Insulin: Mechanisms & Action 1 Flashcards
Blood glucose levels:
- which tissues are highly dependent on extracellular glucose concentration? (2)
- brain and rbc both highly dependent on extracullar glucose concentration
- the brain uses 60% of blood glucose !
what can hyperglycaemia lead to ?
hyperglycaemia: lead to cellular damage (particularly endothelial cells)
- macrovascular (atherosclerosis & CV events)
- microvasuclar (kidney and nerve disease)
what is normal range of blood glucose concentrations ?
what is job of insulin?
where is XS glucose stored? (3)
how can glucose be stored? (2)
3.5 - 5.5. mmol / L (quite a narrow range !!)
insulin: when glucose levels are too high -> reduces excess glucose and converted into storage molecules
- *location of glucose storage:**
- skeletal muscle
- liver
- adipose tissue
- *glucose storage:**
- as glycogen (glycogenesis)
- as fatty acids (de novo lipogensis)
where is insulin produced?
where is glucagon produced?
where is somatostatin produced?
pancreatic islets of Langerhans
- alpha cells: produce glucagon
- beta cells: produce insulin
- delta cells: produce somatostatin
=
how is insulin synthesised?
- transcription from insulin gene
- mRNA stability
- mRNA translation
- post translational modifications:
a) initially synthesised as preproinsulin
b) turned into proinsulin
c) proinsulin undergoes maturation (@GA) into active insulin
describe the structure of insulin xox
how does this change according to increased insulin concentrations?
which structure is the storage form of insulin ? which is active form?
insulin structure
- monomer: 21 a.a. A chain & 30 a.a. B chain linked by 3 disulfide linkages
when insulin concentration increases:
- monomer forms dimers when insulin conc increases
- (Zn2+ prescence and specific pH dimers) = dimers form hexamers
- once hexamers secreted, insulin dissociates into monomers
- hexamer: storage form - stored in storage granules !
- monomer: active form ! groooovy chica
why is insulin synthesis and secretion largely independent?
so that insulin is ready to go ! when need :)
storage and synthesis is independent !!!
what is the mechanism of insulin secretion?
- glucose enters B cells through glucose transport GLUT 1&3
- glucokinase (converts glucose to glucose-6-phosphate) acts as gluocse sensor for insulin secretion
- high Km of glucokinase ensures that the initation of of insulin secretion by glucose only occurs when blood glucose levels are high
- glucose converted to glucose-6-phosphate and to pyruvate & generates ATP through ECT = increases ATP:ADP ratio
- increased ATP:ADP ratio: closes ATP-sensitive K channel on B cell
- causes voltage-gated Ca2+ channels open: Ca moves into the cell
- high intracellular Ca2+ triggers insulin secretion !
describe the different phases of insulin release due to glucose stimulation xo (2)
1st phase: immediate release due to increased blood glucose levels
2nd phase: sustained, slow release of newly formed insulin for storage vesciles
which cells can respond to insulin?
explain the structure of ^?
- only cells that have a specific insulin receptor at the plasma membrane: belongs to tyrosine kinase receptors
- insulin binds to alpha subinit with the receptor: causes a conformational change that activates the tyrosine kinase domain
(has a ligand binding domain -> causes enzymatic activity on intracellular side - tyrosine kinase)
explain the main mechanism of insulin action to allow glucose into the cell !
when not enough insulin:
- IRS (adaptor protein) & PI3K (lipase kinase) & Akt (protein kinase) are all in the cytoplasm and inactive. causes:
- GLUT4 transporters are stored intracellularly. (cant get glucose across (or LOTS of glucose across)
- glucose cant cross membrane
when enough insulin:
- insulin binds to tyrosine-kinase receptor: causes autophosporylation of tyrosine-kinase receptor:
- IRS can bind to the phosphorylated receptor: causes IRS to be phosphorylated
- when IRS is phosphorylated, PI3K binds to IRS-P and PI3K becomes phosphorylated.
- phosphorylated PI3K causes change in membrane lipid: PIP2 –> PIP3
- PIP3 causes activation of Akt
- Akt causes change of GLUT4, to be inserted into membrane = les glucose through !
in short, what does insulin after binding to specific tyrosine-kinase receptor?
causes GLUT 4 receptor to move from intracellular -> integrated into the membrane and allows glucose to transfer in
insulin stimulates glucose uptake in which areas of body? (3)
- insulin stimulates glucose uptake in muscles and adipocytes (into glycogen and lipids)
AND
in the liver:
a) enhances glucose uptake. causes an effect on glucokinase (which causes glucose –> glucose-6-phosphate). = increases glycogen synthesis. then glycogen stored in liver
b) increases lipogensis (triglycerides are then transported to adipose tissues)
what does insulin cause to happen to glucose in muscles?
what does Akt do ?
glucose –> glucose-6-phosphate –> glucose-1-phosphate –> UDP-glucose –> glycgoen. aka glycogenesis
Akt: phosphorylates and inactivates glycogen synthase kianse = activates glyocgen synthase
what happens to glucose in adipocytes? (2)
- in adipocytes: glucose undergoes lipogensis (1) and inhibits lipolysis (1)
- insulin inhibits lipase
does insulin cause increase or decrase of the following?
