PT11

What is the treatment aims for using insulin to regulate glucose?

Maintain blood glucose levels between 4-9 mmol/l, avoid hypoglycaemia

What type of hormone is insulin?

Ananbolic

How does insulin exsert it effects?

Signals through receptor kinase, phosphorylation of residues, active PI3 Akt pathway

What does activation of PI3 Akt pathway allow?

Regulation of gene expression, that are involved in metabolism of glucose, Increased expression of GLUT4 transporters on muscle and adipose tissue

How does Akt play a role insulin actions?

Regulating the expression and activity of transcription factors and enzymes

What does insulin stimulate?

Glucose utilisation via glycolysis and glycogenesis

How does insulin affect glucose metabolism?

Upregulates transcription of enzymes in the rate limiting steps of glycolysis, increases glycogenesis by activating glycogen synthase and inactivating glucose synthase kinase , inhibits gluconeogenesis and glycogenolysis

What are Sulfonylureas use in T2DM?

Insulin secretagogues, stimulate insulin secretion

What is the difference between the 1st and 2nd gen Sulfonylureas?

Same MOA more potent due to changes in absorption and metabolism

Sulfonylureas MOA?

Forcefully close potassium channels no matter ATP state of the cell leading to B cell depolarisation and causing calcium vesicles containing insulin to fuse with the cell membrane releasing insulin

What are the potential adverse effects of Sulfonylureas?

Hypoglycaemia, weight gain, secondary pancreatic B cell failure, hepatic/renal failure, cross placenta

Examples of Sulfonylureas?

Gliclazide, glipizide

Why are megiltanides used in T2DM?

Insulin secretagogues

What is the MOA of Meglitanides?

Same as sulfonylureas but more rapidly absorbed so faster onset of action

What is the only available biguanide?

Metformin

Metformin MOA?

Insulin sensitising, decrease hepatic glucose production by inhibiting gluconeogenesis, inhibition of mitochondrial respiratory chain 1, targets AMPK

How metformin taken into the hepatocytes?

OCT1 transporter

What are the benefits of metformin?

Lack of weight gain, no increase of plasma insulin and therefore hypoglycaemia, persistent efficacy, positive changes in lipid profile, reduction in BP, delay of moving to insulin injections

Adverse effects of metformin?

GI tract effects, metallic taste, lactic acidosis, interactions with other drugs that are excreted by the kidneys

Why can lactic acidosis with metformin occur?

Excessive lactate production due to mitochondrial respiratory chain complex especially when coupled with impaired hepatic metabolism