Diabetes MedChem

Type 1 Diabetes MOA

Beta cell destruction —> insulin deficiency, insulin dependent.

Type 2 Diabetes MOA

Beta cell function impaired —> insulin resistance, reduced sensitivity in muscles and tissues, NOT insulin dependent.

Insulin produced in:

Islets of langerhans

Alpha Cells

Produce glucagon, promote glycogen breakdown.

Beta Cells

Produce Insulin, promote glucose uptake into muscle and fat

Delta Cells

Produce somatostatin, inhibits insulin and glucagon release.

Prepro Insulin

110 amino acids, terminal portion cleaved in the endoplasmic reticulum to form proinsulin.

Pro Insulin

86 amino acids, connected by three disulfide bridges, C-Peptide cleaved in the golgi appartaus to form insulin.

Insulin A Chain

21 amino acids

Insulin B Chain

30 amino acids

Insulin A and B chains

Joined by disulfide bridges, c-peptide is cleaved.

Hexamer

Insulin aggregates, 6 units of insulin stabilized by zinc —> solution and stored form of insulin.

C-Peptide

Cleaved off of ProInsulin in golgi body, no pharmacological activity, indicative in diagnosis of insulin production.

High levels of glucose

GLUT2 receptor on Beta cells allows uptake of insulin into cells —> glycolysis —> ATP produced

After ATP produced

Potassium channel closes, K accumulates in cell, membrane depolarization—> voltage-gated calcium channels open, leading to calcium influx.

High calcium levels in cells:

Vesicles storing insulin break down to release insulin

Insulin target cell receptors are:

transmembrane receptors

Insulin target cell receptor —> 2 alpha units

Located OUTSIDE of cell, receive insulin

Insulin target cell receptor —> 2 beta units

Located INSIDE of cell, help transmit signals from the activated alpha units.

After insulin attaches to alpha subunits:

Series of phosphorylation reactions, end result is Glucose Synthase activation —> GLUT4 receptor on membrane of target cells opens —> Glucose enters cell.

Main targets of insulin:

Liver, muscle, fat

How is insulin administered, why?

Subcutaneous admin, very susceptible to digestive enzymes cannot be given orally.

Insulinase

Enzyme that breaks down disulfide linkage in insulin, causes loss of activity —> insulin has very short half life (stability improved my zinc- hexamer structure)

Rapid acting insulin:

Injected 15 mins before meals. fast onset, short duration: Lispro, Aspart, Glulisine

Short Acting insulin:

Injected 30-45 mins before meals, NATIVE insulin: SUSCEPTIBLE TO INSULINASE, lasts 5-8 hours

Intermediate Acting Insulin

Neutral Protamine Hagedom- 1-2x daily, Zinc and protamine complex in phosphate buffer dissolves gradually

Long Acting Insulin

1x daily: Detemir, Glargine, Degludec

How to alter onset and duration of insulin (fast vs slow)

Change the amino acid sequence —> alters tendency of insulin molecules to aggregate or dissociate.

Faster acting insulin- faster onset:

Want molecules to dissociate faster: create steric hinderance for rapid dissociation into monomers.

Longer acting insulin- prolong action:

Want molecules to stay in aggregated form for longer time: prepare at pH4 to prolong absorption+action (glargine)

Oxidation

Oxidizing di-sulfide bridges- loss of 2+3 structures—> loss of activity, must be protected from air.

Acidic Conditions

@pH 2 or 3: aspargine transformed to aspartic acid, alters insulin structure, keep neutral EXCEPT glargine (pH4)

How to change amino acid sequence

Addition, deletion, or replacement of amino acids on Chain B.