Insulin and glucagon action Flashcards
How is CHO stored and transported?
Stored as glycogen
Transported as glucose
What are the normal glucose concentrations?
Fasted = 4-5mM
After meal = 8-12mM
How is CHO regulated?
By insulin and glucagon
List the actions of insulin
> Stimulates glycogen production in liver and muscle
Stimulates glucose uptake in muscle and adipose via GLUT 4
Stimulates synthesis of FA/TAG from glucose
> Inhibits glycogen breakdown
Inhibits gluconeogenesis in the liver
What is the action of glucagon
> Stimulates gluconeogenesis and glycogen breakdown
No direct effect on muscle or adipose as they have no glucagon receptors
How is glycogen synthesised and stored?
Synthesised from glucose
> Stored in liver for blood glucose maintenance
> Stored in muscle for local energy production (only used by muscle itself
How is glycogen metabolised in the liver in the fed state?
Glycogen synthase and glucokinase activated
Glucose-6-phosphatase and glycogen phosphorylase inhibited
Very little glucose goes through glycolysis
How is glycogen metabolised in the muscle in the fed state?
No G6Pase present in the muscle
Hexokinase and glycogen synthase is activated
Glycogen phosphorylase is inhibited
How is glycogen metabolised in the liver in the fasted state?
There is decreased glucokinase and glycogen synthase activity
Activation of glycogen phosphorylase and G6Pase
Glycogen is broken down into glucose
Glucose is transported back into the bloodstream via GLUT 2 (down conc. gradient)
> Same effect with (nor)adrenaline
- Will always counteract insulin -> far more potent stimulus
How is glycogen metabolised in the muscle in the fasted state?
No effect of glucagon as no glucagon receptors are present
Only (nor)adrenaline
Muscle glycogen is broken down
If depleted -> fatigue; have to switch to FA substrate
What is gluconeogenesis?
The synthesis of glucose from a noncarbohydrate (nonhexose) source
What are the substrates in gluconeogenesis?
Lactate
Pyruvate
Glycerol
Certain amino acids
Where does gluconeogenesis occur?
Mainly in the liver
The kidneys can contribute in prolonged starvation
(Essentially a reversal of glycolysis)
What reactions are irreversible in liver glycolysis
The reactions requiring the following enzymes:
- glucokinase (GK)
- phosphofructokinase (PFK)
- pyruvate kinase (PK)
All involve ATP
How is glucokinase bypassed?
By glucose 6-phosphatase (G6Pase)
How is PFK bypassed?
By fructose 1,6-bisphosphatase (F16bPase)
How is pyruvate kinase bypassed?
By two enzymes: Pyruvate carboxylase (PCOX) Phosphoenolpyruvate carboxykinase (PEPCK)
Which hormones regulate gluconeogenesis?
Glucagon
Adrenaline
Insulin
Steroid hormones
How do hormones regulate gluconeogenesis?
The effect is at the level of gene expression, so more or less enzyme is synthesised
How does glucagon, adrenaline and glucocorticoids affect gluconeogenesis?
Decreases glucokinase activity
Increases G6Pase and PEPCK activity -> stimulate glycogenolysis
How does insulin affect gluconeogenesis?
Increases glucokinase activity
Decreases G6Pase and PEPCK activity -> prevents liver from raising plasma glucose (inhibits gluconeogenesis)
What are the principle actions of insulin in the liver?
Increases glycogen synthesis -> rapid effects, NOT at the level of gene expression
Increases fatty acid synthesis -> slightly slower
Inhibits gluconeogenesis (PEPCK and G6Pase) -> level of gene expression
What are the principle actions of insulin in the muscle?
Increases glucose transport (GLUT4) -> almost instantaneous
Increases glycogen synthesis -> very rapid
What are the principle actions of insulin in the adipose tissue?
Increases glucose transport (GLUT4) Suppresses lipolysis Increases fatty acid synthesis Increases AA transport and protein synthesis in many tissues Has specific effects on some genes
Describe the qualities of TAG
The most fuel-efficient energy store
- Very energy dense and don’t need the same tight packing as glycogen
What is synthesised from glucose in adipocytes?
Lipids - both G-3-P and fatty acids
How does insulin contribute to TAG synthesis?
Stimulates enzymes involved in TAG synthesis
- Lipoprotein lipase (LPL)
- GLUT4
- Acetyl CoA carboxylase
What is lipolysis?
TAG breakdown
What is adrenaline’s effect on adipose tissue?
Stimulates hormone-sensitive lipase to breakdown TAG
Adrenaline -> cAMP -> PKA -> HSA
How does insulin inhibit lipolysis?
Inhibits stimulation of HSL by adrenaline
- this occurs indirectly
- insulin binds to insulin receptor -> PKB/Akt -> inhibits cAMP
What happens during post prandial metabolism?
> Insulin inhibits adipose lipolysis
This causes a reduction in FA concentration in plasma
Muscle switches to oxidation of glucose for fuel
Insulin stimulates uptake of glucose by adipose and skeletal muscle (GLUT 4)
Glucose is used to make glycogen (in muscles and liver), and TAG (in adipose tissue)
NB: Effects in liver are not GLUT 4 mediated, but dependent on glucokinase
No effect on brain glucose usage (same in fed/fasted state)
Describe T1DM
Autoimmune destruction of beta cells
Therapy through insulin injection/pumps to maintain blood glucose
Describe T2DM
Later onset, but getting earlier
Insulin resistant: no longer as sensitive to endogenous insulin
Associated with obesity
How does T2DM progress?
Years of insulin hypersecretion (because of resistance)
Eventually results in beta cell failure
What are the different hypoglycaemic drugs available
Sulphonylureas Biguanides Thiazolidinediones Incretin mimics & DPP-4 inhibitors SGLT2 inhibitors
How do sulphonylureas work?
Inhibit ATP-sensitive K+ channels
Name the sulphonylureas used clinically
Glibenclamide Gliclazide Glimepiride Tolbutamide Glipizide
Name the biguanides used clinically
Metformin
Explain the mechanism of action of metformin
Mimics insulin by inhibiting hepatic gluconeogenesis
Mechanism of action uncertain but all involve inhibition of liver mitochondrial function
- Acts as a weak poison to inhibit mitochondrial ATP synthesis
- Stimulates body to stop gluconeogenesis due to perceived lack of energy
Name the thiazolidinediones used clinically
Pioglitazone still used
Troglitazone and rosiglitazone was withdrawn (latter caused small increased risk in CVD)
Describe the mechanism of action of pioglitazone
ligand for peroxisome proliferator-activated receptor-g (PPARg), a transcription factor, stimulating expression of genes involved in triglyceride storage
Stops inappropriate deposition of lipid in non-adipose tissues (which leads to insulin resistance) -> improves insulin sensitivity
What is the incretin effect?
Observation that if you inject someone with glucose or get them to ingest the same amount of glucose you get different insulin secretion
More insulin is released when glucose is ingested orally
This process is dependent on incretins - gut hormones that sensitise beta cells to stimulate more insulin release
What are incretins?
Gut hormones that potentiate insulin secretion
Name the incretins
Glucagon-like peptide-1 (GLP-1)
Gastric inhibitory peptide (GIP)
How are incretins inactivated?
Rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DDP-4)
Name incretin mimetics
Exanatide
Liraglutide
Describe the mechanism of action of incretin mimetics
Mimin incretins (GLP-1) Engineered for slower breakdown - not cleaved by DDP-4 Injected - improve endogenous insulin secretion
Name DPP-4 inhibitors
Sidagliptin
Vildagliptin
Describe the mechanism of action of DPP-4 inhibitors
Inhibit DPP-4 enzyme that breaks down endogenous incretins
Increase endogenous incretin-mediated increase in insulin secretion
Oral drug
Name the SGLT2 inhibitors
Canagliflozin
Dapagliflozin
Empagliflozin
Describe the mechanism of action of SGLT2 inhibitors
Inhibit renal re-uptake of glucose from filtrate by SGLT2
Reduce hyperglycaemis by increased loss of glucose through urine (NB: makes patients more prone to UTIs)
Marked effect on weight loss and blood pressure
Trials suggest reduces cardiovascular mortality and hospitalisation due to cardiovascular events
