Pharmacological Management

Question 1

How is insulin secreted?

Answer 1

GLUT 2 transporter in B cells regulates glucose

Increase plasma glucose > trafficked into B cell > increase glucose kinase activity > increase ATP > inhibits K+ ATP efflux channels

K+ trapped in B cell depolarising it > activates VG Ca channels = influx

Triggers cytoplasmic granules containing insulin to fuse with B cell membrane > contents exocytosed

Question 2

How is insulin’s receptor activated?

Answer 2

Insulin binding = auto-phosphorylation of receptor = phosphorylation of insulin receptor substrate that act to reduce glucose by increased cellular uptake, utilisation + conversion to glycogen for storage

Question 3

What are the effects of insulin?

Answer 3

• Blocks ketogenesis, proteolysis, glycogenolysis, gluconeogenesis, lipolysis
• Causes glycolysis, glucose uptake, glycogen synthesis, K+ uptake, protein synthesis

Question 4

What is haemoglobin glycation?

Answer 4

• Glycation = uncontrolled CHO reactions
• More glucose = increased chance pathological glycation
• Haemoglobin glycation = advances glycation end-products = oxidative damage
• HbA1c levels = standard measure for protein glycation

Question 5

What are the fasting plasma glucose ranges?

Answer 5

< 4 = hypoglycaemia

> 6.9 = hyperglycaemia

Question 6

What happens to glucose following digestion of a meal?

Answer 6

• Glucose levels rise along with incretin levels
• Incretins = highly regulated by DPP-IV enzymes to help moderate rate at which plasma glucose levels decrease
• B cells directly sense glucose levels + incretins = insulin secretion
• Insulin increases glucose uptake through GLUT 4
• Switches off gluconeogenesis BUT ACTIVATES glycogen synthesis in Liver

Question 7

What are biguanides?

Answer 7

e. g. Metformin
- Orally administered hypoglycaemic drug
- First line for T2D
- Potentiates insulin effects but only works if some level of endogenous insulin production form B cell

Question 8

What is the MOA of biguanides?

Answer 8

• In Liver drugs causes decrease in ATP = increase in AMP
• Triggers increased AMP protein kinase activity =
  1. Switches off transcription factors involved in gluconeogenesis
  2. Switches off glycerol-3-P-DH (= increase NADH + lactate = decrease in gluconeogenesis)

Question 9

What are sulfonylureas?

Answer 9

e. g. Gliclazide
- Orally administered hypoglycaemic drug
- May cause weight gain

Question 10

What is the MOA of sulfonylureas?

Answer 10

• Binds suflonylurea receptor on K+ ATP channel blocking K+ efflux
• B cell depolarises = opening VG Ca channels = Ca influx = enhanced insulin granule release

Question 11

What are gliptins?

Answer 11

e. g. Saxagliptin
- Orally administered hypoglycaemic drug
- Considered if biguanide + sulfonylurea not effective

Question 12

What is the MOA of gliptins?

Answer 12

• Target mechanisms that control incretin activity
• Incretin control mediated by DPP-IV
• Gliptins inhibit DPP-IV so GLP-1 has extended effect on insulin secretion

Question 13

What are incretin mimetics?

Answer 13

e. g. Exenatide
- s.c. injection
- used with biguanide + sulfonylurea to increase insulin sensitivity

Question 14

What is the MOA of incretin mimetics?

Answer 14

• Activated GLP-1 receptor
  1. Enhances insulin secretion
  2. Suppresses glucagon secretion
  3. Slows gastric emptying

Question 15

What are glifozins (SLGT-2 inhibitors)?

Answer 15

• Orally administered
• Used to decrease risk of cardiac failure to T2D
• Increased risk UTI
• Can cause DKA

Question 16

What is the MOA of glifozins?

Answer 16

• Inhibition of Na/glucose symporter in nephron
  = enhances excretion of glucose in urine to reduce plasma [glucose]
• Specificity for SLGT-2 symporter