T1 L14 Drug treatment of T2DM Flashcards
What are the major target tissues affected by insulin?
Liver
Adipose
Skeletal muscle
What are the effects of insulin on hepatic cells?
Decrease gluconeogenesis
Decrease glycogenolysis
Decrease ketogenesis
Increase glycogen synthesis
What are the effects of insulin on muscle cells?
Increases GLUT-4 translocation to the membrane which increases glucose uptake Increase glucose oxidation Increase glycogen synthesis Increase amino acid uptake Increase amino acid release
What are the effects of adipocytes on muscle cells?
Increase glucose uptake
Increase triglyceride synthesis
Decrease free fatty acid and glycerol release
What is the overall effect of insulin?
Hypoglycaemia
Increase fuel storage in muscle, fat tissue and liver
What does T2DM treatment target?
Insulin resistance Renal glucose absorption Beta-cell dysfunction Loss of beta-cell mass Obesity and dyslipidaemia
What drugs target insulin resistance?
Metformin
What drugs target renal glucose absorption?
SGLT2 inhibitors
What drugs target beta-cell dysfunction?
Sulfonylureas
- GLP-1 analogues
- DDP-4 inhibitors
What drugs target the loss of B-cell mass?
Insulin replacement
Give examples of sulfonylureas
Gliclazide
Glipzide
Glimepride
Describe the mechanism of insulin secretion
1) Glucose is picked up by GLUT2
2) Glucose is metabolised to produce ATP
3) ATP inhibits the ATP-sensitive K+ channels
4) Closes K+ channels
5) K+ builds up inside beta cell
6) Depolarises cell
7) Calcium channels open
8) Calcium moves into beta cells
9) Insulin secretion is dependent on these calcium ions
What are the primary mechanisms of sulfonylureas?
Stimulates endogenous insulin release
Binds to site on ATP-sensitive K+ channels to inhibit the opening of the channel in a similar way to ATP
What are the secondary mechanisms of sulfonylureas?
Sensitise beta cells to glucose
Decrease lipolysis
Decrease clearance of insulin by the liver
What is the ideal patient to give sulfonylureas to?
Over 40 years old
DM duration < 10 years
Daily insulin intake ≤40 units
Why can’t sulfonylureas be used in type 1 diabetes?
In type 1 diabetes the beta cells aren’t present so insulin secretion can’t occur
What is the major side effect of sulfonylureas?
Hypoglycaemia
How do biguanides differ from sulfonylureas and meglitinides?
Don’t stimulate insulin release
Don’t cause hypoglycaemia
Increase glucose uptake in muscle
Decrease glucose production in liver
What are the mechanisms of actions of biguanides?
Suppresses hepatic glucose production by gluconeogenesis
AMPK increases expression of nuclear transcription factor SHP
Increases insulin sensitivity
Enhances peripheral glucose uptake
Increases fatty acid oxidation by decreasing insulin-induced suppression of fatty acid oxidation
Decrease glucose absorption from GI tract
What are the properties of metformin?
Orally active Doesn't bind plasma proteins Excreted unchanged in urine Often combined in a single pill with other anti-diabetic medications Also used for PCOS
What are the adverse effects of biguanides?
Metformin produces lactic acidaemia Nausea Abdominal discomfort Diarrhoea Metallic taste Anorexia Vit B12 and folate deficiency
What are the contraindications of metformin?
Hepatic disease
Past history of lactic acidosis
Cardiac failure
Chronic hypoxic lung disease
What do thiazolidinediones do?
Activate peroxisome proliferator-activated receptor gamma
What is PPARy involved in?
Transcription of insulin-responsive genes and in regulation of adipocyte lipid metabolism
