CoA carboxylase)=> Malonyl CoA
Malonyl CoA inhibits carnitine transferase
Glycerol phosphate + 3 FA => TAGS
Describe metabolism in the brain and RBCs
What substrates does it use and why
What GLUT channels are used?
Both rely on glucose, FA cannot cross blood brain barrier, RBC has no mitochondria
Glucose transport independent of insulin GLUT1
Allows use of glucose at high and low conics
Muscle and metabolism here in the fed state
What GLUT transporters are used
What process is dominant here and what enzyme is key
What else happens in the muscle
Glucose transport into muscle increases
GLUT4 transporters increase in no
Glycogen synthase activated, phosphorylase inhibited
AA uptake and protein synthesis increases
Adipose tissue in the fed state
What enzyme is activated by insulin
Why is this enzyme important in storage
What GLUT transporter is found here and why is it important
What enzyme is inhibited by insulin and why
Lipoprotein lipase activated by insulin
Allows FA entry for esterification, TAG storage
Glucose transport increases via GLUT4
Glucose needed for glycerol phosphate production, TAG esterification
Hormone sensitive lipase in adipocytes inhibited, TAG not degraded
What is the fasting state
[glucose] peak an hour after eating
Return to normal by 2 hours after a meal
Blood glucose removed for oxidation/storage
[insulin] decreases and [glucagon] increases
Describe the early events of the fasting state in the liver, adipose tissue
What is the main energy source
What enzyme is activated by which 2 hormones
How are the FA transported to the liver
Liver maintains [glucose] at 4mM
Adipose tissue provides greatest energy source (TAG)
Hormone sensitive lipase activated by glucagon, adrenaline
FA transported => liver, bound to albumin
Describe glucose production by the liver during the fasting state
What is the main source of energy
What is the other process that occurs and what 3 substrates are broken down
After 24hrs, what is the dominant process
1st supplier = liver glycogen
Gluconeogenesis follows from lactate (RBC and muscles), glycerol (adipose), AA (muscle)
After 24hours, glucose comes only from gluconeogenesis
FA and gluconeogenesis precursors
What reaction is inhibited by glucagon and stimulated by insulin
What is the key enzyme here
Reaction catalysed by pyruvate dehydrogenase = irreversible
Pyruvate + CoA + NAD =(pyruvate dehydrogenase)=> acetyl CoA + NADH + H+
PDH is insulin activated, glucagon inhibited
Ensures that in fasting, gluconeogenic substrates are channeled => glucose production not acetyl CoA formation
Describe the pathway for glucose in the liver during the fed state
Glucose Pyruvate (Pyruvate dehydrogenase) Acetyl CoA (Acetyl CoA carboxylase) FA
Describe metabolism during the fasting state in the liver
How are FA used as a fuel source in fasting
What cells can use FA
How does acetyl CoA inhibit the Link reaction
FA can be used as a fuel by liver, adipocytes and muscle
FA => Acetyl CoA => ketone bodies
Acetyl CoA inhibits PDH so lactate, AA, pyruvate => glucose
How are ketone bodies formed
What molecules are they formed from
Name the 3 ketone bodies
What tissues can metabolise KB?
FA =(B oxidation)=> acetyl CoA
Acetyl CoA => KB
- Acetoacetate
- b hydroxybutyrate
- Acetone released into the blood
Most tissues can oxidise FA, KB
RBC only uses glucose,
Brain uses glucose and KB
Why are ketone bodies metabolised
Conserves protein and glucose
What happens during prolonged starvation
How much protein can be lost without adverse affects
What is the main fuel source for muscle
What is the main fuel source for the brain
What processes are less active
If the early pattern continues in prolonged starvation, protein=severely depleted
1/3 of protein can be lost without severe consequences
More KB recovered from kidney
Muscle uses FA
[FA] plateaus, [KB] increases
Brain uses more KB
Need for gluconeogenesis decreases
muscle protein breakdown, urea production decreases
4 main functions of ketone bodies
Acts on pancreas, stimulate insulin release
Limits muscle proteolysis
Limits adipose tissue lipolysis
Muscle tissue conserved, less urea lost
How will you die in starvation
What macronutrient determines your survival
Amount of adipose tissue=important determinant of survival
Death, from fuel exhaustion, loss of function from protein loss, immune system impairment, infection
Describe the glucose tolerance curves of normal and diabetic subjects
Normal,
Starts below renal threshold, increases and decreases slightly. Never exceeds the threshold
T2D
Starts below renal threshold, increases gradually, exceeds threshold but decreases over a long period of time
T1D
Starts on or above the renal threshold.
Plasma glucose conc increases and does not come down
What is the renal threshold
The max conc that the kidney can process and reabsorb
Types of diabetes mellitus
T1, insulin dependent
T2, non insulin dependent
What is T1D
What are the associated symptoms
What 2 conditions are they at risk for
How is it treated
Autoimmune destruction of B cells
Early onset
Polyuria, polydipsia, polyphagia, fatigue, weight loss, muscle wasting, weakness
Hyperglycaemia, keto acidosis (increase in ketones, increased H+, can’t be removed)
Needs insulin
What is T2D
What are they at risk for
How is it managed
Usually late onset, insulin resistant
Lifestyle associated, major increase in incidence
Hyperglycaemia, normally no ketoacidosis
Responds to diet and hypoglycemic agents
Metabolic patterns in uncontrolled diabetes mellitus
In starvation, decrease in insulin, absent in T1D
Glucagon acts unopposed
The following only occurs in starvation, not in T1, T2
KB, produced in starvation, stimulate insulin release
Limits muscle protein breakdown, release of FA from adipocytes
In T1D, sometimes in T2D
- KB => ketoacidosis and v high glucose (no insulin, glucose can’t be taken up)
- Protein breakdown and FA release not inhibited => weight loss
4 main chronic complications of diabetes mellitus
Microangiopathy
Retinopathy
Nephropathy
Neuropathy
Treatment for T1
Exogenous insulin injection
Balance dosage with amounts in food
Treatment for T2D
2 drugs that help manage T2D
Weight reduction, dietary modification
Biguianides increase GLUT4 number
Sulphonyureas act on b cells, increase insulin secretion
Criteria for a metabolic syndrome
High fasting glucose/insulin resistance/diabetes T2
2 of Hypertension Dyslipidaemia (increased TAG, decreased HDL) Central obesity Microalbuminuria
The mechanism by which glucagon functions
GPCR Gs and some Gq
Increased levels of cAMP, activates PKA
PKA can phosphorylate glycogen phosphorylase b => a
More glucose can be released
