Drug treatment of type 2 diabetes

Question 1

What is the net effect of insulin?

Answer 1

hypoglycaemia and increases fuel storage in muscle, fat tissue and liver

Question 2

What is the primary and secondary mechanism of action of sulfonylureas?

Answer 2

Primary: stimulates endogenous insulin release,
binds to site on ATP-sensitive K-channel to inhibit its opening, similar to ATP.
Secondary: sensitise ß-cells to glucose, decrease lipolysis, decrease clearance of insulin by liver.

Question 3

What are the therapeutic uses and major side effect of sulfonylureas?

Answer 3

Useful in type-2 DM only, can be used in combination with other anti-diabetic drugs.
Best patient is >40, DM duration <10 yrs, daily insulin < 40 units.
Hypoglycaemia

Question 4

What are biguanide drugs and their effects?

Answer 4

Oral anti-hyperglycaemic agents.

increases glucose uptake in muscle and decrease glucose production by liver.

Question 5

What is the mechanism of action of biguanide drugs?

Answer 5

• Suppression of hepatic glucose production through gluconeogenesis via AMP-activated protein kinase (AMPK) dependent and independent pathways.
• AMPK increases expression of transcription factor SHP which inhibits expression of gluconeogenic genes PEPCK and glucose-6-phosphatase.
• Enhances peripheral glucose uptake via increased GLUT 4 translocation through AMPK.
• Increases insulin sensitivity by improving insulin binding to insulin receptors.
• Increases fatty acid oxidation by decreasing its insulin-induced suppression.
• Decreases glucose absorption from GI tract.

Question 6

What are the properties of metformin?

Answer 6

orally active, doesn’t bind to plasma proteins, excreted unchanged in urine, often combined with other anti-diabetic medications, PCOS.

Question 7

What are the adverse effects and toxicity of biguanides?

Answer 7

metformin -> lactic acidaemia -> rare.
nausea, abdominal discomfort, diarrhoea, metallic taste, anorexia -> common.
decreased vit B12 + folate absorption -> chronic metformin.
MI or septicaemia -> immediate stoppage (associated renal dysfunction).

Question 8

What are the contraindications of metformin?

Answer 8

hepatic disease
past history of lactic acidosis
cardiac failure
chronic hypoxic lung disease causes metabolic acidosis

Question 9

Regarding thiazolidinediones, what is the only remaining glitazone that is approved and which receptors do they activate?

Answer 9

pioglitazone activates PPARy -> enhances effects of insulin

Question 10

What are the pharmacodynamics of glitazone?

Answer 10

In presence of endogenous or exogenous insulin:
liver -> decrease gluconeogenesis, glucose output + triglyceride production
skeletal muscle -> increase glucose uptake + utilisation
adipose tissue -> increase glucose uptake + decrease fatty acid output
differentiation of adipocytes

Question 11

What are the adverse effects and drug interactions of glitazones?

Answer 11

fluid retention -> oedema + mild anaemia
dose-related weight gain
liver damage -> regular blood tests
lower oral contraceptive levels

Question 12

What are the disadvantages of glucagon-like peptide-1 analogs (GLP-1)?

Answer 12

(not exenatide):
Short duration in plasma.
Not resistant to DPP-4 degredation.

Question 13

Give an example of a GLP-1 analog, its route of administration and how it facilitates glucose control?

Answer 13

Exenatide -> s.c. injection 30-60 mins before last meal of day.
Adjuvant therapy
Suppresses pancreatic glucagon release -> stops liver overproducing glucose.
Slows gastric emptying, reduces appetite and promote satiety via hypothalamic receptors.
Reduces liver fat content

Question 14

What are the side effects of exenatide?

Answer 14

GI -> acidic or sour stomach, belching, diarrhoea, heartburn etc.

Question 15

What is a disadvantage of exenatides?

Answer 15

only injectables are available so far

Question 16

What are DPP-4 inhibitors and what is their mechanism of action and effects?

Answer 16

Class of oral hypoglycemic agents.
Increased -> incretins GLP-1 and GIP: inhibits glucagon release, increased insulin secretion, decreased gastric emptying and hepatic glucose production, improved peripheral glucose utilisation.

Question 17

What are the features of DPP-4 inhibitors and give examples?

Answer 17

Vildagliptin, sitagliptin and saxagliptin.

Orally active, few side effects, potential cancer risk?

Question 18

Where are SGLT1 and SGLT2 receptors found and what are the consequences of blocking these receptors?

Answer 18

SGLT1 - small intestine (to absorb glucose) and proximal straight tubule of nephron.
SGLT2 - proximal convoluted tubule.
Elimination of blood glucose through kidney.

Question 19

Give examples of SGLT2 inhibitors and its effects?

Answer 19

Dapagliflozin and canagliflozin.

• Inhibition of Na+- glucose cotransporter -> reversal of hyperglycaemia + glucotoxicity.
• Increased GLUT4 translocation + insulin signalling -> increased insulin sensitivity in muscle
• Reduced glucose-6-phosphatase -> increased insulin sensitivity in liver
• Decreased gluconeogenesis -> decreased Cori cycle + PEP carboxykinase.
• Improved beta cell function

Question 20

What are the side effects of SGLT2 inhibitors?

Answer 20

Rapid weight loss (due to glycosuria)
Tiredness
Osmotic diuretic so dehydration
Can worsen UTIs and thrush

Question 21

What are the properties of sulfonylureas and give examples?

Answer 21

Gliclazide, glipizide, glimepiride.

All orally active, all bound to plasma protein.