Insulin
[Ref: WG21:p337-351]
Also see Carbohydrate metabolism
Basics
Insulin structure
- 2 chains of amino acids linked by disulfide bridges
- Pork insulin differs from human insulin by only one amino acid residue
--> low antigenicity
- Beef insulin results in low titers of antibodies after 2 months of usage in almost all recipients
Insulin synthesis and secretion
- Synthesized in rough endoplasmic reticulum of B cells
- Packeted in membrane bound granules at Golgi apparatus.
* granules have "halo" (clear space between insulin packet and mumbrane-lined vesicle)
- Encoded on short arm of chromosome 11
- Connecting peptide (C peptide) facilitates the folding between A chain and B chains, but is detached in the granule before secretion.
--> C peptide level can be measured as an index of B cell function
- In B cells, insulin forms polymers and complex with zinc
Metabolism
- Half-life of insulin in circulation
= 5 minutes
- Binds to receptors
* Some internalised and destroyed by proteases in endosomes
Actions
GLUT4
[WG21:p340][See Glucose transporter]
GLUT-4 transporter in muscle and adipose tissue is stimulated by insulin
Normally it is stored in vesicles
When insulin receptors activated
--> Vesicles fuse
--> GLUT4 inserted into membrane
--> Glucose entry into cells
Some pool of GLUT4 are inserted in response to exercise
* Independent of insulin
Effects of insulin (summary)
1. Glucose
- Increase glucose uptake by muscle and adipose tissues
* Via GLUT-4
- Increase glucose uptake by liver
* Via induction of glucokinase
--> Increased phosphorylation
--> Faster diffusion of free glucose
- Decreased hepatic glucose output
2. Potassium
- K+ entry into insulin-sensitive cells
--> Reduction of ECF [K+]
3. Anabolic effect
- Increase lipogenesis
- Increase protein synthesis
Effects of insulin by time line
Rapid
- Increased transport into insulin-sensitive cells:
* Glucose
* Amino acid
* K+
Intermediate (minutes)
- Stimulation of protein synthesis
- Inhibition of protein degradation
- Activation of glycolytic enzymes and glycogen synthase
--> Increased glucose usage and glycogen synthesis
- Inhibition of phosphorylase and gluconeogenic enzymes
--> Decreased gluconeogenesis and glycogen breakdown
Delayed (hours)
- Increase in mRNA for lipogenic and other enzymes
Effects on insulin by tissues
Adipose tissue
- Increased glucose entry
- Increased fatty acid synthesis
- Increased glycerol phosphate synthesis
- Increased triglyceride deposition
- Activation of lipoprotein lipase
* Increasing triglyceride uptake from chylomicrons into adipose tissue
* [WG21:p309,p345]
- Inhibition of hormone-sensitive lipase
* Decreasing FFA release from adipose tissue
- Increased K+ uptake
Muscle
- Increased glucose entry
- Increased glycogen synthesis
- Increased amino acid uptake
- Increased protein synthesis in ribosomes
- Decreased protein catabolism
- Decreased release of gluconeogenic amino acids
- Increased ketone uptake
- Increased K+ uptake
Liver
- Decreased ketogenesis
- Increased protein synthesis
- Increased lipid synthesis
- Decreased glucose output, due to
* Decreased gluconeogenesis
* Decreased glycogen breakdown
* Increased glycogen synthesis
* Increased glycolysis
General
Mechanism of action
Insulin receptor
- Tetramer
- 2 alpha and 2 beta subunits
* Synthesized on a single mRNA
* Proteolytically separated
* Coded on chromosome 19
- Alpha subunits
* Extracellular
* Binds to insulin
- Beta subunits
* Span the membrane
* Intracellular component have tyrosine kinase activity
- Halflife of insulin receptors
~ 7 hours
NB:
- Very similar to IGF-I receptor
* But different from IGF-II receptor
Mechanism of action
Insulin binds to alpha subunits
--> Triggers tyrosine kinase activity of beta subunits
--> Autophosphorylation of the beta subunits
--> Triggers phosphorylation and dephosphorylation of various proteins
Regulation
Normal amount
= 1U/hour, with increases after meals
= 40U/day
Factors affecting insulin secretion
[WG21:p348] Selective
Stimulators
- Glucose
- Mannose
- Certain amino acids
* Arginine, Leucine, and others
- NO
- Intestinal hormones
* GIP and others
- Glucagon
- Beta-adrenergic agonist
- Sulfonylurea
- Theophylline
Inhibitors
- K+ depletion
- Somatostatin
- Alpha-adrenergic agonist
- Thiazide diuretics
- Phenytoin
- Insulin
Glucose
Acts directly on pancreatic B cells to increase insulin secretion
Response to glucose is biphasic
* A rapid but brief increase, followed by
* More slowly developing prolonged increase
Mechanism
[WG21:p349]
Glucose enters B cells by GLUT2
--> Metabolised
--> ATP generated
--> ATP inhibits ATP-sensitive K+ channels
--> Reducing K+ efflux
--> Depolarizaton of B cells
--> Ca2+ influx (via voltage-gated channel)
--> Exocytosis of granules (with insulin in them)
--> Followed by priming of other secretory granules (via glutamate)
Oral hypoglycemic agents
Sulfonylurea
Increase secretion of insulin
Only works when there are B cells remaining
Binds to ATP-inhibited K+ channels in B cells
* Similar mechanism as glucose [see above]
Metformin
Reduce gluconeogenesis
--> Thus decreasing hepatic glucose output
Risk of lactic acidosis
Troglitazone (and other thiazolidinediones)
Increase insulin-mediated peripheral glucose uptake
--> Reducing insulin resistance
cAMP
Factors that increase cAMP in B cells increase insulin secretion
e.g. glucagon, phosphodiesterase inhibitor (e.g. theophylline)
Catecholamine
Inhibits insulin secretion via alpha2-receptor
Stimulate insulin secretion via beta-receptor
Net effect: INHIBITION
In alpha-blockade, effect may be stimulation
Intestinal hormones
Stimulation of insulin secretion:
- Glucagon
- Secretin
- Cholecystokinin (CCK)
- Gastrin
- Gastric inhibitory peptide
But,
- GIP is the only one that produces stimulation with normal oral glucose intake
NB:
- Normal oral glucose intake does not produce levels of other hormones high enough to produce stimulation of insulin secretion
K+ depletion
Decreases insulin secretion
Thus,
Primary aldosteronism
--> K+ depletion
--> Diabetic glucose intolerance
Other notes
[WG21:p355]
Thyrotoxicosis aggravates clinical diabetes
* Thyroid increase GIT absorption of glucose and cause some hepatic glycogen depletion
Glucocorticoids can worsen diabetes
* Increase in protein catabolism
* Increased gluconeogenesis in liver
* Increased hepatic glycogenesis and ketogenesis
* Decrease in peripheral glucose utilisation
Growth hormone can also worsen diabetes
* Mobilise FFA --> Ketogenesis
* Decrease glucose uptake in some tissues
* Increased hepatic glucose output
* May decrease tissue binding of insulin
* Growth hormone does not stimulate insulin directly, but the hyperglycaemia it produces may stimulate insulin