T2DM pt 1 Flashcards
cause of T2DM
insulin resistance and reduced insulin secretion
drugs that increase insulin secretion
sulfonylureas
meglitinides
incretins
sulfonylurea drugs
tolbutamide
tolazamide
chlorpropamide
glyburide
glipizide
glimeperide
meglitinide drugs
nateglinide
repaglinide
mechanism of glucose-dependent insulin secretion in B-cells (high glucose)
- small amounts of glucose are transported into the cell via GLUT 2 transporters
- glucose is phosphorylated by glucokinase (now it cannot leave the cell)
- Glucose undergoes glycolysis and produces ATP
- High concentration of ATP causes a swing in equilibrium in favor of ATP
- ATP bind K+ channel blocking inflow
- the cell depolarizes
- Voltage gated Ca channel is activated allowing influx of Ca
- High concentration of Ca activate exocytosis of insulin
mechanism of glucose dependent insulin secretion in B-cells (low glucose)
- small amounts of glucose are transported into the cell via GLUT 2 transporters
- glucose is phosphorylated by glucokinase (now it cannot leave the cell)
- Glucose undergoes glycolysis and produces ATP
- Low concentration of ATP causes a swing in equilibrium in favor of ADP
- ADP bind K+ channel opening the channel allowing influx of Ca
- the cell hyper polarizes and stabilizes
- Voltage gated Ca channel is closed
- No exocytosis of insulin occurs at low Ca concentration
Mechanism of Sulfonylureas
- Bind and close KATP channel to block inflow of K
- the cell depolarizes
- Voltage gated Ca channel is activated allowing influx of Ca
- High concentration of Ca activate exocytosis of insulin
First generation sulfonylurea drugs
Tolbutamide (Orinase)
Tolazamide (Tolinase)
Chlorpropamide (Diabinese)
Tolbutamide potency/duration
1 / 6 to 12 hours
tolazamide potency/duration
5 / 12 to 14 hours
chlorpropamide potency/duration
6 / 24 to 72 hours
2nd generation sulfonylurea drugs
Glipizide (Glucotrol)
Glyburide or Glibenclamide (Diabeta, Glynase)
Glimepiride (Amaryl)
Glipizide potency/duration
100 / 12 to 24 hrs
glyburide potency/duration
150 / 24 hours
glimerpiride potency/duration
around 150 / 24 hours
Metiglinides “glinides”
Repaglinide (Prandin)
Nateglinide (Starlix)
Repaglinide mechanism
same mechanism as sulfonylureas
Repaglinide onset/duration
quick onset/short duration of action (t1/2 = 1 hr)
Repaglinide dosing
tablet taken before each meal (preprandial)
Nateglinide mechanism
non-sulfonylurea KATP channel blocker
very specific for KATP channels in the pancreas vs CV tissue
Nateglinide onset/duration
quick onset/short duration of action
Nateglinide advantage over repaglinide
nateglinide has a shorter t1/2 so there is less risk of hypoglycemia
Sulfonylurea drug interactions
- drugs which may enhance the action of sulfonylureas and increase the risk of hypoglycemia (salicylates, phenylbutazone, sulfonamides, clofibrate_
- drugs that have their own hypoglycemic effects which may be additive to the sulfonylurea (Alcohol: excessive acute intake, high dose salicylates)
- drugs which cause hyperglycemia which in turn oppose the action of sulfonylureas and insulin therapy (Oral contraceptives, epinephrine, thiazide diuretics, corticosteroids, thyroid)
drugs that decrease glucagon secretion
Incretins
Amylin
Drugs that decrease glucose reabsorption
SGLT2 inhibitors
Drugs that control appetite
Incretins
Amylin
Drugs that increase uptake and utilization of glucose
Thiazolidinediones
Metformin
Drugs that decrease hepatic glucose output
Metformin
Thiazolidinediones
Drugs that work in the GI tract
Incretins
a-glucosidase inhibitors
amylin
Bile acid sequestrant
Drugs that treat lipotoxicity
Thiazolidinediones
GLP-1R agonists
Exenatide (Exendin 4; Byetta)
Liraglutide (Victoza)
Lixenatide (Adlyxin)
Dulaglutide (Trulicity)
Semaglutide (Ozempic)
Drugs that increase the incretin effect
GLP-1R agonists
GLP-1 & GIP dual agonist
DPP-IV inhibitors
Amylin Analogs
GLP-1 & GIP dual agonists
Tirzepatide (Mounjaro, Zepbound)
DPP-4 inhibitor drugs
Saxagliptin (onglyza)
Sitagliptin (Januvia)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
Amylin analog
Pramlintide (Symlin)
Incretins
a group of hormones produced by the gastrointestinal system in response to glucose absorption that stimulate the release of insulin from the pancreas and help preserve the beta cells
GIP and GLP-1
GLP-1 functions
stimulate insulin secretion
suppress glucagon secretion
slows gastric emptying
reduces food intake
increases B cell mass and maintains B cell function
improves insulin sensitivity
enhances glucose disposal
GLP-1 signaling pathway
Gs and Gq
may explain why GLP-1 is more effective
Exenatide
GLP-1 analog
39 amino acid peptide from Gila monster saliva
GIP signaling pathways
Gs
advantages of GLP-1 in treatment of T2DM
reduced hyperglycemia with low risk of hypoglycemia
weight loss
increased beta cell mass (hard to show in humans but has been seen)
strategies of GLP-1 treatment of T2DM
provide long-lasting GLP-1 analog
prevent degradation of endogenous GLP-1
Positive allosteric modulators for the GLP-1 receptor (allows the body to respond to lower concentrations of GLP-1, going in for approval soon)
GLP-1 agonists AE
N/V (usually lasts ~ 1 month), pancreatitis, risk of thyroid C-cell tumors - monitor calcitonin levels (contraindicated in pts with a family history of medullary thyroid cancer)
GLP-1 MOA
activates GLP-1R and enhances 1st phase insulin secretion (postprandial)
Exenatide duration of action
longer half life than endogenous GLP-1
Exenatide dosing
Twice daily injections
once weekly injections (Bydureon)
both are co-administered with metformin, TzDs, or sulfonylureas
Liraglutide
GLP-1 analog
human GLP-1 (hGLP-1) aa 7-37 (cleavage occurs taking away first 6 aa)
Liraglutide duration
t1/2 of 13 hours
Liraglutide dosing
0.6-3 mg SC daily
can be co-administered with metformin, TzDs, and sulfonylureas
Dulaglutide
GLP-1R agonist
alanine is substituted with a valine
Dulaglutide dosing
0.75 or 1.5 mg injected SC once weekly
Lixisenatide
GLP-1R agonist
44 aa peptide (extended with a polylysine tail)
Lixisenatide dosing
50 or 100 µg injected SC daily before breakfast
Semaglutide
GLP-1R agonist
31 aa peptide (alanine is replace with 2-aminoisobutyratye)
Semaglutide duration of action
extensively bound to serum albumin
t1/2 ~ 1 week
Semaglutide (Rybelsus)
orally available GLP-1R agonist
oral bioavailability - 0.4-1.0%
Semaglutide (Rybelsus) dosing
3, 7, or 14 mg once daily
much larger dose, so low availability is counteracted
Soliqua
100 U glargine + 33 µg lixisenatide/ml
max daily dose 60 U/20 µg
dosing Soliqua
injected SC once daily
Xultophy
100 U degludec + 3.6 mg liraglutide/ml
max daily dose 50 U/1.8 mg
Tirzepatide
Full GIP receptor agonist
Biased GLP-1R agonist
Mechanism of Biased GLP-1R agonist
preferential coupling to cAMP over B-arrestin, which reduces internalization (desensitization) of GLP-1R to maintain GLP-1 effect
Coupling of B-arrestin
method by which you desensitize GLP-1 receptors, coupling kicks of internalization of GLP-1 which terminates its activity
Tirzepatide dosing
once weekly SC injections
Tirzepatide advantages
reduces A1c and body weight more effectively than GLP-1R agonists
Dipeptidyl peptidase (DPP) 4
cleave and break down incretins
