Diabetes Flashcards
Outline the synthesis of insulin.
-Synthesised in the Beta cells in pancreatic islets of langerhans.
- Pre-pro insulin is cleaved in ER to form proinsulin.
-proinsulin is cleaved in golgi apparatus to form insulin and C-peptide.
- Stored within vesicles and are released into plasma by exocytosis when needed.
C-peptide is needed for normal folding of insulin.
Insulin has a half life of 6mins.
C-peptide has half life of 30mins - making it a good indicator for insulin secretion.
To what class of receptor does insulin bind to?
Tyrosine kinase receptor
It has an alpha subunit containing the binding site and beta subunit which contains the cytosolic tyrosine kinases.
It is arranged as a tetramer and held together by disulfide bonds.
MOA of insulin - how does it promote glucose uptake into cells?
-Binds to the alpha subunit of tyrosine receptor which causes a conformational change -> signal transmitted intracellularly to beta subunit.
-activation of tyrosine kinase activity
-Tyrosine residues are phosphorylated resulting in a downstream intracellular cascade.
- insulin receptor substrates (IRS’s) are phosphorylated
-IRS activation results in activation of AKT (protein kinase B)
- this promotes movement of GLUT-4 membrane receptors to the cell membrane to allow for glucose uptake.
What happens to insulin once its bound to its receptor?
-When insulin binds to receptor it gets internalised along with the receptor itself.
-Insulin is then degraded in lysosomes.
-the receptors can be degraded or recycled to cell surface.
-in times of high insulin levels, the high levels result in increased internalisation of the receptors thereby downregulating insulin’s effects.
Outline the mechanism behind how glucose stimulates insulin secretion.
-Glucose enters into the beta cells via GLUT-2 transporters.
-The glucose is phosphorylated by glucose kinase and then metabolised producing ATP via glycolysis.
-ATP sensitive potassium channels close resulting in decreased K+ efflux, leading to depolarisation of the plasma membrane.
-Voltage gated calcium channels open causing an influx of calcium.
-Calcium causes exocytosis of insulin from its vesicle, into the blood.
what 2 other hormones causes insulin release and how?
Glucagon-like-protein 1 (GLP 1)
Gastrin inhibitory peptide (GIP)
Binds to GPCR’s
activated adenylyl cyclase
increases cAMP
Closure of beta cell K+ channels
Depolarisation
Calcium influx
insulin release
This is why insulin given orally results in higher insulin release than if same amount given IV.
Where is glucagon produced, what is its structure
Produced in alpha cells of pancreatic islets of langerhans throughout protelotytic cleavage of pre-proglucagon.
It is composed of 29 amino acids, arranged in a single polypeptide chain.
6 metabolic effects of glucagon
increases 5 things:
- glycogenolysis
-gluconeogenesis
-fatty acid oxidation
-ketogenesis
-uptake of amino acids
Decreases 1
- glycogen synthesis.
how does glucagon increase gluconeogenesis? 3 ways
- inhibits conversion of PEP back to pyruvate
-does this through phosphorylation of pyruvate kinase which prevents conversion of PEP back to pyruvate therefore allows for PEP to go down gluconeogenesis pathway. - Increases PEP carboxykinase synthesis
- allows for more conversion of oxaloacetate -> PEP for gluconeogensis. - Raises levels of Fructose 1-6 biphosphatase
-favours gluconeogenic pathway over glycolytic pathway.
How does type 1 diabetes (low insulin) result in ketoacidosis
Low levels /no insulin + lack of energy derived from glucose will result in disinhibition of hormone sensitive lipase in adipose tissue -> increased lipolysis -> excess acumulation of fatty acids in the liver -> liver processes these via FA beta oxidation -> Acetyl Co-A
Some of this Acetyl CoA is directed down the gluconeogenic pathway to produce glucose
Excess Acetyl Co-A enters the Ketogenic pathway which ultimately produces 3 main ketone body compounds:
-Acetoacetate
-3 hydroxybutyrate
-Acetone
The goals is for these to be taken up into the cells and re-converted back to Acetyl-COA and enter to TCA cycle to produce ATP.
However, as they circulate they release H+ thereby reducing the blood pH.
Ketoacidosis occurs when the rate of ketone body production exceeds the rate of ketone body use.
Outline to ketongenic pathway
2 x Acetyl Co-A -> Acetoacetyl Co A (Thiolase)
Acetoacetyl CoA -> HMG Co A (HMG Co A Synthase)
HMG Co A -> Acetoacetate (HMG Co A Lyase)
Acetoacetate can enter blood and spontaneously decarboxylate to form acetone (released in breath) or for 3-hydroxybutyrate.
5 clinical signs of ketoacidosis
Tachycardia
Hypotension
Kussmaul breathing
Arrythmias
Dehydration (reduced skin turgor/ dry mucous membranes)
3 factors that contribute to diabetic neuropathy
- AGE - Rage
-causes basement membrane thickening, pro-inflammatory cytokine release, endothelial dysfunction, ROS production. - Increase in intracellular sorbitol
- increased uptake of glucose which is then metabolised to form sorbitol by aldose reduction -> water influx/oxidative damage.
- In diabetes, this occurs in tissues that don’t require insulin for glucose uptake: lens, nerves, vessels, kidneys - Protein kinase C activation
- hyperglycemia causes increased intracellular diacyglycerol (DAG) which leads to activation of protein kinase c -> NADPH activity causes oxidative stress. Also causes increased VEGF release.
