Insulin secretion and action Flashcards
What are glucose levels after fasting, and after a meal?
Fasting: 3.5-5.5 mmol/L
After meal: >8 mmol/L
How does the metabolism adapt to fasting?
- increased secretion of glucagon
- increased gluconeogenesis; glycogen release via glycogenolysis = gluconeogenesis
- triglycerides broken down by hormone-sensitive lipase –> glycerol and free fatty acids
- the glycerol is used for gluconeogenesis
- the free fatty acids are used for the Kreb cycle
- there is accumulation of acetyl-CoA therefore ketone bodies form
- glucogenic amino acids are used for gluconeogenesis
What are the main fuel sources in prolonged starvation?
triglycerides
ketone bodies
amino acids
What is the role of the pancreas?
regulates insulin - promoted glucose storage
- regulates glucose output in starvation
Where is insulin synthesised?
by beta cells within islets of langerhans in the pancreas
Apart from beta cells, what other cells are within the islets of langerhans and what do they produce?
delta cells = somatostatin
alpha cells = glucagon
pp cells/f cells = pancreatic polypeptide
epsilon cells = ghrelin
What is the difference between the storage form and active form of insulin?
- monomers of insulin tend to form dimers when concentration is high
- dimers will form hexamers in the presence of Zn2+ and specific pH
- hexamers = STORAGE form of insulin
- once hexamers are secreted, insulin dissociated into monomers (ACTIVE form)
How is insulin formed?
pre-proinsulin – endoplasmic reticulum –> proinsulin – endopeptidase (golgi apparatus) –> insulin
What is the role of endopeptidase?
To cleave off C-peptide from insulin –> break bonds
Describe the process of insulin secretion.
- glucose enters beta cells via GLUT4
- glucokinase = glucose sensor for insulin secretion: converts glucose to G6P to pyruvate
- this enters krebs cycle which progresses to the ETC
- glucose concentration is substimulatory –> K ATP channels open
- resting membrane at hyperpolarised level (~70mV)
- increase in ATP:ADP ratio causing kATP channels to close
- membrane becomes depolarised and voltage-gated Ca2+ channels open
- causes an increase in intracellular Ca2+ resulting in insulin secretion
How can amino acids such as leucine and arginine stimulate insulin release?
Leucine:
- acts through allosteric activation of glutamate dehydrogenase
- can also be transaminated to alpha-ketoisocaproate which is converted to acetyl-CoA (Kreb cycle)
- leads onto ETC which produces energy required to trigger influx of Ca2+ into cell allowing insulin release
Arginine:
- directly depolarise plasma membrane
- stimulate Ca2+ influx, allowing insulin release
What other signals can potentiate insulin release?
- gastrointestinally-derived incretins - act on GLP-1
- glucose dependent insulinotropic peptide - gastric inhibitory peptide, stimulates insulin secretion
- fatty acids
- parasympathetic release of ACh (via phospholipase C)
- Cholecystokinin (CCK, via phospholipase C) –> most can only potentiate glucose-induced insulin secretion
What can activate insulin receptors?
- insulin
- IGF-1
- IGF-2
What class of receptor is the insulin receptor?
tyrosine kinase receptor
Describe how insulin activates the insulin receptor.
- insulin binds to the extracellular portion of the alpha subunit
- causes a change —> activates tyrosine kinase domain (intracellular portion of the beta subunit)
- activated tyrosine domain autophosphorylates tyrosine residues (C terminus of receptor and within the adaptor protein insulin receptor substrate - IRS)
What changes occur in metabolism when insulin is not present?
- IRS, PI3K (lipid kinase) and Akt (protein kinase) = inactive
- No glucose uptake
- No glucose –> glycogen
- GLUT4 contained within intracellular vesicles
What changes occur in the liver, muscle and adipocytes in the presence of insulin?
Liver:
- increased glycogenolysis
- increased lipogenesis
- reduced glycogenesis
Muscle:
- increased glucose uptake
- increased glycogenesis
- reduced protein catabolism
Adipocytes:
- increased glucose uptake
- increased lipogenesis
- reduced lipolysis
How does insulin increase glucose uptake?
- insulin induces Akt activation
- this stimulates GLUT4 translocation from the intracellular vesicles to the plasma membrane
- results in increased glucose uptake (increased glucokinase activity)
How does insulin increase glycogen synthesis?
- insulin activates Akt
- activated Akt dephosphorylates and inactivates glycogen synthase kinase
- glycogen synthase is no longer inhibited
- therefore glycogen is synthesised
How does insulin increase lipogenesis?
- inhibits lipolysis and reduces hormone sensitive lipase
- reduced fatty acids in the blood
- increases malonyl CoA which inhibits the transport fo free fatty acids into the mitochondria via CPT-I in turn inhibiting beta-oxidation therefore free fatty acids used for lipogenesis
What effects does insulin have on the liver (in terms of protein)?
- promotes protein synthesis + storage
- stimulates transport of amino acids into cells
- increases translation of mRNAs
- inhibits catabolism of proteins
- promoted K+ intracellular uptake
How is insulin signalling ‘switched off’?
- endocytosis and degradation of receptor bound to insulin
- dephosphorylation of tyrosine residues by tyrosine phosphatases
- reduced number of (membrane-bound) receptors = reduced insulin signalling
- serine/threonine kinase = reduced activity of insulin receptor
What is the result of insulin resistance?
hyperglycaemia and dyslipidaemia
