Drugs for T2DM Flashcards
what type 2 diabetes drugs are dependent upon insulin
increasing secretion of inulin
- sulfonylureas
- incretin
- glinides
- Gliptins (DPP4-inhibitors)
decreasing insulin resistance and reducing hepatic glucose output
- biguanides
- thiazolidinediones (glitazones)
what type 2 diabetes drugs are independent from insulin
slowing glucose absorption from the GI tract
-glucosidase inhibitors
enhancing glucose excretion by the kidneys
-sodium glucose type-2 inhibitors (SGLT2)
how does high plasma glucose lead to insulin secretion
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
how does ATP cause the closing of the ATPk channel
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
how does low ATP open the Katp channel
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
what do sulfonylureas do
bing to SUR1 and CLOSE the channel causing depolarisation and insulin release independent of plasma glucose concentration
what do sulfonyureas cause
pancreatic B cell insulin secretion - require a functional mass of B cells to be effective
how do sulfonyureas act
by displacing the ADP bound to the SUR1 unit and binding instead to close the K atp channel and stimulate insulin release
what is an important side effect of sulfonyureas
may cause hypoglycaemia by excessive insulin secretion as they are causing insulin secretion without any input from glucose levels
who is at greater risk of hypoglycaemia from sulfonyureas
the elderly
patients with reduce hepatic/renal function (particularly CKD)
those on long acting agents
when are sulfonyureas first line treatment
for patients intolerant to metformin or with weight loss
when are sulfonyureas second line
when used in conjunction with metformin
what affect do sulfonyureas have on weight
cause weight gain
when should you avoid long duration agents (sulfonyureas)
in people with CKD
elderly
pregnancy
breast feeding
How do glinides work
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
what makes glinidines safer than SUs in CKD
mainly metabolised by the liver
when should you avoid glinidines
in severe hepatic impairment
pregnancy
breast feeding
why is oral glucose more affective in releasing insulin than IV glucose
(the incretin effect)
enteroendocrine cells present in the GI tract which in response to glucose release hormones (incretins) into the blood to trigger release of insulin
how do eneteroendocrine cells stimulate decreased glucose production and increased insulin secretion
(the incretin effect)
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
the incretin effect is reduced in T2DM, how does the body try to restore it
by reducing break down of incretins
by administering exogenous incretin analogues resistant to breakdown
What enzyme breaks down GLP-1 and GIP
dipeptidyl peptidase-4 (DPP-4)
What do Gliptins do
inhibit the action of DPP-4 prolonging the actions of GLP-1 and GIP increasing plasma insulin (therefore only affective if insulin is preserved)
when are gliptins used
in combination with SU, or metformin but can be used as mono therapy
What are incretin analogues
peptides that mimic the action of GLP-1 but are much longer lasting due to resistance to breakdown by DPP-4
