insulin

Pharmacological Effects

1. on carbohydrate :decreases blood glucose
2. On fat : decreased fat breakdown - results in increased obesity with non-optimal diet for DM2 & Obesity
3. On protein metabolism :decreased breakdown (anabolic effect): Long-term actions: Stimulation of cell proliferation - for normal growth
4. On electrolytes: decrease potassium ,PO4, Ca++, magnesium blood concentration due to uptake into cells with glucose.
5. Antiketogenic: decrease ketone bodies (acetone, AAA, BHBA) in the liver and help ketolysis

MOA of insulin:

Insulin receptors: Structure: 2 extra-cellular α-subunits & 2 trans-membrane β-subunits.

Mechanism of action: Binding of insulin to α-subunits → ++ of β-subunits → ++ of tyrosine kinase enzyme → trigger series of IC effects → ↑ number of glucose transporters (especially GLUT4) on cell membrane → ↑ transport of glucose into the cell.

After doing its action, insulin-receptor complex is internalized by endocytosis.

Cell membranes are impermeable to glucose, they require a special carrier, called a glucose transporter, to move glucose from the blood into the cell.

GLUT-4 is the insulin-dependent glucose transporter for skeletal muscle and adipose tissueZ

GLUT-2 is the major transporter of glucose into beta cells and liver cells. It has a low affinity for glucose and acts as a transporter only when plasma glucose levels are relatively high, such as after a meal.

GLUT-1 is present in all tissues. It does not require the actions of insulin and is important in transport of glucose into cells of the nervous system.

Factors that ↑ affinity of insulin receptors (up-regulation):

Insulin deficiency (e.g. starvation) → ↑ number of receptor. Drugs:

• Thiazolidinediones: e.g pioglitazone, rosiglitazone.
• Sulphonylureas: e.g gliclazide.
• Biguanides e.g
• Trace elements: e.g selenium and chromium.

Factors that ↓ affinity of insulin receptors (down-regulation)

• Obesity - DM2
• Drugs: e.g. Corticosteroids…….

Sources of insulin:Y

• Traditional (animal) insulin: prepared from: animals (beef and pork).
• Pork insulin differs from human insulin in 1 aa (alanine in pork and threonine in human) while beef insulin differs from human in 3 aa.
• Human insulin:

Human insulin: prepared by 2 methods:

• From pork insulin by chemical replacement of alanine by threonine.
• Recombinant DNA technology (genetic engineering).

Advantages of human insulin:

• Highly purified
• least antigenic.
• Rare resistance.
• Used in insulin resistance and gestational DM.

Administration

• Insulin is administered either IV, IM or SC. Oral, inhaled ………………

Insulin Therapy

The duration of action of insulin can be varied by:

1. Modification of the insulin molecule (by recombinant technology)

2. Conjugation of insulin with protamine in a low soluble complex. After injection proteolytic enzymes degrade protamine so allowing absorption of insulin.

3. Combination of insulin with zinc, to form zinc salts. After injection the salt precipitates and insulin is slowly released.

Different PREPARATIONS of insulin:

Onset & DurationZ

1. Ultrashort -ACTING INSULIN: Insulin Lispro & Aspart
2. SHORT-ACTING INSULIN:
   • Regular, neutral, soluble insulin
   • Semi-Lente insulin
3. Intermediate-ACTING INSULIN
4. Long-Acting Insulin
   • Ultra-lente insulin-insulin zinc suspension:
   • Insulin glargine
5. Mixture of Insulin
   • Pre-mixed formulations (Biphasic) of 30% regular (short) and 70% NPH (intermediate): provide rapid onset and prolonged duration.

Insulin administration

Side effects of insulin:Local side effects:

1. Allergy: at the site of injection (due to formation of IgGE). Treatment:

   • Change the type of insulin to more purified preparation. change site injection regularly
   • Local corticosteroids or antihistamines.

2. Lipodystrophy: atrophy or hypertrophy of s.c tissue after repeated injections. Treatment:

   • Change the site of injection regularly.
   • In lipoatrophy, give cone purified regular insulin in the center and periphery of the atrophic area to stimulate lipogenesis.

3. Local infection.

Systemic side effects:

• Hypoglycemia: the most common and dangerous side effect.
• Hypokalemia: insulin causes shift of K+ from extracellular to intracellular fluid.
• Hypersensitivity reactions: urticaria, angioedema or anaphylactic shock.
• Weight gain

Other Effects:

- Insulin resistance (IR)

- Pseudo-insulin resistance (Somogyi phenomenon):

- Dawn phenomenon

Events Requiring an Increase in Dosage of Insulin in Diabetic Patients

• Infections
• High fever
• Trauma, surgical operations
• Myocardial infarction
• Pregnancy
• Hyperthyroidism
• Diabetic ketoacidosis