Drugs and their Targets In Type 2 Diabetes

Question 1

what are the 2 broad types of action in type 2 diabetes drugs?

Answer 1

insulin dependant

insulin independant

Question 2

what do insulin dependant drugs do?

Answer 2

increase secretion of insulin (SURs, glinides, DPP-4 inhibitors)
decrease insulin resistance and reduce hepatic glucose output (biuanides, thiazolidines (glitazones))

Question 3

what do insulin independent drugs do?

Answer 3

slow glucose absorption from the GI tract

enhance glucose excretion by kidney (SGLT2 inhibitors)

Question 4

what are the steps in insulin secretion from beta cells?

Answer 4

increase in blood glucose
increased diffusion of glutamate into beta cell via GLUT2
phosphorylation of glucose by glucokinase
glycolysis of glucose-6-phosphate in mitochondria yielding ATP
increasing ATP/ADP ratio within the cell closes the K+ ATP channels causing membrane depolarisation
opening of voltage activated calcium channels in response to depolarization
increase in Ca2+ which triggers insulin secretion

Question 5

what regulates potassium channel activity?

Answer 5

SUR1 subunits

Question 6

what are the components of the K+ ATP channel?

Answer 6

octomeric complex

• 4 inward rectifier subunits (kir6.2)
• 4 sulphonylurea receptor 1 subunits (SUR1)

Question 7

how does ATP interact with the potassium channel?

Answer 7

binds to each of the kir6.2 subunits closing the channel causing depolarization and insulin release

Question 8

how does ADP-Mg2+ interact with the potassium channel?

Answer 8

binds to the SUR1 subunit and opens the channel maintaining the resting potential of the beta cell and inhibits insulin release

Question 9

what do SURs do?

Answer 9

bind to SUR1 and close the channel causing depolarization and insulin release independent of plasma glucose concentration

Question 10

relationship between glucose and ATP?

Answer 10

high glucose = high ATP

low glucose = high ADP

Question 11

what are SURs? what does this mean?

Answer 11

insulin secretagogues - they cause insulin secretion so need a functional mass of beta cells to be effective

Question 12

give 4 examples of SURs?

Answer 12

tolbutamide
glibenclamide
gliclazide
glipizide

Question 13

structure of SURs?

Answer 13

all incorporate the sulphonylurea moiety but have different R and R2 subunits

Question 14

how do SURs act?

Answer 14

displace the binding of ADP-Mg2+ from the SUR1 subunit thus closing the channel

Question 15

how do SURs affect blood glucose?

Answer 15

decrease fasting and post prandial blood glucose

Question 16

short vs long acting SURs?

Answer 16

insulin peaks after 1-2 hrs but duration of action can vary
short acting = tolbutamide
long acting = glibenclamide, gliclazide, glipizide

Question 17

advantages of SURs?

Answer 17

long term reduce microvascular complication risk
orally active
generally well tolerated

Question 18

disadvantages of SURs?

Answer 18

can cause hypoglycaemia by excessive insulin secretion
risk in
- long acting agents
- elderly
- people with kidney disease
tend to cause weight gain - less loss of glucose, appetite increased, anabolic effect of insulin increased

Question 19

when are SURs used?

Answer 19

first line if metformin intolerant or with lots of weight loss
second line in conjunction with metformin
third line in conjunction with metformin and thiazolidinediones

Question 20

when are long duration SURs avoided?

Answer 20

renal impairment
elderly
pregnancy
breast feeding

Question 21

how do glinides act?

Answer 21

similarly to SURs but action is augmented by glycaemia

bind to SUR1 at distinct site to close the channel and trigger insulin release

Question 22

give 2 examples of glinides

Answer 22

repaglinide

nateglanide

Question 23

advantages of glinides?

Answer 23

orally active
rapid onset/offset and promote insulin secretion in response to meals
reduce post prandial blood glucose
less likely to cause hypoglycaemia than longa acting SURs
safer than SURs as subject to mainly hepatic metabolism

Question 24

how are glinides used?

Answer 24

used in conjunction with metformin and thiazolidinediones but not first line
avoid in severe hepatic impairment, pregnancy and breast feeding

Question 25

why is oral glucose response higher than the response to IV glucose?

Answer 25

incretin effect enteroendocrine cells in the GI tract which secrete hormones (incretins) into the blood in response to glucose which stimulate insulin release

Question 26

what are the 2 incretins?

Answer 26

GLP-1 GIP enter the portal circulation and reach the pancreas

Question 27

what does GIP do?

Answer 27

enhance insulin release from beta cells and delays gastric emptying causing enhanced glucose uptake and utilization

Question 28

what does GLP-1 do?

Answer 28

same as GIP also decreases glucagon release from alpha cells causing decreased glucose production by the liver

Question 29

what is the combined effect of incretins?

Answer 29

decreased blood glucose

Question 30

how do DPP-4 inhibitors ("gliptins") act?

Answer 30

restore incretin effect by reducing breakdown of the endogenous incretins or administering exogenous incretin analogies resistant to breakdown

Question 31

what terminates the action of the incretins?

Answer 31

``` dipeptidyl peptidase (DPP-4) rapidly terminates ```

Question 32

what are the effects of DPP-4 inhibitors?

Answer 32

prolong the actions of incretins by inhibiting DPP-4 and increasing plasma insulin

Question 33

how are DPP-4 inhibitors used?

Answer 33

only work if insulin secretion is preserved usually only used in combination with SUR or metformin but can be a monotherapy oral tablet once daily

Question 34

adverse effect of DPP-4 inhibitors?

Answer 34

nausea | weight neutral

Question 35

main DPP-4 inhibitor?

Answer 35

sitaglipin

Question 36

what are incretin analogues?

Answer 36

peptides that mimic action of GLP-1 but are far longer lasting due to resistance to breakdown by DPP-4

Question 37

how do incretin analogues act?

Answer 37

bind as agonists to GPCR GLP-1 receptors that increase intracellular cAMP concentration in beta cells to stimulate insulin expression and release

Question 38

what are the effects of incretin analogues?

Answer 38

``` increase insulin secretion supress glucagon secretion slow gastric emptying decrease appetite weight loss reduce hepatic fat may cause nausea ```

Question 39

how are incretin analogues given?

Answer 39

subcutaneously

Question 40

what are alpha glucosidase inhibitors?

Answer 40

inhibitors of the brush border enzyme alpha glucosidase which breaks down starch and disaccharides to absorb glucose

Question 41

how are alpha glucosidase used?

Answer 41

in type 2 diabetes patients badly controlled by lifestyle or other drugs taken with a meal

Question 42

adverse effects of alpha glucosidase inhibitors?

Answer 42

``` flatulence loose stools diarrhoea abdominal pain bloating accumulation of colonic bacteria (undigested carbohydrates) ```

Question 43

what type of drug is metformin?

Answer 43

biguanide

Question 44

what are the effects of metformin?

Answer 44

reduce hepatic gluconeogenesis increase glucose uptake and utilization by skeletal muscle reduces carbohydrate absorption increases fatty acid oxidation

Question 45

when is metformin used?

Answer 45

first line for type 2 irrespective of obesity - with normal hepatic and renal function

Question 46

advantages of metformin?

Answer 46

reduced microvascular complications of diabetes suitable orally prevents hyperglycaemia but doesn't cause hypoglycaemia causes weight loss may be combined with other agents

Question 47

disadvantages of metformin?

Answer 47

GI upset | can cause lactic acidosis

Question 48

who is metformin contraindicated in?

Answer 48

alcoholics | hepatic or renal disease

Question 49

what do TZDs/glitazones do?

Answer 49

enhance action of insulin at target tissues but don't increase insulin secretion (reduce resistance)

Question 50

advantages of TZDs?

Answer 50

promote fatty acid uptake/storage in adipocytes rather than liver and muscle reduce hepatic glucose output enhance peripheral glucose uptake don't cause hypoglycaemia

Question 51

when are TZDs contraindicated?

Answer 51

heart failure

Question 52

disadvantages of TZDs?

Answer 52

weight gain fluid retention some cause serious hepatotoxicity increased fracture rates

Question 53

what is the only TZD used in the UK?

Answer 53

pioglitazone as doesn't cause liver dysfunction | can be used in combination with metformin or SURs

Question 54

how do SGLT2 inhibitors work?

Answer 54

block reabsorption of glucose by SGLT2 in proximal tubule of the kidney nephron to deliberately cause glucosuria causes a decrease in blood glucose with little risk of hyoglycaemia

Question 55

what do SGLT2 inhibitors cause?

Answer 55

weight loss due to calorific loss (glucose in urine) and water loss which accompanies glucose

Question 56

list some examples of SGLT2 inhibitors

Answer 56

dapagliflozin canagliflozin empagliflozin