insulin 1 Flashcards
why is it necessary to control blood glucose
glucose is an obligatory energy source of the brain
food supply is intermittent
a variable metabolic demand
islets of langerhans are located
in the endocrine pancreas
beta cells
insulin producing
alpha cells
produce glucagon
D cells
produce somatostatin
adrenaline made in
adrenal medulla
glucocorticoids made in
adrenal cortex
growth hormone made in
pituitary
the only hormone that decreases blood glucose
insulin
hormones that raise blood glucose
glucagon, adrenalin, glucocorticoids, growth hormone
insulin stored in
beta cell granules
insulin stored as
pro-insulin
when insulin is cleaved
undergoes proteolytic cleavage
protease removes C peptide
mature insulin is the alpha and beta chain
stimulants for release of insulin
hyperglycaemia
amino acids and FAs
peptide gut hormones - incretins (GLP1 glucagon like peptide 1, GIP and others)
incretins
peptide gut hormones
GLP1, GIP
released from the gut, not triggered when glucose is give IV
3 metabolic targets of insulin
CHO
Fat
Protein
CHO metabolism in the liver being acted on by insulin
decrease gluconeogenesis
decrease glucogenolysis
increase glycolysis
increase glycogenesis
insulin action on fat metabolism
increase lipogenesis
decrease lipolysis
insulin action on protein metabolism
decrease protein breakdown
increase amino acid uptake
increase protein synthesis
insulin action on CHO
increase glucose uptake
increase glycolysis
insulin effects on adipose tissue
increase fat storage
increase TGs and FAs
reduce fat breakdown
insulin receptor
receptor tyrosine kinase insulin binds insulin receptor dimerisation and autophosphorylation phosphorylates IRS1,2,3,4 (insulin receptor substrate) activates PI3K/Akt pathway which activates GLUT4 transporter which brings glucose into the cells
GLUT4
glucose transporter which brings glucose into the cell
glycogen synthase
activated by insulin
produces glycogen from glucose
PI3K/Akt pathway
- GLUT4
- glycogen synthase
- cell growth
diabetes is
chronic metabolic disorders characterised by hyperglycaemia
diabetes is caused by
relative or absolute insulin deficiency
diabetes presents with
polyuria - due to glycosuria polydipsia - thirst polyphagia - hunger weight loss - catabolism tiredness/confusion/irritability poor wound healing and infections - candidiasis
diagnosing hyperglycaemia
fasting blood glucose > 7mmol/L
2h after meal (OGTT)>11.1
casual blood test >11.1
pre diabetic state
FBG 5.6-6.9
impaired OGTT - 7.8-11.0
glycated haemoglobin
covalent modification of haemoglobin
random event where heamoglobin is covalently modified with a haemoglobin
increased event with raised blood glucose
long term measure of blood glucose control as opposed to a snapshot
<6% normal
6-6.4% pre diabetes
>6.5% diabetes
<7% good control
>8% poor control
TYPE 1 DM
absolute insulin deficiency
auto immune destruction of beta cells
usually juvenile onset
not associated with obesity
type 2 diabetes
most cases of adult cases
relative insulin deficiency
peripheral resistance to normal insulin levels
subsequent progressive decreased in beta cell function
many become insulin dependant over time
strongly associated with obesity
genetic of DM
both types are caused by a mix of genetic and environmental factors
but the genetic causes differ
diabetes rates
rising globally population growth population aging increasing age specific rates of diabetes due to obesity higher in men
acute complications of diabetes
diabetic ketoacidosis - insufficient or absent insulin in IDDM, fats are used for energy they produce acetyl CoA, ketones which are strong acids - osmotic pull leads to low pH and dehydration
life threatening hyperosmolar state
treatment of acute diabetic ketaacidosis
check potassium
if less than 5, they need potassium
delay insulin if less than 3.3
then give insulin
causes of acute diabetic ketaacidosis
poor therapeutic adherence
new diagnosis
infection
complications of chronic diabetess
vascular disease
microvascular - increases CVS risk, hypertensive, heart attack, stroke
75% diabetes death due to cardiovascular event
microvascular - diabetic retinopathy, increases vascular permeability and neovacularisation, new blood vessels prone to bleeding causing haemorrhages and lipid exudates
blindness in diabetes
commonest cause of working age blindness - diabetic retinopathy
cataracts, blindness
kidney chronic complications in diabetes
diabetic nephropathy
glomerular disease
decreased GFR and albuminuria
may go on to need dialysis and renal transplant
diabetic foot
common and costly
ulcers, gangrene, amputation
increase risk of amputation risk
cause of diabetic foot
neuropathy - loss of feeling
motor neuropathy - foot dephormaties
lead to neuropathic ulcers
PVD - ischaemic ulcers in peripheral vascular disease
immunosuppression leading to infections
autonomic neuropathy
CVS - postural hypotension, arrythmias, sudden death
erectile dysfunction, abnormal sweating, gut motility problems
treating type 1 diabetes
insulin discovered 1921
recombinant human insulin introduced in the 80s
aim of therapy - maintain normoglycemia to prevent complications
treatment of type 1 diabetes
recapitulate physiological pattern of pancreatic insulin secretion
administration of insulin
peptide - destroyed in the gut
administered subcutaneously, or IV in emergency
injection sites must be rotated to prevent scarring which reduces scarring which may affect absorbtion
pharmacokinetics of insulin
absorption affected by formulation, blood flow, scars
short lived effects - short half life
enzymatically inactivated in cells after uptake
types of insulin
ultra rapid acting short acting intermediate acting long acting mixtures
regular/neutral insulin
short acting
30-60 minutes
1-2 hour peak
ultra rapid acting
aspart, lispro, glulisine
15 minute onset
30-60 minute peak
long acting insulin
glargine determir degludec 1-2 onset flat peak
mimicking normal insulin levels
- constant basal insulin production and post prandial insulin surges
basal bolus injection - long acting insulin at bedtime
prandial rapid acting insulin - bolus
4 or more injections per day
superior control, especially analogues
insulin pump
basal infusion and patient activated bolus
intensive insulin therapy
decreased complication rates
reduced injury to GFR and eye disease
intensive insulin therapy problems
increase in hypoglycaemic events, especially with multiple injections
fear of hypoglycaemia
lack of hypoglycaemia awareness in autonomic neuropathy patients
artificial pancreas system
closed loop system
continuous glucose monitoring
delivery of insulin and glucose
decrease in hypo and hyperglycaemia
adjunct T1D therapies
therapeutic adherence for intensive insulin therapy is poor
sotagliflozin - SGLT1/2 inhibitor
decrease glucose absorption in the gut, decrease renal glucose absorption
decrease in hypoglycaemia and creates weightloss
increase in diabetic ketoacidosis events
side effects of inulin ttherapy
hypoglycaemia - increased with intensive insulin therapy - IM/IV glucagon
weight gain
injection site problem - scarring, lipohypertrophy, lipoatrophy leads to poor absorption
