diabetes

Question 1

What is the primary mechanism of action of metformin?

Answer 1

• Activates AMPK in hepatocyte mitochondria
• Inhibits ATP production
  
  • Blocks gluconeogenesis and subsequent glucose output
  • Also blocks adenylate cyclase which promotes fat oxidation
• Both help to restore insulin sensitivity

Question 2

What is the target of metformin?

Answer 2

5′-AMP-activated protein kinase (AMPK) in hepatocyte mitochondria

Question 3

What are the main side effects of metformin?

Answer 3

• GI side effects (20-30% of patients):
  
  • abdominal pain
  • decreased appetite
  • diarrhoea
  • vomiting
• Evident when v high doses given- slow increase in dose may improve tolerability

Question 4

Why can metformin accumulate in the liver (therapeutic effect) and GI tract (side effect)?

Answer 4

Metformin is highly polar and requires organic cation transporter (OCT-1) to access tissues

Question 5

Where is metformin most effective?

Answer 5

It is most effective in the presence of endogenous insulin (so when there’s residual functioning pancreatic islet cells)

Question 6

What drugs are given for diabetes?

Answer 6

• Metformin
• Dipeptidyl-peptidase 4 (DPP-4) inhibitor
• Sulphonylurea
• Sodium-glucose co-transporter (SGLT2) inhibitors

Question 7

Give an example of a DPP-4 inhibitor

Answer 7

Sitagliptin

Question 8

What is the primary mechanism of action of DPP-4 inhibitors?

Answer 8

• Inhibits action of DPP-4 which is present in vascular endothelium and can metabolise incretins in plasma
• Incretins (e.g. GLP-1) are secreted by enteroendocrine cells and help stimulate insulin production after eating & reduce glucagon production by liver when not needed e.g. during digestion
• Incretins also slow down digestion and decrease appetite

Question 9

What is the target of DPP-4 inhibitors?

Answer 9

DPP-4 in vascular endothelium

Question 10

What are the main side effects of DPP-4 inhibitors?

Answer 10

• Upper resp tract infections
• Flu-like symptoms e.g.
  
  • Headache
  • Runny nose
  • Sore throat
• Less common but serious allergic reactions
• Avoid in patients with pancreatitis

Question 11

Do DPP-4 inhibitors cause weight gain?

Answer 11

No

Question 12

When and how are DPP-4 inhibitors taken?

Answer 12

Orally, before or after meals.

These drugs act mainly by augmenting insulin secretion and so are only effective when there’s some residual pancreatic beta cell activity present.

Question 13

Give an example of a sulphonylurea

Answer 13

Gliclazide

Question 14

What is a primary mechanism of action of sulphonylurea?

Answer 14

• Inhibit ATP-sensitive K channel (KATP) on pancreatic beta cell
• This channel controls beta cell membrane potential
• Inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis

Question 15

What is the target of sulphonylurea?

Answer 15

ATP-sensitive K channel on pancreatic beta cell

Question 16

What are the main side effects of sulphonylurea?

Answer 16

• Weight gain is likely
• Hypoglycaemia (2nd most common)

Question 17

When are sulphonylureas taken?

Answer 17

With or shortly after a meal.

These drugs act by augmenting insulin secretion and so are only effective when there’s residual pancreatic beta cell activity.

Question 18

How can weight gain from sulphonylurea be mitigated?

Answer 18

Weight gain is mitigated by also giving metformin

Question 19

What should patients be informed about before taking sulphonylurea?

Answer 19

Patients should be informed about hypoglycaemia risk, especially if they are on other glucose-lowering drugs

Question 20

Give an example of a sodium-glucose co-transporter (SGLT2) inhibitor

Answer 20

Dapaglifozin

Question 21

What is the primary mechanism of action of a SGLT2 inhibitor?

Answer 21

Reversibly inhibits SGLT2 in renal PCT to reduce glucose reabsorption and increase urinary glucose excretion

Question 22

What is the target of SGLT2 inhibitors?

Answer 22

SGLT2 in PCT

Question 23

What are the main side effects of SGLT-2 inhibitors?

Answer 23

• Urogenital infections due to increased glucose load (5% of patient)
• Slight decrease in bone formation
• Can worsen DKA (stop immediately)

Question 24

What are some less common side effects of SGLT-2 inhibitors?

Answer 24

Weight loss and reduction in BP

Question 25

Why are SGLT2 inhibitors less effective in renal impairment patients?

Answer 25

Drug action depends on normal renal function so are less effective in renal impairment patients.