Biochemistry Flashcards
what makes insulin
beta cells found in pancreatic islet
what do the cells of the pancreatic islets produce
β cells - secrete insulin
α cells - secrete glucagon
δ cells - secrete somatostatin
PP cells - secrete pancreatic polypeptide
where about in the beta cell is insulin synthesised and what is the make up of the cell
in the rough ER
Contains two polypeptide chains linked by disulfide bonds.
Connecting (C) peptide, a byproduct of cleavage
how does glucose enter the beta cell and what enzyme is responsible for its phosphorylation
through the GLUT2 glucose transporter
glucokinase
what else is glucokinase responsible for
glucose sensor
i.e. change of glucose concentration leads to a dramatic change in glucokinase activity
pathway of secretion of insulin
1 - glucose enters beta cell
2 - increase in intracellular ATP concentration
3 - ATP inhibits the ATP-sensitive K+ channel Katp
4 - inhibition of this channel leads to depolarisation of the membrane
5 - results in opening of voltage-gated calcium channels
6 - increase in calcium concentration leads to fusion of secretory vesicles with the cell membrane and release of insulin
how much ATP is produced per glucose
36
what does inhibition of Katp lead to
depolarisation of cell membrane
what does depolarisation of cell membrane result in
opening of voltage-gated Ca2+ channels, an increase in internal calcium concentration, fusion of secretory vesicles with the cell membrane and release of insulin
what type of pattern is insulin release
biphasic
what are the two phases of insulin release
1st phase - Readily Releasable Pool (RRP)
2nd phase - Reserve pool
what are the two proteins of the Katp channels
An inward rectifier subunit (KIR) - pore subunit - Kir6.1
A sulphonylurea receptor - regulatory subunit - SUR1
what do sulphonylurea class of drugs do
directly inhibit Katp channel
causing channel to open, increase in calcium and eventually insulin release
what drug stimulates Katp to inhibit insulin secretion and what conditions is it used in
Diazoxide
congenital hyperinsulinism due to mutations in Kir6.2 or SUR1
what mutation can lead to neonatal diabetes
Kir6.2
overactive Katp channel
what condition is a Monogenic diabetes with genetic defect in β cell function
Maturity-onset diabetes of the young (MODY)
what genes can be mutated to cause MODY
glucokinase
why does a mutation in glucokinase cause MODY
glucokinase activity impaired Glucose sensing defect, blood glucose threshold for insulin secretion is increased
why should we differentiate whether a patient has MODY or Type I diabetes
allows treatment with sulphonylurea rather than insulin.
Type I diabetes features
Loss of insulin secreting beta cells
MODY features
defective glucose sensing in the pancreas and/or loss of insulin secretion
Type II diabetes features
Initially hyperglycemia with hyperinsulinemia so primary problem is reduced insulin sensitivity in tissues
what is the insulin receptor that insulin binds to
Receptor Tyrosine Kinases
what is the Receptor Tyrosine Kinases composed of
dimeric
two extracellular α subunits with insulin binding domains
two transmembrane β subunits
linked by disulfide bonds
what binds at each subunit of the RTK
alpha subunit
- hormone binding domains
beta subunit
- ATP-binding and tyrosine kinase domains
where does insulin bind and what does it cause
bind at alpha subunit
causes beta subunit to phosphorylate themselves (autophosphorylation)
what happens after the beta subunit phosphorylate
Releases Insulin receptor substrates and it works 2 ways:
1 - IRS activates Ras»_space; MAP kinase pathway»_space; gene expression
2 - IRS activate PI3K»_space; PKB»_space; glycogen synthesis
what stimulates GLUT 4 translocation and what does this cause
PKB
glucose to be taken up and cell growth to be stimulated
what is Leprechaunism – Donohue syndrome
Mutations in the gene for the insulin receptor
Caused by defects in insulin binding or insulin receptor signalling
Severe insulin resistance
Developmental abnormalities
what abnormalities are seen in Leprechaunism – Donohue syndrome
elfin facial appearance
growth retardation
absence of subcutaneous fat, decreased muscle mass
what is Rabson Mendenhall syndrome
Severe insulin resistance, hyperglycemia and compensatory hyperinsulinemia
Developmental abnormalities
Acanthosis nigricans (hyperpigmentation)
where are ketone bodies formed
in liver mitochondria
- derived from acetyl-CoA from β oxidation
what are ketone bodies important for
energy metabolism for heart muscle and renal cortex
- converted back to acetyl-CoA, which enters TCA cycle
what does Acetyl CoA depend on for the formation of citrate
oxaloacetate
when is gluconeogenesis needed and what is used in the Kerb cycle to do this
when glucose is not available and fatty acids need to be broken down for energy
oxaloacetate needed
what happens because of gluconeogenesis
Excess acetyl-CoA is converted to ketone bodies, blood levels increase
what does accumulation of ketone bodies cause
acidosis
coma, death
