IP3 insulin pharmacology

Insulin Structure

Two chains (A: 21 aa, B: 30 aa) linked by 2 inter-chain and 1 intra-chain disulfide bonds

Insulin Synthesis

Preproinsulin → proinsulin → insulin + C-peptide

C-peptide Role

Marker of endogenous insulin secretion

GSIS Mechanism

↑ ATP → close K⁺ channels → depolarization → Ca²⁺ influx → insulin exocytosis

Insulin Receptor Type

Heterotetrameric tyrosine kinase (α2β2)

Insulin Signaling Cascade

IRS → PI3K → PDK1 → AKT → GLUT4 translocation

GLUT4 Location

Muscle, adipose (insulin-dependent)

GLUT2 Location

Liver, β-cells, kidney (glucose sensing)

Insulin Half-Life

3-6 minutes

Endogenous Clearance

Liver (60%), kidney (35-40%)

Exogenous Clearance

Kidney (60%), liver (30-40%)

Fiasp MOA

Aspart + niacinamide (↑ absorption) + arginine (stabilizer)

Lyumjev MOA

Lispro + citrate (↑ permeability) + treprostinil (vasodilation)

Afrezza MOA

Inhaled insulin with fumaryl diketopiperazine carrier

Lispro Structure

B28 Pro ↔ B29 Lys

Aspart Structure

B28 Pro → Asp

Glulisine Structure

B3 Asn → Lys, B29 Lys → Glu

Rapid-Acting Onset

5-15 min

Rapid-Acting Duration

3-4 hrs

Rapid-Acting Use

PPG control, CSII pumps

Regular Insulin Onset

30-60 min

Regular Insulin Duration

6-8 hrs

U-500 Use

Severe insulin resistance; high-alert med

IV Use

Only regular insulin (U-100)

NPH Composition

Insulin + protamine + zinc

NPH Appearance

Cloudy

NPH Duration

10-20 hrs

NPH ADR

Nocturnal hypoglycemia, protamine allergy

Glargine Structure

A21 Asn → Gly; +Arg at B31/B32

Glargine MOA

Precipitates at physiological pH

Glargine Duration

24-30 hrs

Glargine CI

Do not mix with other insulins

Degludec Structure

B30 Thr deletion + C16 FA at B29 via Glu spacer

Degludec MOA

Multihexamer formation + albumin binding

Degludec Duration

>42 hrs

Icodec Structure

B30 Thr deletion + C20 FA + 3 aa substitutions

Icodec Duration

~196 hrs (once weekly)

Afrezza Onset

5-15 min

Afrezza CI

COPD, asthma, smokers

Afrezza ADR

Cough, bronchospasm

70/30 Mix

70% NPH / 30% regular

75/25 Mix

75% lispro protamine / 25% lispro

Ryzodeg

70% degludec / 30% aspart

Rapid-Acting SAR

Prevent hexamer formation → faster absorption

Long-Acting SAR

Promote precipitation (glargine) or albumin binding (detemir, degludec)

Degludec SAR

Multihexamer + albumin depot = ultra-long action

Icodec SAR

C20 FA + 3 substitutions = once-weekly dosing

Absorption Factors

Site (abdomen fastest), temperature, massage, exercise

SC Absorption Order

Abdomen > arm > thigh > buttocks

Do Not Mix

Glargine, degludec, U-500

Storage

2-8°C; room temp ≤28 days once opened

Stability Risks

Acidic pH → deamidation, aggregation

U-100 vs U-500

U-500 = 5x concentrated; high alert

Hypoglycemia

Most common; treat with oral glucose (not sucrose)

Hypokalemia

Insulin drives K⁺ into cells

Lipohypertrophy

Rotate injection sites

Weight Gain

Common with insulin

Drug Interactions

↑ Hypoglycemia: SUs, alcohol, β blockers; ↑ Hyperglycemia: corticosteroids, thiazides, sympathomimetics

Rule of 15

15g glucose → recheck in 15 min

IV Insulin Monitoring

Check potassium

Humalog

Insulin lispro - Rapid-acting insulin

Admelog

Insulin lispro - Rapid-acting insulin

Lyumjev

Insulin lispro - Ultra-rapid-acting insulin

Novolog

Insulin aspart - Rapid-acting insulin

Fiasp

Insulin aspart - Ultra-rapid-acting insulin

Apidra

Insulin glulisine - Rapid-acting insulin

Humulin R

Regular insulin - Short-acting insulin

Novolin R

Regular insulin - Short-acting insulin

Novolin R ReliOn

Regular insulin - Short-acting insulin

Humulin R U-500

Regular insulin (concentrated) - Short-acting insulin

Myxredlin

Regular insulin IV solution - Short-acting insulin

Afrezza

Inhaled human insulin - Ultra-rapid-acting insulin

Humulin N

NPH insulin - Intermediate-acting insulin

Novolin N

NPH insulin - Intermediate-acting insulin

Novolin N ReliOn

NPH insulin - Intermediate-acting insulin

Lantus

Insulin glargine - Long-acting insulin

Toujeo

Insulin glargine - Long-acting insulin (concentrated)

Basaglar

Insulin glargine - Long-acting insulin

Rezvoglar

Insulin glargine-aglr - Long-acting insulin (biosimilar)

Semglee

Insulin glargine-yfgn - Long-acting insulin (biosimilar)

Tresiba

Insulin degludec - Ultra-long-acting insulin

Ryzodeg

70% insulin degludec / 30% insulin aspart - Premixed insulin

Humulin 70/30

70% NPH / 30% regular insulin - Premixed insulin

Novolin 70/30

70% NPH / 30% regular insulin - Premixed insulin

NovoLog Mix 70/30

70% aspart protamine / 30% aspart - Premixed insulin

Humalog Mix 75/25

75% lispro protamine / 25% lispro - Premixed insulin

Humalog Mix 50/50

50% lispro protamine / 50% lispro - Premixed insulin

Icodec (Awiqli)

Insulin icodec - Ultra-long-acting insulin (once-weekly, pending US approval)