Lec14 Drug treatment of Type 2 DM Flashcards
On which pathways does insulin have its effects on?
Insulin affects all major metabolic pathways:
Carbohydrate
Fat
Protein
What are the main target tissues of insulin?
Liver
Adipose Tissue
Muscle
What effect does insulin have on hepatic cells?
Insulin causes decrease in gluconeogenesis, glycogenolysis and ketogenesis
What effect does insulin have on muscle cells?
Increases GLUT4 translocation to the membrane and hence increase glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake, protein synthesis
Decreases glycogenolysis and proteolysis
What effect does insulin have on adipocytes?
Increase glucose uptake, increase triglyceride synthesis
Decrease FFA and glycerol release
What is the net effect on insulin?
To cause hypoglycaemia and increase fuel storage in muscle, fat tissue and liver
What factors contribute to hyperglycaemia that can be targeted with drugs?
Beta cell dysfunction
Insulin resistance
Loss of beta cell mass
Renal glucose absorption
What drug targets beta cell dysfunction?
Sulfonylureas - cause endogenous insulin release
e.g. Gliclazide
Glucagon Like Peptide 1 analogs (GLP1 analogs)
Dipeptidyl peptidase 4 inhibitors (DDP4 inhibitors)
What is the mechanism of action in sulfonylureas?
Sulfonylureas enter Beta cells via Glut2 receptors
They inhibit ATP sensitive K channels causing them to close
K builds up inside the cell causing the voltage inside the cell to become positive
Voltage dependent channels open - calcium enters
Vesicles containing insulin are released from beta cell by exocytosis
What are the therapeutic uses of sulfonylureas?
The only drug to stimulate endogenous insulin release
Best pt to use in:
over 40 years old (but also can give to under 40)
DM duration less that 10 years
Daily insulin if taking is less than 40 units
What is the major side effect of sulfonylureas?
Hypoglycaemia
Name 3 sulfonylureas?
Gliclazide
Glipizide
Glimepiride
Which class of drugs increases insulin sensitivity?
Biguanides - Metformin
Thiazolidinediones (TZDs) - Pioglitazone
How do biguanides work?
By increasing glucose uptake in muscle and decrease glucose production in the liver
What is an advantage of metformin?
It does not cause hypoglycaemia
What is the mechanism of action in biguanides?
Suppression of gluconeogenesis
Increases insulin sensitivity - improved insulin binding to insulin receptors
Increases peripheral glucose uptake
Increases fatty acid oxidation
Decreases glucose absorption from the GI tracts
Explain the mechanisms of action in further detail
Suppression of gluconeogenesis through AMP activated protein kinase (AMPK) dependent and independent pathways
Increases insulin sensitivity - improved insulin binding to insulin receptors
AMP is a second messenger for insulin
Metformin directly activates the AMPK pathway in hepatocytes
Increase of peripheral glucose uptake:
Increased GLUT4 translocation through AMPK - so skeletal muscle and adipose tissue is forced to use glucose and not FFA and other sources of energy
Metabolically changes the heart through p38 MAPCK and PKCdependent mechanisms to preferentially use glucose
Increases fatty acid oxidation
Decreases glucose absorption from the GI tracts - excites GI bacteria - may cause tummy upsets
What other disease is metformin used to treat?
Polycystic Ovarian Syndrome
Properties of metformin:
Orally active
Half life 1.5-4.5h
Does not bind plasma proteins - affects the genomic levels in hepatocytes
Decreased expression of the enzymes so the drug doesn’t need to be there all the time - can go a couple of days without
List the adverse effects of metformin:
Lactic acidaemia (esp in pts with renal impairment)
Nausea, abdominal discomfort, diarrhoea, metallic taste, anorexia
Vit b12 and folate malabsorption with chronic use of metformin
MI or septicaemia
Contraindications of metformin
Hepatic disease
PHx of lactic acidaemia - or renal impairment
Cardiac failure
Chronic hypoxic lung disease - causes metabolic acidosis
What other class of drugs increase insulin sensitivity?
Thiazolidinediones - Pioglitazone only one still approved for use
How do thiazolidinediones work?
They activate the peroxisome proliferator activated gamma receptors (PPAR-gamma) which are involved in transcription of insulin responsive genes and in regulation of adipocyte lipid metabolism
What effect do thiazolidinediones have?
In the presence of endogenous or exogenous insulin, glitazones will:
Increase glucose uptake and utilisation in skeletal muscle
Decrease hepatic gluconeogenesis, glycogenolysis and triglyceride production in the liver
Increase glucose uptake in adipose tissue and decrease FFA metabolism
What is a disadvantage of this drug?
It causes pts to put on weight
Diabetics are already overweight which is part of the problem
What are the adverse effects of glitazones?
Fluid retention - causing oedema, mild anaemia
Dose related weight gain
Safety in pregnancy and lactation not determined
Can cause liver damage as it is metabolism by the liver - needs frequent tests
Interactions of pioglitazone:
May lower the oral contraceptive levels containing ethinyl oestrodiol and norethindrone
GLP1 analogs are:
Newer drugs
Designed to have fewer side effects
Name a DLP1 analog
Exenatide
How is exenatide administered?
Injected
Subcutaneously 30-60 mins before last meal of the day because it is a peptide and can be broken down in the GI tract
How do DLP1 analogs like Exenatide work?
Augment the pancreas response - increase glucose dependent insulin secretion
Suppresses pancreatic release of glucagon to stop liver overproducing glucose
Slows down gastric emptying
Reduces appetite and promotes satiety
Reduces liver fat content
Side effects of DLP1 analogs e.g. exenatide
GI effects e.g. acid, sour stomach, belching, diarrhoea, heartburn etc.
What are Dipeptidyl Peptidase 4 (DPP4) inhibitors?
They are a class of drugs which increase insulin sensitivity
How do DPP4 inhibitors work?
By inhibiting break down of incretins like GLP1 and GIP
What is the effect of having increased incretins?
They suppress glucagon release from pancreas which stops liver overproducing glucose
Increased glucose-induced insulin secretion
Improved peripheral glucose utilisation
Reduce gastric emptying
Increases satiety
Give examples of DPP4 inhibitors
Vildagliptin (reversible)
Sitagliptin (reversible)
Saxagliptin (covalently bound)
What are the side effects of DPP4 inhibitors
Few side effects
Weight neutral no GI side effects
Cancer risk? - because DPP4 known to function as a tumour suppressor
no studies have shown it increases risk of cancer
What factor contributing to hyperglycaemia do SGLT 2 inhibitors act on
Renal glucose absorption
How do Sodium glucose transporter 2 inhibitors work?
100% Glucose has to reabsorbed in the kidney tubule
By inhibiting the sodium glucose transporter, glucose is excreted by the kidneys
Give examples of SGLT2 inhibitors
Dapagliflozin
Canagliflozin
Side effects of SGLT2 inhibitors
Rapid weight loss because you are peeing out the glucose
Tiredness
Osmotic diuretic so dehydration
Can worsen UTIs and thrush but generally doesn’t
