Drugs and their Targets In Type 2 Diabetes Flashcards
what are the 2 broad types of action in type 2 diabetes drugs?
insulin dependant
insulin independant
what do insulin dependant drugs do?
increase secretion of insulin (SURs, glinides, DPP-4 inhibitors)
decrease insulin resistance and reduce hepatic glucose output (biuanides, thiazolidines (glitazones))
what do insulin independent drugs do?
slow glucose absorption from the GI tract
enhance glucose excretion by kidney (SGLT2 inhibitors)
what are the steps in insulin secretion from beta cells?
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
what regulates potassium channel activity?
SUR1 subunits
what are the components of the K+ ATP channel?
octomeric complex
- 4 inward rectifier subunits (kir6.2)
- 4 sulphonylurea receptor 1 subunits (SUR1)
how does ATP interact with the potassium channel?
binds to each of the kir6.2 subunits closing the channel causing depolarization and insulin release
how does ADP-Mg2+ interact with the potassium channel?
binds to the SUR1 subunit and opens the channel maintaining the resting potential of the beta cell and inhibits insulin release
what do SURs do?
bind to SUR1 and close the channel causing depolarization and insulin release independent of plasma glucose concentration
relationship between glucose and ATP?
high glucose = high ATP
low glucose = high ADP
what are SURs? what does this mean?
insulin secretagogues - they cause insulin secretion so need a functional mass of beta cells to be effective
give 4 examples of SURs?
tolbutamide
glibenclamide
gliclazide
glipizide
structure of SURs?
all incorporate the sulphonylurea moiety but have different R and R2 subunits
how do SURs act?
displace the binding of ADP-Mg2+ from the SUR1 subunit thus closing the channel
how do SURs affect blood glucose?
decrease fasting and post prandial blood glucose
short vs long acting SURs?
insulin peaks after 1-2 hrs but duration of action can vary
short acting = tolbutamide
long acting = glibenclamide, gliclazide, glipizide
advantages of SURs?
long term reduce microvascular complication risk
orally active
generally well tolerated
disadvantages of SURs?
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
when are SURs used?
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
when are long duration SURs avoided?
renal impairment
elderly
pregnancy
breast feeding
how do glinides act?
similarly to SURs but action is augmented by glycaemia
bind to SUR1 at distinct site to close the channel and trigger insulin release
give 2 examples of glinides
repaglinide
nateglanide
advantages of glinides?
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
how are glinides used?
used in conjunction with metformin and thiazolidinediones but not first line
avoid in severe hepatic impairment, pregnancy and breast feeding
why is oral glucose response higher than the response to IV glucose?
incretin effect
enteroendocrine cells in the GI tract which secrete hormones (incretins) into the blood in response to glucose which stimulate insulin release
what are the 2 incretins?
GLP-1
GIP
enter the portal circulation and reach the pancreas
what does GIP do?
enhance insulin release from beta cells and delays gastric emptying
causing enhanced glucose uptake and utilization
what does GLP-1 do?
same as GIP
also decreases glucagon release from alpha cells
causing decreased glucose production by the liver
what is the combined effect of incretins?
decreased blood glucose
how do DPP-4 inhibitors (“gliptins”) act?
restore incretin effect by reducing breakdown of the endogenous incretins or administering exogenous incretin analogies resistant to breakdown
what terminates the action of the incretins?
dipeptidyl peptidase (DPP-4) rapidly terminates
what are the effects of DPP-4 inhibitors?
prolong the actions of incretins by inhibiting DPP-4 and increasing plasma insulin
how are DPP-4 inhibitors used?
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
adverse effect of DPP-4 inhibitors?
nausea
weight neutral
main DPP-4 inhibitor?
sitaglipin
what are incretin analogues?
peptides that mimic action of GLP-1 but are far longer lasting due to resistance to breakdown by DPP-4
how do incretin analogues act?
bind as agonists to GPCR GLP-1 receptors that increase intracellular cAMP concentration in beta cells to stimulate insulin expression and release
what are the effects of incretin analogues?
increase insulin secretion supress glucagon secretion slow gastric emptying decrease appetite weight loss reduce hepatic fat may cause nausea
how are incretin analogues given?
subcutaneously
what are alpha glucosidase inhibitors?
inhibitors of the brush border enzyme alpha glucosidase which breaks down starch and disaccharides to absorb glucose
how are alpha glucosidase used?
in type 2 diabetes patients badly controlled by lifestyle or other drugs
taken with a meal
adverse effects of alpha glucosidase inhibitors?
flatulence loose stools diarrhoea abdominal pain bloating accumulation of colonic bacteria (undigested carbohydrates)
what type of drug is metformin?
biguanide
what are the effects of metformin?
reduce hepatic gluconeogenesis
increase glucose uptake and utilization by skeletal muscle
reduces carbohydrate absorption
increases fatty acid oxidation
when is metformin used?
first line for type 2 irrespective of obesity - with normal hepatic and renal function
advantages of metformin?
reduced microvascular complications of diabetes
suitable orally
prevents hyperglycaemia but doesn’t cause hypoglycaemia
causes weight loss
may be combined with other agents
disadvantages of metformin?
GI upset
can cause lactic acidosis
who is metformin contraindicated in?
alcoholics
hepatic or renal disease
what do TZDs/glitazones do?
enhance action of insulin at target tissues but don’t increase insulin secretion (reduce resistance)
advantages of TZDs?
promote fatty acid uptake/storage in adipocytes rather than liver and muscle
reduce hepatic glucose output
enhance peripheral glucose uptake
don’t cause hypoglycaemia
when are TZDs contraindicated?
heart failure
disadvantages of TZDs?
weight gain
fluid retention
some cause serious hepatotoxicity
increased fracture rates
what is the only TZD used in the UK?
pioglitazone as doesn’t cause liver dysfunction
can be used in combination with metformin or SURs
how do SGLT2 inhibitors work?
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
what do SGLT2 inhibitors cause?
weight loss due to calorific loss (glucose in urine) and water loss which accompanies glucose
list some examples of SGLT2 inhibitors
dapagliflozin
canagliflozin
empagliflozin
