Pharmacology of Insulin

Question 1

Describe the actions of insulin

Answer 1

• Increase glucose transport into adipose tissue and skeletal muscle
• Increase glycogenesis and decrease glycogenolysis in liver and muscle
• Increase lipogenesis and decrease lipolysis in adipose tissue
• Decrease ketogenesis in liver
• Increase amino acid uptake and protein synthesis in liver, muscle and adipose tissue
• Decrease proteolysis in liver, muscle and adipose tissue

Question 2

Describe the mechanism of action of insulin

Answer 2

• Insulin binds to target cells through insulin receptor (tyrosine kinase)
• Stimulates insertion of glucose transporter (GLUT-4) onto target cell membrane of skeletal muscle or adipose tissue
• Glucose moves from plasma inside the cell
• When insulin binds to liver, stimulates glycogen synthesis

Question 3

Describe the actions of glucagon

Answer 3

• Increase glycogenolysis and decrease glycogenesis in liver
• Increase gluconeogenesis in liver (synthesize glucose from amino acids)
• Increase ketogenesis in liver
• Increase lipolysis in adipose tissue
• Stimulated in high amino acid in starvation - digestion of muscle

Question 4

Describe the mechanism of action of glucagon

Answer 4

• Glucagon binds to GPCR receptors which activate adenylyl cyclase
• Increases cyclic AMP which activates protein kinase A
• Phosphorylates and thereby activates important enzymes in target cells

Question 5

State the main categories of insulin analogues

Answer 5

• Ultrafast acting
• Rapid acting
• Short acting
• Intermediate acting
• Long acting/very long acting

Question 6

Describe the action of ultrafast acting insulin analogue

Answer 6

• Mimics normal insulin response after eating

- Eg. Aspart

Question 7

Describe the action of rapid acting insulin analogue

Answer 7

• Rapid onset of action 5 to 15 minutes
• Inject just before eating
• Peaks at 60 min and lasts 4-6 hours
• Eg. Humalog, Novorapid, Apidra

Question 8

Describe the action of short-acting insulin analogue

Answer 8

• Starts to work 30-60 minutes after injection
• Need to inject at least 15-30 minutes before eating several times daily to cover meals
• Peaks at 2-3 hours and lasts 8-10 hours
• Eg. Actrapid, Humulin S, Hypurin Bovine and Porcine Neutral

Question 9

Describe the action of intermediate acting insulin analogue

Answer 9

• Slower onset 2-4 hours
• Peaks 4-8 hours and lasts 12 -20 hours - covers in-between meals and through night
• Eg. Insulatard, Humulin I, Hypurin Bovine and Porcine Isophane

Question 10

Describe the action of long acting insulin analogue

Answer 10

• Slow onset 2-6 hours
• Duration up to 24 hours for long acting and 50+ hours for very long acting
• Eg. Glargine, Detemir, Degludec

Question 11

Describe possible insulin regimes for type 1 diabetics

Answer 11

• 4 injections - 3 rapid acting after each meal and 1 intermediate/long acting
• 2 injections - 2 intermediate/long acting
• 1 injection - 1 long acting
• Regime depends on possibility of complications - a patient suffering from multiple macrovascular complications may have more injections

Question 12

Describe how insulin pump therapy is used

Answer 12

• Constant stream of rapid acting insulin when button is pressed
  
  • Used for type 1 diabetes after meals and when glucose levels high
• Sensor augmented pump therapy with threshold suspend
  
  • Monitors glucose level in tissue and can switch on/off depending on levels

Question 13

What are possible adverse effects of insulin therapy

Answer 13

• Hypoglycaemia
• Hyperglycaemia
• Lipodystrophy - lipohypertrophy (lumps of fat) or lipoatrophy (death of fat cells)
• Painful injections
• Insulin allergies

Question 14

What are the major oral hypoglycaemics used to treat diabetes

Answer 14

• Metformin
• Sulphonylureas
• Acarbose
• Glitazones
• Glucagon like peptide 1
• Gliptins / DPP-4 inhibitors
• Dapagliflozin

Question 15

Describe the mechanism and effects of metformin

Answer 15

• Decreases insulin resistance leading to increased glucose into tissues
• Reduces hepatic gluconeogenesis
• Limits weight gain
• Decreases CVS events

Question 16

List the main side effects of metformin

Answer 16

• GI symptoms
• Lactic acidosis - tiredness, weakness, muscle pain, trouble breathing
• Hypoglycaemia - headache, weakness, confusion
• Side effects more common in patients with organ failure - avoid giving to these patients
• Stop if severe CKD

Question 17

Describe the action of sulphonylureas

Answer 17

• Makes KATP more sensitive to ATP, so more insulin released
• Eg. Gliclazide most used

Question 18

What are the main side effects of sulphonylureas

Answer 18

• Weight gain
• Hypoglycaemia - confusion, sweating, headache, dizziness
• Hunger

Question 19

Describe the mechanism of action of acarbose

Answer 19

• α glucoside inhibition
• Inhibits breakdown of carbohydrates to glucose by blocking action of the enzyme α glucoside in gut
• Decreased breakdown means less glucose absorbed

Question 20

What are the main side effects of acarbose

Answer 20

• Flatulence
• Loose stools
• Diarrhoea
• Stomach pain
• Constipation

Question 21

Describe the mechanism of action of glitazones

Answer 21

• Increase insulin sensitivity in muscle and adipose tissue and decrease hepatic gluconeogenesis
• Bind to and activate one or more peroxisome proliferator-activated receptors (PPARs)

Question 22

What are the main side effects of glitazones

Answer 22

• Weight gain
• Fluid retention and heart failure
• Effects on bone metabolism
• Bladder cancer

Question 23

Describe the mechanism of action of glucagon like peptide 1

Answer 23

• Increase insulin secretion from beta cells
• Decreases production of glucagon from alpha cells
• Decrease food intake through increased satiety - can help weight loss
• Decrease gastric emptying

Question 24

What are the main side effects of glucagon like peptide 1

Answer 24

• Nausea
• GI symptoms - loose stools, diarrhoea
• Gastro oesophageal reflux
• Low risk of hypoglycaemia
• Not given to CKD patients

Question 25

Describe the mechanism of action of gliptins or DPP-4 inhibitors

Answer 25

• Inhibits DPP-4 activity increasing postprandial (after meal) active GLP-1 concentrations
• Not as effective as giving GLP-1

Question 26

What are the main side effects of gliptins

Answer 26

• GI symptoms
• Pancreatitis
• Low risk of hypoglycaemia

Question 27

Describe the mechanism of action of Dapagliflozin

Answer 27

Blocks glucose reabsorption in proximal convoluted tubule (SGLT2 inhibitors)

Question 28

What are the main side effects of Dapagliflozin

Answer 28

• Increased risk of lower urinary tract symptoms - genital and UTI
• Polyuria - osmotic diuresis (less sodium reabsorbed in PCT)
• Hypoglycaemia

Question 29

Describe the management of type 1 diabetes

Answer 29

• Non-pharmacological - increase exercise, reduce glucose diet, reduce weight
• Subcutaneous insulin injections - life long

Question 30

Describe the stepwise management of type 2 diabetes

Answer 30

• Non-pharmacological - increase exercise, reduce glucose diet, reduce weight
• Initial treatment
  
  • Metformin
• First intensification
  
  • Dual therapy with metformin and:
    
    • DPP-4, pioglitazone, sulphonylurea, glifoxins
• Second intensification
  
  • Triple therapy with metformin, sulphonylurea and:
    
    • DPP-4, pioglitazone +/- glifoxins
  • Consider insulin therapy
• Give hypertensive drugs if applicable - calcium channel blockers, ACE inhibitors