01-07 PHARM Insulins

Question 1

How does insulin travel to the periphery?

Answer 1

nsulin travels to the liver via the portal system, and then to the periphery.

Question 2

What are the target tissues of insulin?

Answer 2

Insulin target tissues are liver, muscle, and fat.

Question 3

What intestinal peptides is released w/ p.o. intake of nutrients to potentiate insulin release?

Answer 3

incretins

Question 4

What are the steps by which rising glucose levels trigger insulin release?

Answer 4

1. glucose enters via GLUT 2
2. incr ATP prod causes an ATP-sensitive K+ channel to close
3. as a result the cell depolarizes
4. this causes voltage-gated Ca2+ channels to open
5. Ca2+ binds to vesicles containing insulin complexed with Zn and causes them to fuse with the cell membrane exocytosing their contents

Question 5

Describe the post-translational processing of insulin?

Answer 5

1. synth’d as pre-pro-insulin
2. pre- sequence targets protein to ER and then is cleaved off
3. pro-insulin is then cleaved into insulin + C-peptide (both of which are stored and released)

Question 6

Describe the insulin receptor

Answer 6

This receptor consists of 2 α subunits and 2 β subunits.
—α subunits contain the insulin binding domains
—β subunits have tyrosine kinase activity. Binding of insulin to the α subunits promotes autophosphorylation of the β subunits.
—this then phosphorylates effector proteins, like IRS-Insulin Receptor Substrates which can have short-term and long-term (i.e. ∆s in gene expression ↑ anabolism and ‪↓‬ catabolism)

Question 7

Describe the downstream signal effects insulin has when it binds its receptor on fat and muscle cells.

Answer 7

—insulin promotes the build- up and storage of nutrients, and inhibits their breakdown (promotes storage of glucose as glycogen, AAs as prots, and FAs as TGs. Furthermore, insulin inhibits the breakdown of glycogen, proteins, and fats.)
—it causes GLUT-4-containing vesicles to fuse with membrane allow ↑ glucose uptake and thus ‪↓‬ serum [gluc]

Question 8

List the five types of insulin we learned in class in order of their relative T1/2s and specify what (if any) modifications have been made to the protein

Answer 8

Short-acting insulin
Regular insulin
NPH Insulin
Insulin detemir
Insulin glargine

Question 9

Short-acting insulin

Answer 9

Lispro insulin (Humalog)
—In Insulin Lispro, Lys and Pro are reversed at amino acid positions at 28 and 29 of the B chain.
—Regular insulin aggregates w/ Zn requiring time for disaggregation and absorption.
—Lispro aggregates less, which allows for more rapid absorption.
—only needs to be taken 0-15 pre-meal!
—actual genetic ∆ to rDNA (vs. a structural ∆ w/ NPH)

Question 10

Regular insulin (e.g. Humulin-R)

Answer 10

rDNA via e. coli
—relatively short acting
—must be taken 30-60 mins pre-meal

Question 11

NPH-insulin (e.g. Humulin-N)

Answer 11

—Neutral Protamine Hagedorn
—precipitated w/ protamine, has to dissolve
—cloudy

Question 12

Insulin detemir (Levemir)

Answer 12

—a.a. added to end
—binds albumin in serum
—length of action almost as long as glargine

Question 13

Insulin glargine (Lantus)

Answer 13

—End of A chain Gly → Asparagine ∆
—End of B chain +2 Arg’s
—precipitates at subQ pH
—called “peakless” insulin b/c it is absorbed very slowly over time → no distinct [insulin] peak