Insulin Secretion & Signalling Flashcards
which cells in the body make insulin?
beta cells in the pancreas
how is insulin secreted from beta cells?
directly into the blood
what do alpha cells secrete?
glucagon
what do delta cells secrete?
somatostatin
what do PP cells secrete?
pancreatic polypeptide
what is the preprohormone of insulin called?
preproinsulin
where is preproinsulin formed?
in the RER of pancreatice beta cells
what does insulin look like?
two polypeptide chains linked by disulfide bonds
what happens to preproinsulin to make insulin?
it’s cleaved
is animal or human insulin preferred and why?
animal insulin creates a slight antigenic reaction in the body when given for long periods of time so human insulin is preferred
how does glucose enter beta cells from the blood?
through GLUT2 glucose transporter
what phosphorylases glucose in beta cells & wheat does this produce?
glucose -> glucose-6-phosphate
by glucokinase
is glucokinase’s Km for glucose within or out with the physiological range of glucose?
within
what does having a Km within the physiological range of glucose mean glucokinase can do?
phosphorylate glucose quickly in reaction to a small change, maintain normal range
does the metabolism of glucose need to increase or decrease to increase intracellular ATP concentration?
increase
how many ATP are produced in the metabolism of one glucose molecule?
36
what does ATP do in the secretion of insulin?
inhibits ATP-sensitive K+ channel Katp
what does the inhibition of Katp lead to in the secretion of insulin?
depolarisation of the cell membrane
what does the depolarisation of the cell membrane cause in the secretion of insulin?
opening of voltage-gated Ca2+ channels
what does an increase in internal Ca2+ concentration lead to in the secretion of insulin?
fusion of secretory vesicles with the cell membrane& release of insulin
how many phases are there in the release of insulin?
2
what is the 1st phase of insulin release in response to?
immediately after a large bolus of glucose entering the body to prevent a rapid rise in blood glucose
what is the purpose of the 2nd phase of insulin release?
to maintain the correct levels of glucose in the blood
which two proteins make up the Katp channel?
Kir6.1
SUR1
what is Kir6.1 & what does it do?
an inward rectifier subunit
pore subunit
what is SUR1 & what does it do?
sulphoylurea receptor
regulatory subunit
what does the Katp channel exist as?
an octomeric structure
which class of drug directly inhibits the Katp channel?
sulphonylurea
which drug stimulates Katp to inhibit insulin secretion?
diazoxide
if a patient is produces too much insulin what do you want to do to the Katp channel & which drug would use?
stimulate the Katp channel
use diazoxide
if a patient is producing too little insulin what do you want to do to the Katp channel & which drugs would you use?
inhibit the Katp channel
sulphonylurea
in humans what can mutations of Kir6.1 mutations cause?
neonatal diabetes
- activated Katp channels or increase in Katp numbers
what can some Kir6.1 or SUR1 mutations lead to?
congenital hyperinsulinism
- trafficking/inhibiting mutations
what does MODY stand for?
maturity-onset diabetes of the young
what is MODY?
a familial form of early-onset type 2 diabetes
what causes MODY?
genetic defect in beta cell function cause monogenic diabetes
what happens to insulin secretion in MODY?
primary defects in insulin secretion (don’t secrete properly)
mutations in what can cause MODY?
6 different mutations:
- 1 for glucokinase
- 5 for transcription factors
which 2 ways can MODY be caused?
- glucokinase activity is impaired
- glucose sensing defect, threshold for insulin secretion is increased
how would a patient with MODY present?
like a type 1 diabetes patient but older
what do HNF transcription factors do?
- play key role in pancreas foetal development & neogenesis
- regulate beta cell differentiation & function
what’s the difference in treatment of type 1 diabetes & MODY?
type 1 diabetes - insulin
MODY - sulphonylurea
what happens in type 1 diabetes?
loos of insulin secreting beta cells
what happens in type 2 diabetes?
initially hyperglycaemia with hyperinsulinaemia so insulins sensitivity in tissues is reduced
to which family of receptors does insulin’s receptor belong to?
receptor tyrosine kinases
what do kinases do?
promote phosphorylation
what is phosphorylation?
addition of a phosphate group
which enzymes reverse phosphorylation?
phosphatases
which chemical group is the phosphate acceptor on a protein molecule?
the hydroxyl group
what does a phosphate group do to the charge of a protein structure?
introduces a large negative charge
what is the insulin receptor structure like?
dimeric
what is the insulin receptor made of?
2 extracellular alpha subunits
2 transmembrane beta subunits
what do the 2 alpha subunits of the insulin receptor have?
insulin binding domains
what are the subunits of the insulin receptor linked by?
disulfide bonds
what do the beta subunits have the ability to do?
bing ATP
what does binding of insulin do to the alpha subunits do?
causes beta subunits to phosphorylate themselves
what does the autophosphorylation of the beta subunits of the insulin receptor do?
activates the catalytic activity of the insulin receptor to all the substrates to be phosphorylated
what does IRS (substrate of insulin receptor) activating the RAS pathway do?
activates MAP kinase pathway & gene expression
what does IRS activating PI3K do?
activates PKB which causes glycogen synthesis
what does PKB stimulate?
GLUT4 translocation into the cell
what serious side effect can arise from the over stimulation of insulin signalling?
cancerous issues can arise
name some of the biological effects of insulin
- amino acid uptake in muscle
- DNA synthesis
- protein synthesis
- growth responses
- glucose uptake in muscle & adipose tissue
- lipogenesis in adipose tisse & liver
- glycogen synthesis in liver & muscle
- gene expression
- lipolysis & gluconeogenesis in liver
what is the inheritance pattern of leprechaunism?
rare autosomal recessive
where does the mutation occur in leprechaunism?
mutations in gene for insulin receptor
what happens in leprechaunish?
severe insulin resistance due to defects in insulin binding or insulin receptor signalling
what are the abnormalities found in leprechaunism?
- elfin facial appearance
- growth retardation
- absence of subcutaneous fat, decreased muscle mass
what is the other name for leprechaunish?
donohue syndrome
what is the inheritance pattern of Rabson Mendenhall Syndrome?
rare autosomal recessive
what happens in raisin mendenhall syndrome?
severe insulin resistance, hyperglycaemia & compensatory hyperinsulinaemia
what are the characteristics of raisin mendenhall syndrome?
- developmental abnormalities
- acanthosis nigricans (hyperpigmentation)
- fasting hypoglycaemia
- DKA
where are ketone bodies formed?
in liver mitochondria
what are ketone bodies derived from?
acetyl-coa from beta oxidation
how do ketone bodies leave the liver?
diffuse into the blood stream & move to peripheral tissues
what are ketones important for?
molecules of energy metabolism for heart muscle & renal cortex
what reaction does acetyl-CoA come from?
fatty acid oxidation
what can the accumulation of ketone bodies lead to?
acidosis
what is the most common clinical symptoms of DKA?
dehydration (exacerbates acidosis)
name 3 important ketone bodies
- acetone
- acetoacetic acid
- beta-hydroxybutyric acid
which type of diabetes is most associated with DKA?
type 1 when insulin has not been injected, cells fail to receive enough glucose & switch to fat breakdown
