Desai Diabetes

Question 1

Describe the main pathophysiology with type 2 diabetes. DM 1?

Answer 1

DM 2 involves reduced ability of target cells to respond to insulin DM 1 involves inability of beta-islets of Langerhans to produce insulin

Question 2

By which major mechanism does insulin bring in glucose in cells? What are other mechanisms?

Answer 2

1) Stimulates GLUT-4 2) inhibits glucagon secretion 3) Prevents use of FA for energetic purposes 4) Inhibits gluconeogenesis 5) stimulates glucose to glycogen conversions

Question 3

Without insulin, where does the body get its energy? What are problems with this?

Answer 3

Adipose cells –> production of ketone bodies Muscle cells –> amino acids lead to ammonia Liver cells –> both

Question 4

Why are ketone bodies produced?

Answer 4

Ketones are hydrophobic and aggregate with each other

Question 5

Which gene, if mutated, has a strong link to insulin resistance?

Answer 5

Glucokinase gene (G –> G6P)

Question 6

Why is high blood glucose levels bad long term? (chemically speaking)

Answer 6

The aldehyde group of glucose will be converted by aldose reductase to sorbitol. Sorbitol does not pass through membranes so osmolality increases in cells until the point of lysis and rupture.

Question 7

Which configuration of insulin is the active species? What bonds are hold together insulin?

Answer 7

The 21 AA residue is the active one (held by disulfide bonds) - Proinsulin consists of a connecting peptide

Question 8

What happens if you store insulin for too long?

Answer 8

Deamidation of asparagine A21 to form an anhydride.

Also deamidation of asparagine B3 to form aspartate and isoasparatate

Question 9

Removal of which residues on insulin destroys its activity? Which dimishes activity?

Answer 9

Removal of 8 residues from the C-terminus of B chain destroys activity

Removal of N-Gly from the A chain dimishes activity

Question 10

Which form of sulfonyl ureas predominate in blood? Draw the structure? What is its MOA?

Answer 10

The anionic form predominates in the blood

SU stimulates release of insulin from B-cells. Act through potassium ion-channels that generate Ca++ influx

Question 11

Which first generation sulfonyl urea has active metabolites?

Answer 11

Chlorpropamide

2’-OH and 3’OH groups

Question 12

Can sulfonyl ureas be used as an antibiotic? Why?

Answer 12

Typical sulfa drugs mimic the action of p-aminobenzoic acid (PABA).

SU are not antibiotics because of the absence of the primary amine missing on the phenyl group

Question 13

What are some key points of Glinides?

Answer 13

• Functionally similar to SUs
• MOA is identical
• shorter DOA
• have carboxylic acids

Question 14

What is the structure of Metformin? Why is it called a biguanide?

Answer 14

It has two guanido groups

Question 15

What are TZD structure an isostere for?

Answer 15

Isostere for COOH group of prostanoids that recognize PPARy

Question 16

Which glitazone is associated with ADR events? Why?

Answer 16

Troglitazone

Because of the quinone structure

Question 17

What is the transition state of hydrolysis of glucose chains? What does Acarbose try to do with this?

Answer 17

Azonium ion

Acarbose mimics this structure

Question 18

What is the MOA of gliptins?

Answer 18

Enhance lifespan of GLP-1 and G1P which regulate insulin secretion

Question 19

What structural moeities does DPP4 recognize? What is the structural moeity that is special in gliptins?

Answer 19

DPP4 recognizes proline structures similar to gliptins. Gliptins contain nitriles that make them reversible.