PT12

Examples of Thiazolidinediones?

rosiglitazone, pioglitazone, troglitazone

How do Thiazolidinediones aid in the treatment of T2DM?

Insulin sensitising, same affect of metformin but different mechanism

Describe Thiazolidinediones MOA?

TZDs are PPAR\\gamma agonists, so regulate insulin responsive genes involved in glucose production, transport and utilisation

What two mechanisms does PPARgamma have?

Transactivation, Transrepression

What do TZDs mainly regulate?

Complex dyslipidaemia, lower triglyceride and total cholesterol via PPRE, allowing upregulation or downregulation of target genes

What are the therapeutic benefits of TZDs?

Increased insulin secretion and sensitivity, decreased plasma glucose, FFA, triglycerides, liver fat, increases insulin HDLs

What are the adverse effects of TZDs?

Minimal hypoglycaemia, weight gain, CYP450 enzymes involved in metabolism

Define incretins?

Hormones that are released in the GI tract after a meal to stimulate glucose-induced release from the pancreas

Examples of incretins?

Glucagon-like peptide (GLP-1), Gastric Inhibitory Polypeptide (GIP)

Describe the role of GLP-1?

Affects biosynthesis and secretion of insulin postprandially, signal satiety to reduce food intake, levels are reduced in T2DM

Where if GLP-1 released from?

Enteroendocrine cells in the intestines when there is food present, in circulation stimulates the release of insulin and inhibits glucagon

What are examples incretin mimetics?

Exenatide (2005) and liraglutide (2006) via SC injection

Why is Exenatide (2005) and liraglutide (2006) used in the treatment of T2DM?

GLP-1 analogues bind to GLP-1 receptors in pancreas stimulating insulin to be secreted, treatment is aimed at overweight T2DM as it slows down stomach emptying

What is the main adverse effect of GLP analogues?

Nausea

Examples of gliptins?

sitagliptin (2007) and vildagliptin (2008)

What are gliptins?

DD-4 inhibitors

What is DDP-4 inhibitors?

Dipeptidyl peptidase 4 enzyme responsible for the rapid break down of GLP1- GIP so they block DD4s increasing plasma GLP-1

What are the benefits of DPP-4 inhibitors?

Enhanced insulin secretion, suppress glucagon secretion and slowed gastic emptying

Example of a-glucosidase inhibitors?

Acarbose

Describe Acarbose’s MOA in T2DM?

Reduces the digestion of complex carbohydrates, reduces post meal glycaemia, acts as a substrate to be metabolised instead of the sugars keeping them large complexes

What are the adverse effects with acarbose?

Flatulence and diarrhoea not well tolerated, effectiveness may depend on diet and lifestyle

What are some of the benefits of acarbose?

Oligosaccharide metabolised in liver by enzymes and bacteria so can be used in poor renal function and liver problems, does not cause hypoglycaemia, hyperinsulinemia or weight gain

Examples of SGLT2 inhibtors?

Canagliflozin, dapagliflozin

Describe SGLT2 inhibitors MOA?

Inhibit Sodium glucose co transporter in renal PCT reduce glucose reabsorption, increase glucose excretion

What is a marker for diabetes?

Glucose in urine, now can be a marker for efficacy of SGLT2 inhibitors

Why is SGLT2 inhibitors used in T2DM?

SGLT2 cotransporter uses gradient for sodium potassium ATPase to create sodium conc gradient, patients with T2DM have increase number of SGLT and GLUT 2 in PCT so glucose uptake is elevated

What are the effects of SGLT2 inhibtors?

Possible risk of UTIs