Biochemistry of Insulin Flashcards
what type of hormone is insulin?
anabolic peptide
describe the therapeutic window of insulin?
narrow
can be deadly if given at wrong time or wrong amounts
how can insulin cause death?
can induce a hypoglycaemic coma
what cells make insulin?
beta cells in islets in pancreas
what cells are present within pancreatic islets?
beta cells - secrete insulin
alpha - secrete glucagon
delta - secrete somatostatin
PP - secrete polypeptide
where is insulin synthesised in the cell?
rough ER
how is insulin formed?
preproinsulin cleaved to form insulin
describe the structure of insulin
2 polypeptide chains linked by disulphide bonds
connecting “C” peptide which is a byproduct of cleavage but has no function
what are the types of insulin preparations available?
ultra fast/ultra short-acting short-acting intermediate-acting long-acting ultra-long-acting
describe an ultra fast/ultra fast acting insulin and its use
insulin lispro
monomeric and not antigenic
rapid action
should be injected within 15 mins of beginning a meal and in combination with longer acting preparation for type 1 diabetes unless used for continuous infusion
describe an ultra-long acting insulin and its use
insulin glargine
recombinant insulin analog which precipitates in the neutral environment of subcutaneous tissue
peakless prolonged action
administered as single bed time dose
how is insulin secreted?
glucose enters beta cell through GLUT2 transporter via concentration gradient
glucose is phosphorylated by glucokinase
metabolism of glucose leads to an increase in intracellular ATP concentration (TCA cycle etc)
ATP inhibits the ATP sensitive K+ channel (KATP)
Inhibition of KATP leads to depolarisation of the cell membrane
depolarisation of the cell membrane results in opening of voltage gates Ca2+ channels
Ca2+ increase causes fusion of secretory vesicles with the cell membrane and release of insulin
which enzyme senses glucose and how is its activity controlled?
glucokinase
change in glucose concentration causes change in activity
how is glucokinase affected in diabetes?
the Km of glucokinase is within the normal range of blood glucose so if this goes outwith normal range (i.e diabetes), glucokinase activity with be reduced
when is insulin secretion stimulated in beta cells?
when blood glucose rises above normal level (5mM)
how are beta cells affected in diabetes?
type 1 = beta cells are lost (attacked by immune system)
other types = beta cells lose ability to sense changes in glucose (glucose conc outwith Km of glucokinase)
describe the pattern of insulin release
biphasic
1st phase = fast release of insulin granules in response to any increase in glucose, immediate and ready for release (5% of insulin store)
2nd phase = reserve pool, needs preparation to be released, occurs after 1st if glucose isn’t controlled by 1st phase
why are there 2 phases of insulin secretion and how is this affected in type 2 diabetes?
so you don’t use complete insulin store for every slight change in glucose
secretion flattens and weakens in T2DM due to downregulation of sensing process
how is insulin secretion regulated pharmacologically?
restore glucose to physiological level - should enhance insulin secretion
some drugs mimic action of the ATP to depolarise beta cells (e.g SURs)
what makes up the K ATP channel?
2 proteins
- inward rectifier (Kir) = pore subunit
- sulphonylurea (SUR) = regulatory subunit
channel exists as an octometric structure
what genes are responsible for the K ATP channel subunits?
Kir = Kir6 SUR = SUR1
how is K ATP regulated?
ATP inhibits by binding to the Kir subunit
Diazoxide stimulates by binding to SUR
how do SURs work and when are they used?
same effect as ATP in inhibiting K ATP by binding to SUR subunit
second line therapy for type 2 diabetes - if cant inject insulin or have improved control and lessened stress on islets
how can genes be involved in diabetes?
mutations in Kir6 and SUR1
Kir6 mutation = neonatal diabetes as constantly activates K ATP channels or increase in amount
Kir6 or SUR1 = congenital hyperinsulinism
how is neonatal diabetes managed?
SURs
how is congenital hyperinsulinism managed?
diazoxide can inhibit insulin secretion if channels are still getting to the membrane
what is MODY?
maturity onset diabetes of the young
monogenic diabetes with genetic defect in Beta cell function
familial form of early onset type 2
defective glucose sensing in the pancreas and/or loss of insulin secretion
what causes MODY?
primary defect in insulin secretion due to mutations in at least 6 different genes (glucokinase, transcription factors etc)
how is glucokinase affected in MODY?
activity impaired
causes glucose sensing defect where blood glucose threshold for insulin secretion is increased
how are HNF transcription factors involved in MODY?
play key roles in pancreas foetal development and neogenesis
regulate beta cell differentiation and function (GLUT2 expression, insulin secretion etc)
how is MODY diagnosed and managed?
differentiated from type 1 via genetic screening
managed with SURs instead of insulin as patients usually have some beta cell function
what is type 2 diabetes?
initially hyperglycaemia with hyperinsulinaemia so problem is reduced insulin sensitivity in tissues
which biological processes does insulin switch on?
amino acid uptake in muscle DNA synthesis protein synthesis growth response glucose uptake in muscle and fat lipogenesis in fat and liver glycogen synthesis in liver and muscle
what biological processes does insulin switch off?
lipolysis
gluconeogenesis in the liver
what does insulin regulate?
gene expression
what type of receptor is the insulin receptor?
receptor kinase
type of tyrosine kinase
what happens when insulin binds to its receptor?
binds to alpha subunit causing beta subunits to dimerise and phosphorylate themselves, activating the catalytic activity of the receptor
what commonly causes insulin resistance?
due to reduced insulin sensing and/or signalling
usually due to obesity but can be due to a complete lack of adipose tissue
type 2 = polygenic (obesity and insulin resistance)
mutation in signalling pathways (e.g MODY)
name a genetic mutation which can cause severe insulin resistance
AKT2 mutation
what is leprechaunism?
autosomal recessive genetic disorder of severe insulin resistance due to mutation in gene for insulin receptor
causes defects in insulin binding or insulin receptor signalling
what are the features of leprechaunism?
elfin facial appearance growth retardation absence of subcutaneous fat decreased muscle mass short stature
what is Rabson Mendenhall syndrome?
autosomal recessive genetic condition of severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia
some cases linked to insulin receptor mutation
what are the features of Rabson Mendenhall syndrome?
developmental abnormalities
acanthosis nigricans (hyperpigmentation)
fasting hypoglycaemia due to hyperinsulinaemia
DKA more common
what are the symptoms of diabetic ketoacidosis (DKA)?
vomiting
dehydration
increased heart rate
acetone smell on breath
what is the function of ketone bodies?
diffuse into bloodstream and to peripheral tissues
important molecules of energy metabolism for heart muscle and renal cortex, then converted back to acetyl CoA which enters the TCA cycle
where are ketone bodies formed?
in liver mitochondria
derived from acetyl CoA from beta oxidation of fats
how are ketones affected by diabetes?
low levels of insulin inhibits lipolysis and prevents ketone body overload
DKA can occur in type 1 if insulin is missed
why is DKA rare in type 2?
as there is still inhibition of lipolysis as insulin is being produced
can still occur as insulin resistance and deficiency increases alongside glucagon increase
how are ketones formed?
carbohydrates and fatty acids act as fuel for TCA
carbohydrates form pyruvate which forms acetyl CoA
fatty acids are oxidised to also form acetyl CoA
acetyl CoA enters TCA which eventually forms oxaloacetate which recombines with acetyl CoA to restart TCA
if oxaloacetate is limited (e.g no glycolysis occurring) then the acetyl CoA is diverted to form ketones
how do glucose limiting conditions (diabetes, starvation) cause DKA?
if glucose unavailable, fatty acids are oxidised to provide energy and excess acetyl CoA converted to ketone bodies
blood levels of ketones increases
accumulation of ketones leads to acidosis
high glucose excretion causes dehydration and exacerbates acidosis
leads to coma and possibly death
how is DKA treated?
insulin and rehydration
which diabetes type is autoimmune?
type 1
