CVD WK3 pharmacology of type ii diabetes 2

Which two classes of antidiabetic drugs affect cellular energy metabolism?

Biguanides (metformin) and PPARγ agonists (pioglitazone)

Do metformin and PPARγ agonists increase insulin secretion?

No - they do NOT increase insulin secretion

Do metformin and PPARγ agonists require functioning β-cells?

No - they work on cellular energy metabolism

What is metformin's mechanism of action?

Activates AMPK by inhibiting mitochondrial complex I → inhibits gluconeogenesis, increases glucose uptake, improves insulin sensitivity

What is the primary target of metformin?

Mitochondrial complex I of the respiratory chain

What does metformin do to the AMP:ATP ratio?

Increases it (more AMP, less ATP)

What does AMPK stand for?

AMP-activated protein kinase

What does AMPK do?

Inhibits gluconeogenesis, increases glucose uptake, increases insulin receptor function, inhibits lipid synthesis, increases GLP-1 secretion

What is the effect of metformin on gluconeogenesis?

Inhibits gluconeogenesis (reduces liver glucose production)

What is the effect of metformin on peripheral glucose uptake?

Increases glucose uptake in skeletal muscle and adipose tissue

What is the effect of metformin on insulin sensitivity?

Improves insulin sensitivity

What is the effect of metformin on carbohydrate absorption?

Reduces carbohydrate absorption from the GIT

What is the effect of metformin on lipid synthesis?

Decreases lipid synthesis (reduces LDLs and VLDLs)

Does metformin cause hypoglycaemia?

No - it does NOT cause hypoglycaemia

Does metformin cause weight gain?

No - it is weight-neutral or causes mild weight loss

What is the first-line drug for Type 2 diabetes?

Metformin

What is the mechanism of PPARγ agonists (e.g., pioglitazone)?

Bind to PPARγ nuclear receptor → regulate genes for fatty acid storage and glucose metabolism → increase insulin sensitivity

What type of receptor is PPARγ?

Nuclear receptor (transcription factor)

Where is PPARγ mainly found?

Adipose tissue (also liver and skeletal muscle)

What are the endogenous ligands for PPARγ?

Lipids (e.g., fatty acids)

What does PPARγ do when activated?

Together with RXR, it regulates transcription of genes involved in fatty acid storage and glucose metabolism

What are the effects of PPARγ agonists?

Increase insulin sensitivity, reduce hepatic glucose production, increase glucose uptake in muscle and fat

What are the side effects of pioglitazone?

Weight gain, fluid retention (oedema), increased risk of heart failure

Which PPARγ agonist was withdrawn?

Rosiglitazone (increased risk of myocardial infarction)

What is the difference between metformin and pioglitazone for weight?

Metformin = weight-neutral/loss. Pioglitazone = weight gain

What is the difference between metformin and pioglitazone for hypoglycaemia?

Neither causes hypoglycaemia

What is the role of cAMP in metformin's mechanism?

Decreased ATP → decreased cAMP (glucagon second messenger) → further decrease in gluconeogenesis

What is the effect of metformin on GLP-1 secretion?

Increases GLP-1 secretion from the GIT

What is the effect of metformin on fat oxidation?

Increases fat oxidation

What is the effect of metformin on transcription of gluconeogenesis genes?

Decreases transcription of genes for gluconeogenesis

What is lactic acidosis?

A rare but serious side effect of metformin, especially in renal impairment