Drugs for T2DM

Question 1

what type 2 diabetes drugs are dependent upon insulin

Answer 1

increasing secretion of inulin

• sulfonylureas
• incretin
• glinides
• Gliptins (DPP4-inhibitors)

decreasing insulin resistance and reducing hepatic glucose output

• biguanides
• thiazolidinediones (glitazones)

Question 2

what type 2 diabetes drugs are independent from insulin

Answer 2

slowing glucose absorption from the GI tract
-glucosidase inhibitors

enhancing glucose excretion by the kidneys
-sodium glucose type-2 inhibitors (SGLT2)

Question 3

how does high plasma glucose lead to insulin secretion

Answer 3

high blood glucose leads to increased disunion of glutamate into the B cell by GLUT2

then glucose is phosphorylated by glucokinase

glycolysis of glucose-6-phosphate in mitochondria yields ATP

increased ATP/ADP ratio within cell closes ATP k+ channels causing membrane depolarisation

opening of voltage-activated Ca2+ channels allowing Ca++ in triggers insulin secretion

Question 4

how does ATP cause the closing of the ATPk channel

Answer 4

high glucose means the ATP levels are high causing the closing of the K channel by ATP binging to a Kir6.2 unit in the channel leading to depolarisation and insulin release

Question 5

how does low ATP open the Katp channel

Answer 5

low glucose means there are low ATP levels (less glycolysis) so ADP levels are high

ADP binds to the SUR1 subunit which opens the channel to maintain the resting action potential of the B cell abnd preventing insulin release

Question 6

what do sulfonylureas do

Answer 6

bing to SUR1 and CLOSE the channel causing depolarisation and insulin release independent of plasma glucose concentration

Question 7

what do sulfonyureas cause

Answer 7

pancreatic B cell insulin secretion - require a functional mass of B cells to be effective

Question 8

how do sulfonyureas act

Answer 8

by displacing the ADP bound to the SUR1 unit and binding instead to close the K atp channel and stimulate insulin release

Question 9

what is an important side effect of sulfonyureas

Answer 9

may cause hypoglycaemia by excessive insulin secretion as they are causing insulin secretion without any input from glucose levels

Question 10

who is at greater risk of hypoglycaemia from sulfonyureas

Answer 10

the elderly
patients with reduce hepatic/renal function (particularly CKD)
those on long acting agents

Question 11

when are sulfonyureas first line treatment

Answer 11

for patients intolerant to metformin or with weight loss

Question 12

when are sulfonyureas second line

Answer 12

when used in conjunction with metformin

Question 13

what affect do sulfonyureas have on weight

Answer 13

cause weight gain

Question 14

when should you avoid long duration agents (sulfonyureas)

Answer 14

in people with CKD
elderly
pregnancy
breast feeding

Question 15

How do glinides work

Answer 15

similar to sulfonylureas
action is augmented by glycaemia

promote insulin secretion in response to meals

bind to SUR1 to close Katp channels and trigger insulin release

less likely to cause hypoglycaemia

Question 16

what makes glinidines safer than SUs in CKD

Answer 16

mainly metabolised by the liver

Question 17

when should you avoid glinidines

Answer 17

in severe hepatic impairment
pregnancy
breast feeding

Question 18

why is oral glucose more affective in releasing insulin than IV glucose

(the incretin effect)

Answer 18

enteroendocrine cells present in the GI tract which in response to glucose release hormones (incretins) into the blood to trigger release of insulin

Question 19

how do eneteroendocrine cells stimulate decreased glucose production and increased insulin secretion
(the incretin effect)

Answer 19

enteroendocrine cells and activated by the ingestion of food to release GLP-1 (glucagon like peptide) and GIP (insulinotropic peptide)

GLP-1 and GIP enter the portal blood causing increased insulin release from B cells and GLP-1 also decreased glucagon release

the increase in insulin increases glucose uptake and the decrease in glucagon decreased glucose production

this leads to a decrease in blood glucose

Question 20

the incretin effect is reduced in T2DM, how does the body try to restore it

Answer 20

by reducing break down of incretins

by administering exogenous incretin analogues resistant to breakdown

Question 21

What enzyme breaks down GLP-1 and GIP

Answer 21

dipeptidyl peptidase-4 (DPP-4)

Question 22

What do Gliptins do

Answer 22

inhibit the action of DPP-4 prolonging the actions of GLP-1 and GIP increasing plasma insulin (therefore only affective if insulin is preserved)

Question 23

when are gliptins used

Answer 23

in combination with SU, or metformin but can be used as mono therapy

Question 24

What are incretin analogues

Answer 24

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

Question 25

Adverse affects of gliptins

Answer 25

weight neutral

nausea

Question 26

adverse affects of incretin analogues

Answer 26

modest weight loss

reduce hepatic fat accumulation

Question 27

what are alpha glucosidase inhibitors

Answer 27

glucosidase is an enzyme which breaks down starch to glucose at the brush border. Inhibition of this delays glucose absorption so reduces the post-prandial spike in blood glucose

Question 28

what is alpha glucosidase

Answer 28

brush border enzyme that breaks down starch and disaccarhides into absorbable glucose

Question 29

when are aplpha glucosidase inhibitors used

Answer 29

in T2DM patients with inadequately controlled by life style measures or other drugs eg. SUs

Question 30

adverse affects of alpha glucosidase inhibitors

Answer 30

flatulence, loss stools, diarrhoea, abdominal pain, bloating

no risk of hypoglycaemia but only moderately improve glycemic control

infrequently used in UK

Question 31

What is the first line treatment in T2DM

Answer 31

metformin (biguanide)

Question 32

how does metformin work

Answer 32

reduces hepatic gluconeogenesis (stimulates AMP-activated protein kinase (AMPK)

increases glucose uptake by skeletal muscle

reduces carbohydrate absorption

increases fatty acid oxidation

Question 33

what are the clinical pros of metformin

Answer 33

reduces microvascular complications of disease

suitable for oral administration

prevents hyperglycaemia but does not cause hypoglycaemia

causes weight loss

may be combined with other agents

Question 34

what are the adverse affects of metformin

Answer 34

GI upset (diarrhoea, nausea, anorexia)

early lactic acidosis - excessive alcohol consumption may increase incidence of lactic acidosis

Question 35

how to thiazolidinediones work (TZD, glitazones)

Answer 35

enhance the action of insulin at target tissues - but do not affect insulin secretion (so reduce insulin resistance)

Question 36

what are the desirable affects of thiazolidinediones

Answer 36

promote fatty acid uptake and storage in adipocytes rather than in skeletal muscle and liver

reduce hepatic glucose output

enhance peripheral glucose uptake

do not cause hypoglycaemia

Question 37

adverse affects of thiaxolidinediones

Answer 37

weight gain
fluid retention
serious hepatoxicity
increased incidence of bone fractures

Question 38

how do sodium-glucose cotransportat inhibitors work (SGLT2)

Answer 38

not dependent on insulin

work by acting to block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron

causes decrease in blood glucose with little risk of hypoglycaemia

Question 39

adverse affects of SGLT2

Answer 39

weight loss due to calorific loss of glucose being voided