insulin and other hypoglycaemic agents Flashcards
Why is it necessary to have rigid blood glucose control?
- obligatory energy source for the brain
- tightly regulated to keep blood glucose levels within normal range
What are the main glucose regulating hormones?
Insulin - β / B cells
Glucagon - α / A cells
Somatostatin - D cells
What are some supplementary hormones that regulate glucose?
adrenalin - adrenal medulla
glucocorticoids - adrenal cortex
growth hormone - pituitary
How is insulin formed?
Proteolytically cleaved –> mature insulin and C-peptide
What stimulates insulin release?
increase glucose - hyperglycaemia
amino acid and fatty acids
peptide gut hormones - incretins - GLP1
What are the main areas that insulin targets?
liver, muscle and adipose tissue
What are the metabolic targets of insulin?
- CHO
- Fat
- Protein
What is the insulin receptor (Ins-R)?
receptor tyrosine kinase (RTK)
What happens when insulin binds to Ins-R?
dimerisation and auto-phosphorylation
What substrate does Ins-R phosphorylates?
IRS-1
what does phosphorylated IRS-1 activate?
PI3K and Ras-MAPK pathway
What does the PI3K and AKT pathway activate?
- GLUT4 transporter –> glucose into cells
- glycogen synthase
- cell growth
What is Diabetes Mellitus?
metabolic disorders characterised by HYPERGLYCAEMIA
What is chronic metabolic disorders caused by?
relative or absolute insulin deficiency
What is type 1 diabetes?
ABSOLUTE insulin deficiency
auto-immune destruction of β cells
What is type 2 diabetes?
RELATIVE insulin deficiency
peripheral resistance to ‘normal’ insulin levels
subsequent progressive decrease in β cell function/mass
What are some complications of diabetes?
acute
chronic
What are some acute complications of diabetes?
diabetic ketoacidosis (DKA) insufficient/absent insulin in IDDM
What does insufficient/absent insulin in IDDM cause?
fats used for energy = ketones (strong acids)
decrease pH
dehydration
What are the chronic complications of diabetes?
macrovascular –> cardiovascular risk
microvascular –> huge burden/costs
What are ways of treating type 1 diabetes?
recapitulate normal pattern of pancreatic insulin secretion - insulin, lifestyle and monitoring
How is insulin administered?
subcutaneously
injection sites must be rotated
What is the pharmacokinetics of insulin?
absorption affected by formulation, blood flow, scars
short-lived effects
enzymatically inactivated in cells after uptake
What are ways to mimic normal insulin levels?
ideal
basal-bolus regimen
insulin pump
What is ideal mimicking technique?
constant basal insulin production
+ post-prandial insulin surges
What is the basal-bolus regimen?
long acting insulin at bedtime = basal
prandial rapid-acting insulin = bolus
4 or more injections/day
What is the insulin pump technique?
basal infusion + patient-activated boluses
improved glycaemic control
What are some side-effects of insulin therapy for diabetes type 1?
hypoglycaemia
weight gain
injection site
What is the main goal of treatment of type 2 diabetes?
lower blood glucose levels –> prevents microvascular complications
individualised treatments
What are the treatments for type 2 diabetes?
lifestyle
oral hypoglycaemic agents
insulin
What are some hypoglycaemic drugs?
metformin sulfonylureas incretin-based therapies dapagliflozin (SGLT2 inhibitor) acarbose (intestinal α-glucosidase inhibitor) pioglitazone (thiazolidinediones)
What is the mechanism of metformin?
mainly decrease hepatic gluconeogenesis
may cause GLP1 release
What are the effects/benefits of metformin?
no hypoglycaemia
improved lipid profile
probable anti-cancer properties
What is the pharmacokinetics of metformin?
40-60% orally bioavailable excreted unchanged in urine
decrease drug clearance with other renally excreted drugs
What are some side-effects/caution of metformin?
GI - transient anorexia + diarrhoea
vitamin B12 deficiency
lactic acidosis
C/I in severe renal failure + severe hepatic impairment
What is the mechanism of sulfonylureas?
insulin secretagogues
What is the mechanism of insulin secretagogues?
block SU receptor (SUR1) / K+ channel on β cells –> Ca2+ influx activates insulin secretion
What is the pharmacokinetics of sulfonylureas?
albumin binding, hepatic metabolism, renal excretion
drug interactions –> increase hypoglycaemic effect
What is the benefits of sulfonylureas?
robust glucose decrease in early stages of type 2 diabetes
cheap and effective
What are some side-effects/cautions of sulfonylureas?
hypoglycaemia
weight gain
C/I in liver failure - hepatic metabolism
What is the incretin effect?
oral glucose induces a much greater insulin response than an equivalent IV glucose dose
What are incretins?
gut peptides that increase insulin release after food
What are some incretin-based therapies?
GLP1 receptor agonists
DDP-4 inhibitors
GIP receptor agonist
Why is DDP-4 inhibitors used?
blocks DDP-4 enzyme which inactivates GLP-1
What is GLP1 used for?
stimulates insulin release
inhibits glucagon release
What does SGLT2 inhibitors use?
inhibit sodium glucose co-transporter 2
block glucose reabsorption in proximal tubule –> lost in urine
S/E = urinary tract infections
What is the use of intestinal α-Glucosidase inhibitors?
competitive inhibition of maltose –> glucose
S/E = bloating, flatuelence, diarrhoea
What is the use of Thiazolidinediones?
PPARγ agonist - activate gene transcription
increase insulin sensitivity
