15 The control of blood glucose and drug treatment of diabetes mellitus

Question 1

15.01 INSULIN

Human recombinant insulin (or analogues) - actions

Answer 1

promotes tissue uptake and storage of glucose, amino acids and fats
acutely lowers blood glucose
inhibits hepatic glycogenolysis and gluconeogenesis
inhibits lipolysis
increases glycogen synthesis in muscle/liver
stimulates protein synthesis
longer-term effects on growth and gene expression

Question 2

15.01 INSULIN

Human recombinant insulin (or analogues) - MOA

Answer 2

binding to its receptor (tyrosine kinase type) causes autophosphorylation of the receptor
subsequent tyrosine phosphorylation of ‘insulin receptor substrates’ leads to activation of SH2 domain proteins, which regulate the action of various intracellular enzymes and cell membrane glucose transporters

Question 3

15.01 INSULIN

Human recombinant insulin (or analogues) - abs/distrib/elim

Answer 3

free insulin in the blood has a half-life of only 10 min so slow-release preparations are needed for regular use
given SC or IV
short-acting (3-5h): soluble (regular) insulin, insulin lispro, insulin aspart
intermediate-acting (10-12h): isophane insulin
long-acting (24h): insulin zinc suspension (crystalline), insulin glargine or detemir

Question 4

15.01 INSULIN

Human recombinant insulin (or analogues) - clinical use

Answer 4

life-long treatment of type 1 diabetes
also for type 2 diabetes not controlled by oral hypoglycaemic agents
soluble insulin also for emergency IV treatment of diabetic ketoacidosis

Question 5

15.01 INSULIN

Human recombinant insulin (or analogues) - adverse effects

Answer 5

hypoglycaemia - treated by glucose administration (by mouth, if conscious, otherwise IV or glucagon (IM))
weight gain (mainly in type 2 diabetes)

Question 6

15.02 SULFONYLUREAS

Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - actions

Answer 6

increase insulin release from functioning β-cells, thus producing the effects of insulin

Question 7

15.02 SULFONYLUREAS

Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - MOA

Answer 7

interaction with the sulfonylurea receptor (a subunit of the KATP channel in the cell membrane of β-cells) causes the K+ channel to close
this causes the cell to depolarise and activates voltage-dependent Ca2+ channels
Ca2+ entry stimulates exocytosis of insulin

Question 8

15.02 SULFONYLUREAS

Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - abs/distrib/elim

Answer 8

given orally, they bind extensively to plasma proteins
half-lives: tolbutamide 4h, glipizide 4h, glimepiride 5h, glibenclamide 10h
actions prolonged in patients with renal disease

Question 9

15.02 SULFONYLUREAS

Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - clinical use

Answer 9

type 2 diabetes mellitus, effective in 30% of patients

Question 10

15.02 SULFONYLUREAS

Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - adverse effects

Answer 10

association with cardiovascular disease and hypoglycaemia
weight gain

Question 11

15.03 BIGUANIDES

Metformin - actions

Answer 11

lowers blood glucose concentration

Question 12

15.03 BIGUANIDES

Metformin - MOA

Answer 12

inhibits gluconeogenesis in the liver by activating AMP-activated protein kinase
may also enhance tissue sensitivity to insulin
increases glucose uptake into tissues

Question 13

15.03 BIGUANIDES

Metformin - abs/distrib/elim

Answer 13

given orally
half-life 3h
mostly excreted unchanged in urine (avoid in patients with renal insufficiency)

Question 14

15.03 BIGUANIDES

Metformin - clinical use

Answer 14

type 2 diabetes (alone or with other oral hypoglycaemic agents)
particularly useful in obese patients

Question 15

15.03 BIGUANIDES

Metformin - adverse effects

Answer 15

anorexia and GI upset including diarrhoea (leading to weight loss)
may rarely cause potentially fatal lactic acidosis
unlike sulfonylureas, does not cause hypoglycaemia

Question 16

15.04 MEGLITINIDES

Repaglinide, nateglinide - actions

Answer 16

lowers blood glucose concentration
stimulates insulin release from β-cells in pancreatic islets

Question 17

15.04 MEGLITINIDES

Repaglinide, nateglinide - MOA

Answer 17

similar to sulfonylureas
interaction with the sulfonylurea receptor (a subunit of the KATP channel in the cell membrane of β-cells) causes the K+ channel to close
this causes the cell to depolarise and activates voltage-dependent Ca2+ channels
Ca2+ entry stimulates exocytosis of insulin

Question 18

15.04 MEGLITINIDES

Repaglinide, nateglinide - abs/distrib/elim

Answer 18

quick onset and short duration of action
half-lives: repaglinide 1h, nateglinide 1.5h
(its actions can be reduced by drugs that induce hepatic P450 enzymes, e.g. carbamazepine)

Question 19

15.04 MEGLITINIDES

Repaglinide, nateglinide - clinical use

Answer 19

type 2 diabetes mellitus
rapid action allows good control of postprandial hyperglycaemia
may be combined with metformin or a glitazone
mainly metabolised in liver, so useful in patients with renal insufficiency

Question 20

15.04 MEGLITINIDES

Repaglinide, nateglinide - adverse effects

Answer 20

hypoglycaemia (uncommon unless its metabolism is inhibited by other drugs, e.g. gemfibrozil)

Question 21

15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS

Exenatide, liraglutide, lixisenatide, dulaglutide, albliglutide - actions

Answer 21

lowers blood glucose after a meal by increasing insulin secretion, suppressing glucagon secretion and slowing gastric emptying

Question 22

15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS

Exenatide, liraglutide, lixisenatide, dulaglutide,
albliglutide - MOA

Answer 22

glucagon-like peptide-1 (GLP-1) is secreted by L cells which are widely distributed in the gut, including in the ileum and colon as well as more proximally
release of gastric inhibitory polypeptide (GIP) and GLP-1 in response to ingested food provides an early stimulus to insulin secretion before absorbed glucose or other products of digestion reach the islet cells in the portal blood
GLP-1 also inhibits pancreatic glucagon secretion and slows the rate of absorption of digested food by reducing gastric emptying
it is also implicated in control of food intake via appetite and satiety

Question 23

15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS

Exenatide, liraglutide, lixisenatide, dulaglutide, albliglutide - abs/distrib/elim

Answer 23

given via SC injection either daily or weekly (dulaglutide, albliglutide)
half lives: exenatide 2.4h, liraglutide 13h, lixisenatide 3h, dulaglutide 4.5 days, albiglutide 5 days

Question 24

15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS

Exenatide, liraglutide, lixisenatide, dulaglutide, albliglutide - clinical use

Answer 24

type 2 diabetes mellitus, alone or in combination with other drugs
liraglutide is approved for treatment of obesity

Question 25

15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS Exenatide, liraglutide, lixisenatide, dulaglutide, albliglutide - adverse effects

Answer 25

nausea and diarrhoea acute pancreatitis, rapid weight loss, hypoglycaemia (especially when used in combination with sulfonylureas)

Question 26

15.06 DIPEPTIDYL PEPTIDASE INHIBITORS Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - actions

Answer 26

lowers blood glucose by inhibiting dipeptidylpeptidase-4 (DPP-4)

Question 27

15.06 DIPEPTIDYL PEPTIDASE INHIBITORS Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - MOA

Answer 27

competitively inhibit DPP-4, thereby lowering blood glucose by potentiating endogenous incretins (GLP-1 and GIP) which stimulate insulin secretion

Question 28

15.06 DIPEPTIDYL PEPTIDASE INHIBITORS Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - abs/distrib/elim

Answer 28

absorbed from the gut and administered once daily orally eliminated partly by renal excretion and also metabolised by cytochrome P450 enzymes half-lives: sitagliptin 12h (mainly renal clearance), saxagliptin 2-3h, vildagliptin 3h

Question 29

15.06 DIPEPTIDYL PEPTIDASE INHIBITORS Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - clinical use

Answer 29

type 2 diabetes mellitus in addition to other oral hypoglycaemic drugs

Question 30

15.06 DIPEPTIDYL PEPTIDASE INHIBITORS Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - adverse effects

Answer 30

heart failure (particularly saxagliptin or alogliptin), liver disease, GI adverse effects, pancreatitis concern they may act as tumour promoters

Question 31

15.07 SGLT-2 INHIBITORS Canagliflozin, dapagliflozin, empagliflozin - actions

Answer 31

reduce concentration of circulating glucose by promoting glucose excretion into the urine

Question 32

15.07 SGLT-2 INHIBITORS Canagliflozin, dapagliflozin, empagliflozin - MOA

Answer 32

act by promoting glucose excretion into the urine, thereby reducing the concentration of circulating glucose the resulting glycosuria is associated with an osmotic diuresis and salt excretion

Question 33

15.07 SGLT-2 INHIBITORS Canagliflozin, dapagliflozin, empagliflozin - abs/distrib/elim

Answer 33

rapidly absorbed, with time to peak plasma concentrations of less than 2h they are highly bound to plasma proteins (>80%)

Question 34

15.07 SGLT-2 INHIBITORS Canagliflozin, dapagliflozin, empagliflozin - clinical use

Answer 34

type 2 diabetes mellitus - either alone (when metformin is inappropriate) or in combination with insulin or other oral hypoglycaemic agents

Question 35

15.07 SGLT-2 INHIBITORS Canagliflozin, dapagliflozin, empagliflozin - adverse effects

Answer 35

significant increase in the risk of urinary tract and fungal infections such as candidal vaginitis or balanitis susceptibility to diabetic ketoacidosis, volume depletion, fractures, acute renal impairment and lower limb amputations

Question 36

15.08 α-GLUCOSIDASE INHIBITORS Acarbose, miglitol - actions

Answer 36

delay carbohydrate absorption from intestine

Question 37

15.08 α-GLUCOSIDASE INHIBITORS Acarbose, miglitol - MOA

Answer 37

inhibits intestinal α-glucosidase and pancreatic α-amylase so reduces the rise in blood glucose which follows a meal α-glucosidase is the enzyme responsible for breaking down starches and oligosaccharides to yield the absorbable monosaccharides

Question 38

15.08 α-GLUCOSIDASE INHIBITORS Acarbose, miglitol - abs/distrib/elim

Answer 38

metabolised in GIT by bacteria and digestive enzymes half-life 2h

Question 39

15.08 α-GLUCOSIDASE INHIBITORS Acarbose, miglitol - clinical use

Answer 39

type 2 diabetes mellitus not controlled by other drugs

Question 40

15.08 α-GLUCOSIDASE INHIBITORS Acarbose, miglitol - adverse effects

Answer 40

GI discomfort - flatulence, diarrhoea

Question 41

15.09 GLUCAGON Human recombinant glucagon - actions

Answer 41

elevates blood glucose concentration increases rate and force of heart contraction

Question 42

15.09 GLUCAGON Human recombinant glucagon - MOA

Answer 42

glucagon activates adenylate cyclase by acting on G protein-coupled receptors linked to Gs its actions thus mimic those of adrenaline-activating β adrenoceptors it elevates blood glucose by stimulating hepatic gluconeogenesis and glycogenolysis and by inhibiting glycogen synthesis

Question 43

15.09 GLUCAGON Human recombinant glucagon - abs/distrib/elim

Answer 43

glucagon is a peptide hormone - must be given by injection plasma half-life 5 min

Question 44

15.09 GLUCAGON Human recombinant glucagon - clinical use

Answer 44

emergency treatment of hypoglycaemia (caused by insulin overdose), when oral or IV glucose administration is not possible (also used to treat heart failure precipitated by α-adrenoceptor antagonists)

Question 45

15.09 GLUCAGON Human recombinant glucagon - adverse effects

Answer 45

uncommon cardiac stimulation in patients taking β blockers or with pheochromocytoma