lecture 25 - drug targets for treating type 2 diabetes

Question 1

type 2 diabetes

Answer 1

polygenic disorder
defects in insulin action
defects in glucose-induced insulin secretion

Question 2

obesity in associated with insulin resistance and compensating by enlargement of islets

Answer 2

individuals with good beta cell capacity can compensate better for insulin resistance
type 2 diabetes develops once the beta cells can no longer compensate for insulin resistance

Question 3

calorie excess and physical inactivity leads to obesity, causing insulin resistance

Answer 3

robust beta cells increase insulin secretion
susceptible beta cells become dysfunctional causing hyperglycaemia and T2D

Question 4

therapy

Answer 4

lifestyle changes (diet and exercise)
drugs (first line drug is metformin)

Question 5

targeting carbohydrate absorption

Answer 5

enzymes that break down carbohydrates have alpha-glucosidase activity
inhibitors of this enzyme have been used to inhibit breakdown (alpha glucosidase inhibitors (AGIs)
they are competitive inhibitors (substrates for enzymes)
1st generation: acarbose, cant be absorbed
2nd generation: can be absorbed but not metabolised and excreted in the urine

Question 6

AGIs adverse effects

Answer 6

small effects of blood glucose levels
abdominal discomfort because undigested carbohydrates pass from SI to colon

Question 7

targeting renal glucose excretion (pass more glucose through urine)

Answer 7

glucose it reabsorbed from urine to blood by GLUTs and SGLTs (symporters (same direction) of glucose and sodium, use sodium gradient)
SGLT inhibitors prevent the reabsorption of glucose causing excretion in urine
SGLT2 - only expressed in the kidney, selective inhibitors just inhibit SGLT2

Question 8

SGLT adverse effects

Answer 8

increased urine volume
risk of UTIs
risk of genital fungal infections

Question 9

targeting insulin secretion (1)

Answer 9

sulphonylureas
bind to SUR1 in the potassium ATP channels of the beta cells
at low blood glucose levels the potassium channel stays open and theres no insulin secretion
high glucose (high ATP) the potassium ATP channel closed and insulin is secreted
sulphonylureas is and antagonist, closes the channel, membrane depolasises and more insulin is secreted

Question 10

targeting insulin secretion (2)

Answer 10

incretin receptors
incretins = intestinal peptides produced in response to food that stimulate insulin release
K cells in the gut release GIP which stimulates insulin release
in the small intestine the L cells release GLP-1, they have the same affect

Question 11

GLP-1 effects

Answer 11

receptor is expressed on alpha and beta cells
GLP-1 increases:
-the amount of insulin secreted from the cell
-the amount of insulin gene expression and protein synthesis
-beta cell proliferation

Question 12

mechanisms of action (GLP-1)

Answer 12

exenatide, liraglutide, semaglutide mimic the action of GLP-1
binds to GLP-1 receptor (GPCR) on plasma membrane of beta cell
produces cAMP
rise in cAMP causes PKA to act directly on the K/ATP channel and promote its closure
causes depolarisation and uptake of calcium
cAMP also acts of EPAC which can act on the K/ATP channel and the ER causing the ER release the calcium

Question 13

DPP-4 inactivates

Answer 13

incretins
can be membrane bound or soluble
removes 2 residues of GLP-1 making it inactive
DPP4 inhibitors would increase half life of GLP-1 therefore reduce blood glucose

Question 14

sulphonylureas

Answer 14

they increase insulin independently to blood glucose - risk of hypoglycaemia

Question 15

GLP-1 analogues and DDP-4 inhibitors

Answer 15

secrete insulin depending of blood glucose levels

Question 16

target adipose tissue

Answer 16

obesity causes increase in cell volume and number
adipose cells can attain their maximum capacity of lipid storage causing lipid levels to raise in the blood
PPAR-gamma drugs favour adipocyte proliferation and further lipid storage preventing damage by lipids in other organs

Question 17

PPAR-gamma drugs

Answer 17

thiazolidinediones (TZDs) - PPAR gamma ligands
1. ligand binding to PPAR gamma
2. heterodimer with retinoic acid receptor
3. recruitment to PPRE on DNA promoter
4. recruitment of co-activator (e.g. P300)
P300= histone acetylase
6. acetylation of histones exposes chromatin
7. increases transcription of PPAR gamma target genes

Question 18

TZD effects

Answer 18

more capacity to store more fat
increase body weight due to fat mass
associated with liver damage, heart attacks
pioglitazone is in current use

Question 19

targeting the liver

Answer 19

metformin
decreases hepatic glucose production
increases fatty acid oxidation
increase insulin sensitivity
increases glucose utilisation

Question 20

metformin mechanism

Answer 20

metformin enters calls via OCT1 transporter
localises to mitochondria due to its positive charge as mitochondria is -ve inside
inhibitors complex I - decrease in ATP/ADP, increase of AMP which activates AMP kinase which inhibits acetyl-coa, decreases FA synthesis and increases FA oxidation