Insulin & Drugs for Type 2 Diabetes (Crider)
What is the strucutre of ATP-sensitive K+ channels?
-4 pore forming Kir6.x subunits joined together with -4 regulatory SURx subunits
What are the first generation sulfonylureas?
-Acetohexamide -Chlorpropamide -Tolazamide -Tolbutamide
Be able to recognize the acidic function and the lipophilic groups for a first generation sulfonylurea.
-Acidic group: middle S-N bond of sulfonylurea -2 lipophilic groups on each end of sulfonylurea
Have a general understanding of the structures of nateglinide and rapaglinide, how these compounds differ from sulfonylureas, and what possible advantage they have over sulfonylureas.
-Carboxylic acid + amide -More rapid onset -Shorter duration of action -May mimic a more physiological pattern of insulin release
What are the second generation sulfonylureas?
-Glipizide -Glyburide -Glimepiride
What is the role of phenol in the formulation of insulin degludec?
-Injected SC in a formulation with Zn & phenol as dihexamer conformation. -After injection, the phenol diffuses out & the hexamers change to a multi-hexamer chain conformation. -With slow release of Zn, the chains break down to dimers which will rapidly dissociate into absorbable monomers. phenol is used to stabilize the structure by binding to hydrophobic pockets. As phenol diffuses away, the dihexamers undergo a conformational change forming multihexamers
Have a general knowledge concerning the structure of the insulin products: insulin aspart
-Insulin + Asp at 28 -Contains Zn++
Have a general knowledge concerning the structure of the insulin products: insulin glargine
-Insulin + Gly at G-21 + Arg at R-31 + Arg at R-32 -Replacement of Asn with Gly at G-21 on A-chain -Addition of 2 Arg residues R-31 & R032 on B-chain --> raises isoelectic point -Clear solution with pH of 2 (more stable) -Stabilized insulin hexamer -Prolonged & predictable absorption
Have a general knowledge concerning the structure of the insulin products: insulin lispro
-Insulin + Lys at 28 + Pro at 29 + Asn instead of Asp at 3 -Contains Zn++
Have a general knowledge concerning the structure of the insulin products: insulin detemir
-Insulin + Lys at 29 -Removal of The B30 -Associates at injection site -Strongly bound to plasma proteins -Myristic Acid attached to the amino group of Lys B29 -Highly lipophilic -Forms dexamers & dihexamers at the injection
Have a general knowledge concerning the structure of the insulin products: insulin glulisine
-Insulin + Lys at 3 + Glu at 29 -Does not contain Zn++
Have a general knowledge concerning the structure of insulin degludec and why this product has a long-duration of action.
-Multi-hexamer formation coupled with protein binding -Extremely stable & predictable release pattern -Forms multihexamers in SC tissue = prolonged absorption -Lipophilic side chain enhances protein binding = long duration of action
What is involved in the conversion of benzylic methyl groups to carboxylic acid metabolites?
-P-450 -Alcohol dehydrogenase -Aldehyde dehydrogenase
What are the Type 2 antidiabetic agents?
-Thiazolidindiones (TZDs) -Sulfonylureas & related insulinotropes or secretagogues -Biguanides -alpha-Glucosidase inhibitors -Amylin analogs -GLP-1R agonists -DPP4 inhibitors -SGLT2 inhibitors
Understand the reason that sulfonylureas are weak acids.
-the sulfonyl group exerts an electron withdrawing effect, thus activating the NH proton -upon ionization, the resulting anion is stablizied by resonance onto both oxygen atoms of the sulfonyl group & the carbonyl group of the urea group
Quick summary of regulation of insulin release from pancreatic beta cells
1) Glucose enters the pancreatic beta cell by GLUT2 2) Increase ATP levels 3) ATP binds to K+ channel 4) K+ channel closes 5) Depolarization via increase in trapped intracellular K+ 6) Increase in calcium influx 7) Insulin secretion from beta cells
What is the pathway of regulation of insulin release from pancreatic beta cells?
1) Glucose enters the pancreatic beta cell by means of the GLUT2 transporter 2) Increase glucose metabolism raises ATP levels 3) ATP binds to the K+ channel favoring closing 4) K+ closing traps a greater portion of K+ ions within the cell, rendering the intracellular environment less negative vs extracellular fluids (depolarization) 5) Depolarization increases Ca++ influx 6) Increases Ca++ causes insulin exocytosis
Be able to describe the synthesis of insulin from preproinsulin.
1) Preproinsulin -proteolytic cleavage -24 amino acids 2) Proinsulin -folding & disulfide bond formation -Endopeptidases 3) Insulin
How is tolbutamide metabolized?
1) para-methyl group on the far left is rapidly metabolized by CYP2C9 to give a hydroxymethyl metabolite (OH-methyl) that retains some activity 2) The alcohol is oxidized further by a combination of alcohol and aldehyde dehydrogenase to give an inactive carboxylic metabolite
What is the approximate daily dose of Glimepiride?
1-2 mg
What is the approximate daily dose of Glipizide?
10 mg
What is the approximate daily dose of Tolbutamide?
1000-1500 mg
A-chain of human insulin has ___ amino acids
21
What is the approximate daily dose of Chlorpropamide?
250-375 mg
What is the approximate daily dose of Tolazamide?
250-375 mg
B-chain of human insulin has ___ amino acids
30
Insulin detemir is ____ potent than human insulin
4x less
What is the approximate daily dose of Glyburide?
5 mg
What is the approximate daily dose of Acetohexamide?
500-750 mg
Be able to describe the chemical structure of insulin.
A-chain: 21 amino acids (internal S-S bond C6-C11) B Chain: 30 amino acids (S-S bond C7 & C7 of A-Chain & S-S bond of C19 & C20 of A-Chain)
A-chain of human insulin has a S-S bond at ____
C6-C11
B-chain of human insulin has a S-S bond at ____
C7 & C7 of A-chain C19 & C20 of A-chain
What is nateglinide metabolized by?
CYP 2C9 & 3A4
What is repaglinide metabolized by?
CYP3A4 & 2C8
What is the brand name for insulin aspart?
Fiasp
_____ acts like ATP in that it binds to K+ channel to cause depolarization --> influx of Ca++ --> release of insulin
Glyburide
What is the brand name of insuline glargine?
Lantus
What is the brand name of insulin detemir?
Levemir
Insulin aspart is formulated containing _____ & ____
Nicotinamide & L-Arg
Are the disulfide linkages formed in proinsulin?
No
Is a sulfonylurea group essential for binding to the sulfonylurea receptor?
No
Have a general understanding of the SUR1-Kir6.2 binding site in pancreatic β-cells.
Ok
Understand that insulin self associates into hexamers and that only insulin monomers and to a much lesser extent dimers can pass through capillary walls.
Ok
Nateglinide is the ____ enantiomer
R
Which meglitinide has a shorter half life?
Repaglinide
What are Meglitinides?
Repaglinide & Nateglinide
Recognize the differences in binding between rapaglinide and nateglinide at the ATP-sensitive potassium channel.
Repaglinide is a B-ligand that binds at the B site Nateglinide is an A-ligand that binds at the A side Both have an acidic group that binds to the anionic site
Understand the difference in metabolism between tolbutamide and chlorpropamide.
Review slide 23
Have a general understanding of how glipizide, glyburide, and glimepiride are metabolized.
Review slide 24
Repaglinide is the ___ enantiomer
S (+)
Be able to recognize the structure of a sulfonylurea
SO2 + urea
If given the structure, be able to recognize the structural difference between first and second generation sulfonylureas.
Second generation sulfonylureas have a lot larger structures
Understand that the SUR1-Kir6.2 receptor in pancreatic β-cells contains a binding site A (on the SUR1) and a binding site B (on the SUR1-Kir6.2) site.
Slide 30
Have a general understanding of the differences in binding of glimepiride and tolbutamide at the SUR1-Kir6.2 receptor.
Tolbutamide: -highly selective for the A site -sulfonylurea binds to the anionic site -benzene ring binds to the phenyl binding site Glyburide/glimepiride: -binds to A + B sites -much more potent than tolbutamide -binds more specifically, but not selectively
What is the structure of insulin hexamer?
Two Zn++ coordinated to 6 His residues on the B-chain 3 coordinated H2O molecules
What does nicotinamide cause in insulin aspart?
a decrease in chemical stability causing increased levels of high molecular weight proteins
Understand the reason that insulin detemir is a long-acting insulin preparation.
amide between lys side chain of Lys 29 on the B-chain & the carboxylic acid of myristic acid --> creates highly lipophilic area --> highly bound to plasma proteins such as albumin --> long-acting
PC3 cleaves at _____ & ______
arginine & arginine
Preproinsulin is synthesized in the ____
beta-cells of the pancreas
How is preproinsulin converted to proinsulin?
by catalytic removal of 24 amino acids from the N-terminal end
Be able to recognize a benzylic carbon
carbon alpha to a benzene ring
Understand the benzylic methyl groups usually are metabolized to ________.
carboxylic acid metabolites (COOH)
Where are Kir6.2/SUR2A found?
cardiomyocytes
What do compounds that bind at the SUR do?
close the channel & stimulate insulin secretion
What do alpha-glucosidase inhbitors do?
decrease glucose absorption
What do biguanides do?
decrease hepatic glucose production & enhances peripheral glucose uptake
The amino acid substitutions on the rapdily-acting insulins have been made at regions on the peptide that _____
do not bind to the insulin receptor
Why is insulin detemir less potent than human insulin?
due to steric effect of the myristic acid at the insulin receptor
How is proinsulin converted to insulin?
endopeptidases PC2 & PC3 cleave the connecting peptide (C-chain)
Meglitinide are ____ protein bond
extensively
Regular insulin self associated in a ____ form
hexamer
What does L-Arg cause in insulin aspart?
improves chemical stability
Where does the conversion from preproinsulin to proinsulin occur?
in the rough endoplasmic reticulum
What do thiazolidindiones do?
increase insulin sensitivity & peripheral glucose uptake
____ bind to A, B, or A+B sites
insulinotropes
What happens to the connecting peptide once insulin is formed?
it is processed via folding & disulfide bond formation
What must happen before insulin can be absorbed through blood capillaries?
it must dissociate into dimers & then monomers
PC2 cleaves at _____ & _____
lysine & arginine
Be able to give a possible explanation why nateglinide may have less cardiovascular side effects compared to rapaglinide.
may be due to lack of selectivity at Kir6.2-ATP channels of repaglinide in the pancreas
At low physiological conditions, insulin is found in the _____ form
monomer
Only the ____ form of insulin is able to interact with insulin receptors
monomer
The rapidly acting insulins exist as the ____ form at the injection site
monomer or dimer
The second generation sulfonylureas are _____ potent than first generation compounds
more
Insulin degludec forms ___ in the SC tissue
multihexamers therefore, absorption is prolonged
B-ligands is ___selective in closing pancreatic ATP-sensitive K+ channels
non-
What is the selecitivity of repaglinide?
non-selective for pancreatic KATP
Insulin degludec has ____ daily dosing
once
Where are Kir6.2/SUR1 found?
pancreatic Beta-cells
What does Kir stand for?
potassium inward rectifier channel
Insulin glargine _____ when injected SC
precipitates
Meglitinides are _____ absorbed
rapidly
Tolbutamide is a _____ acting sulfonylurea
short
What on the structure of insulin detemir contibutes to the strong binding to albumin?
the lipophilic side chain
Where is repaglinide eliminated?
through the bile
Where are Kir6.1/SUR2B found?
vascular myocytes
A-ligands is ___selective in closing pancreatic ATP-sensitive K+ channels
very
