Biochemistry of Insulin Flashcards
how you insulin kill you
go into hypoglycemic coma
what makes insulin
beta cells in the pancreas, islets of langerhans
what do alpha cells make
glucagon
what do gamma cells make
somatostatin
what do PP cells in the pancreatic islets make
pancreatic polypeptide
what is the counter hormone (starvation hormone) to insulin
glucagon
where in beta cells is insulin synthesised
rough endoplasmic reticulum
describe the process of insulin synthesis
starts as larger single chain preprophormone (preproinsulin)
cleaved to form insulin
what is the structure of insulin
two polypeptide chains linked by disulfide bonds
connecting C peptide (a byproduct of cleavage)
what preparation of insulin is ultrafast/ultra short acting
insulin lispro
what affected how long insulin lasts
position of amino acids- affects how stable it is
what is the most rapidly acting insulin
insulin lispro
how is insulin lispro used clinically
Injected within 15 minutes of beginning a meal
short duration of action- must be used in combination with longer-acting preparation for Type 1 diabetes unless used for continuous infusion
describe the structure of insulin lispro
monomeric, not antigenic
what prep of insulin is ultra long lasting
glargine
when is glargine administered
single bedtime dose
describe the action of glargine
Recombinant insulin analog that precipitates in the neutral environment of subcutaneous tissue
Peakless- prolonged action
how does glucose enter beta cells
GLUT2 glucose transporter (goes down concentration gradient)
what happens to glucose once it enters beta cells
phosphorylated by glucokinase
what senses the amount of glucose that enters a beta cell
glucokinase
what does increased metabolism of glucose lead to
an increase in intracellular ATP concentration
lists the steps of carb metabolism
glucose-6-P
glycolysis (also makes e- and CO2)
acetyl- CoA
TCA cycle
(e- go to oxidative phosphorylation)
=
36 ATP per glucose
what does ATP do in beta cells
inhibits the ATP sensitive K+ channel KATP- causes depolarisation of the cell membrane
what happens when the cell membrane of beta cells depolarises
voltage gates Ca2+ channels open - increase in Ca2+ conc leads to fusion of secretory vesicles within the cell membrane that release insulin
what blood glucose level should cause insulin to be released
> 5 mM
how does the secretion of insulin related to the tyeps of diabetes
type 1 loss of beta cells
other types beta cells lose the ability to sense changes in glucose (due to hyperglycaemia takin glucose conc outwith the Km of glucokinase)
describe the flow of the release of insulin
is biphasic-
as only 5% ready for immediate release (first phase)
reserve pool must become mobilised to be released in the second phase
what happens to the biphasic release of insulin in poorly controlled T2DM- why
becomes flattened
- down regulation of the sensing process
what drug can mimic the action of ATP to depolarise beta cells (and cause release of insulin) by inhibiting KATP
sulphonylurea (SURs)
what two proteins make up the KATP channels
Kir6- inward rectifier subunit (pore)
SUR1- sulphonylurea receptor (regulatory subunit)
what stimulates KATP (inhibits the secretion of insulin)
diazoxide
when are SURs used
for patients who cant inject insulin (second line therapy as makes beta cells work very hard) or patients who have improved their glucose control
what can mutations in Kir6.2 and SUR1 cause
Kir6.2- neonatal diabetes (constantly active KATP channels)
Kir6.2 or SUR1 mutations- congenital hyperinsulinism
what is MODY
maturity onset diabetes of the young (familial form of type 2 diabetes)
monogenic diabetes with genetic defect in beta cell function
what happens to glucokinase in MODY2
glucokinase activity impaired
glucose sensing defect- threshold for insulin release increased
what are the roles of HNF transcription factors
play key roles in pancreas foetal development and neogenesis
regulate beta cell differentiation and function
what is the important of genetic screening to differentiate MODY from type 1 diabetes
allows treatment of MODY with sulphonylurea rather than insulin as MODY patients have some beta function available
name the diabetes:
loss of insulin secreting beta cells
type 1
name the diabetes:
defective glucose sensing in the pancreas and/ or loss of insulin secretion
MODY
name the diabetes:
intially hyperglycemia with hyperinsulinemia so primary problem is reduced insulin sensitivity in tissues
type 2 diabetes
what does insulin ‘turn on’
amino acid uptake in muscle DNA synthesis protein synthesis growth responses glucose uptake in muscle and adipose tissue lipogenesis in adipose and liver cells glycogen synthesis in liver and muscle
what does insulin ‘turn off’
lipolysis
gluconeogenesis in liver
what receptor does insulin bind to
receptor tyrosine kinases
what happens when insulin binds to the alpha subunits of tyrosine kinases
beta subunits dimerise and phosphorylate themselves (autophosphorylation)
e.g. activate the catalytic activity of the receptor
what does insulin prevent
hyperglycemia
what causes insulin resistance
reduced insulin sensing and/ or signalling
associated with obesity and complete lack of adipose tissue
can occure in monogenic diabetes due to mutation
why is type 2 diabetes polygenic
as has input from environmental causes
what is leprechaunism - donohue syndrome
autosomal recessive mutation in the gene for the insulin receptor
- severe insulin resistance
- developmental abnormalities (elfin facial appearance, short stature, absence of fat and muscle mass)
what causes leprechaunism
defects in insulin binding or insulin receptor signalling
what rabson mendenhall syndrome
autosomal recessive trait
severe insulin resistance, hyperglycemia and compensatory hyperinsulinemia
-developmental abnormalities
-acanthosis nigricans (hyperpigmentation)
-fasting hypoglycaemia
-diabetic ketoacidosis
what are the symptoms of diabetic ketoacidosis
vomiting, dehydration, increased heart rate, acetone smell on breath
where and how are ketone bodies formed
in liver mitochondrian
derived from acetyl-CoA
beta oxidation of fatty acids yields acetyl-CoA which enters TCA cycle (when fat and carb degeneration balanced)
if no oxaloacetate (e.g. due to no glycolysis) then acetyl CoA diverted to ketones
what is the role of ketone bodies
diffuse into the blood stream and to peripheral tissues
important molecule of energy metabolism for heart muscle and renal cortex
emergency energy supply for brain during fasting
what prevents ketone body overload
low levels of insulin inhibit lipolysis
when is DKA at risk in T1DM
if insulin supplementation is missed
when is DKA at risk in T2DM
rarer- can happen as insulin resistance and deficiency increases- alongside increase in glucagon
how does DKA happen
Oxaloacetate is consumed for gluconeogenesis
When glucose is not available-fatty acids are oxidised to provide energy
Excess acetyl-CoA is converted to ketone bodies
Accumulation of ketone bodies can lead to acidosis
High glucose excretion causes dehydration, exacerbates acidosis
Coma, death
what do ketone bodies do to the pH of the blood
decrease it
when is ketosis seen
in glucose limiting conditions
how do you treat DKA
insulin and rehydration
what is the only hormone that can maintain euglycema following food ingestion
insulin
