Insulin and Insulin Therapy Comprehensive Study Guide

Introduction and Historical Context

Discoverers: Insulin therapy was made possible through the revolutionary work of Banting and Best in $1922$. Their contribution earned the Nobel Prize in Medicine in $1923$.
Impact: It is considered the most active hypoglycemic treatment regardless of the type of diabetes. It revolutionized the treatment for "insulin-deprived" diabetics, who were previously doomed to undernutrition and always-fatal ketoacidosis.
Primary Indications: - Type 1 Diabetes (DT1): Represents the main and vital treatment. - Type 2 Diabetes (DT2): Increasingly introduced early in the management of certain patients.

Structure of Insulin

Nature: A polypeptide hypoglycemic hormone produced by the beta cells of the Islets of Langerhans in the pancreas.
Synthesis: Produced from proinsulin, which is cleaved into Peptide C (composed of $31$ amino acids or AA) and the active insulin molecule.
Polypeptide Chains: - Chain A: Consists of $21$ AA. - Chain B: Consists of $30$ AA. - Bridges: The two chains are linked by two disulfide bridges between residues A7-B7 and A20-B19.
Stereochemistry: In its normal state, the two chains coil around each other. This 3D spatial configuration allows the insulin to bind to and activate specific receptors on target organs.
Aggregation States: - In commercial preparations, native insulin tends to undergo auto-aggregation, transforming from monomeric insulin into hexameric complexes. - The residues implicated in this aggregation are the last amino acids of the B chain (residues B28, B29, and B30). - This tendency explains why most modifications to create rapid analogues (which remain monomeric) focus on the distal end of the B chain.

Categories and Classifications of Insulin

Except in emergencies or resuscitation, insulin is administered via subcutaneous injection. Classification is based on the duration of action:

Rapid Insulin Analogues (and Ultra-rapid insulin).
Regular or Ordinary Insulins (Rapid action).
Intermediate Action Insulins (Semi-slow or Semi-delayed; known as NPH: Neutral Protamine Hagedorn).
Fixed-proportion Mixtures (Premix): Combining rapid/ultra-rapid insulin with intermediate insulin.
Slow Insulins (Prolonged analogues).

Detailed Profile of Action Types

Regular Human Insulins (Soluble; Prandial): - Identical structure to native human insulin ($51$ AA). - Form hexamers in the vial, which must dissociate into dimers and monomers in the subcutaneous tissue before absorption. - Requirement: Must be injected at least $30$ minutes before a meal.
Retard Human Insulins (Basal; NPH): - Created by adding zinc and a protein (protamine) to regular insulin. - This forms crystals that slow the diffusion from the subcutaneous tissue to the blood. - Half-life: Between $5$ and $10$ hours. - Duration: Does not cover the entire $24$-hour cycle (nycthemeron), often requiring two daily injections (morning and evening).
Rapid Insulin Analogues (Monomeric): - Lispro (Humalog®): Position B28 (Proline) and B29 (Lysine) are inverted. - Novo Aspart (Novo Rapid®): Proline at B28 is replaced by aspartic acid. - Glulisine (Apidra®): Lysine at B29 is replaced by glutamic acid; Asparagine at B3 is replaced by lysine.
Ultra-rapid Insulin Analogues: - Goal: Activity peak around the $20^{th}$ minute; duration $\le 2$ hours. - Benefits: Better control of postprandial peaks and avoidance of hypoglycemia between $3$ and $4$ hours post-injection. - Development methods: Hyaluronidases or "biochaperones."
Slow Insulin Analogues: - Insulin Detemir (Levemir®): Attachment of a $14$-carbon fatty acid to B29 and deletion of Threonine at B30. This creates a $98\%$ affinity for albumin, slowing absorption. - Insulin Glargine U100 (Lantus®): Addition of two arginine residues at B31 and B32, and replacement of asparagine by glycine at A21. Zinc is added to facilitate recrystallization.
Slow Hyperconcentrated/Ultra-slow Analogues: - Glargine U300 (Toujéo®): $300$ Units/mL. Half-life is $19$ hours (vs $13.5$ hours for U100). - Degludec: Acylation with a $16$-carbon fatty acid at the B chain. Acting as a "flat insulin," its duration reaches $48$ hours.
Biosimilars: - Equivalent to "generics" for chemical drugs. A biosimilar must have the same chemical structure, physicochemical properties, and clinical safety/efficacy as the reference biological product. - Example: Abasaglar® is the biosimilar of Lantus®.
Premixed Insulins (Premix): - Fixed ratio mixtures, usually a rapid/ultra-rapid component and an NPH component. - Examples: Humalog Mix 25®, Humalog Mix 50®, Novo Mix 30®, $50$, or $70$. - The number represents the percentage of the rapid analogue.

Practical Modalities of Insulin Therapy

Concentration: Standardized at $100$ U/ml.
Packaging: $10$ ml vials or $3$ ml pen cartridges.
Administration Devices: - Syringe: Increasingly rare; inconvenient and less precise. - Self-injector Pen: Uses cartridges; better patient acceptance for multi-injection regimens. - Insulin Pump: Delivers rapid/ultra-rapid insulin continuously (basal rate) with boluses before meals. Most effective method.
Administration Routes: - Intravenous (IV): Hospital setting only; rapid/ultra-rapid only. - Intramuscular (IM): For mild ketosis without dehydration; rapid/ultra-rapid only. - Subcutaneous (SC): Standard practice for all insulin types. - Intraperitoneal: Reserved for implantable pumps or dialysis patients (DPCA). - Inhaled: Briefly commercialized (Exubera®, Afrezza®) but withdrawn from the market.

Injection Technique and Timing

Timing Guidelines: - Rapid Analogues/Premixes (Analogue): Just before, during, or immediately after a meal. - Rapid/Biphasic Insulins: $15$ to $30$ minutes before meals. - Intermediate Monophasic: $45$ to $60$ minutes before meals. - Slow Analogues: Independent of meals; must be at the same time daily (usually bedtime).
Injection Methods: - With Skin Fold (using $6$, $8$, $10$, or $12.7$ mm needles): Lift skin without muscle, inject at base of fold, hold fold during injection, count to $10$ before withdrawal. No massage. - Without Skin Fold (using $4$, $4.5$, or $5$ mm needles): Inject at $90^{\circ}$ while stretching skin. Count to $10$. No massage.
Sites and Absorption: - Order of speed: Abdomen > Arms > Thighs > Buttocks. - Absorption Data ($50\%$ absorption in $1$ hour): Abdomen ($1$ hour), Arms ($1.5$ hours), Thighs ($3$ hours). - Precaution: Avoid muscles about to be exercised to prevent accelerated resorption. Space injections by $1$ cm to avoid lipodystrophy.

Storage and Conservation

Unopened: Several years in the refrigerator at $2^{\circ}C$ to $8^{\circ}C$. Keep away from light and heat. Denatures if frozen or if temperature $> 30^{\circ}C$.
Opened: Vials or pens can stay at room temperature ($25^{\circ}C$ to $30^{\circ}C$) for $20$ to $30$ days if protected from light and extreme heat.

Indications for Insulin Therapy

Definitive and Vital: All patients with Type 1 Diabetes (DT1).
Definitive (DT2): When insulin-requiring, or in cases of renal or hepatic insufficiency.
Transient (DT2): - Metabolic decompensation (Category A). - Pregnancy. - Intercurrent pathologies (severe infection, surgery, corticosteroid use, myocardial infarction [IDM]). - Hyperalgic neuropathy.

Insulin Therapy Regimens

Initial titration should occur in a hospital to determine the adaptation dose and provide therapeutic education. The ideal regimen mimics physiology: a basal rate for fasting periods and boluses for meal-related sugar spikes.

1. Optimized Insulin Therapy (Basal-Bolus)

Indications: Motivated and educated DT1 with high life expectancy; DT2 failing oral drugs (ADO); Pregnancy; Severe infections.
Objectives: - Fasting Glycemia (GAJ) and Preprandial: $0.7$ to $1.10\,$g/l. - Postprandial Glycemia (GPP): $< 1.40\,$g/l. - HbA1c: $< 6.5 \text{ to } 7\%$.
Modality: Initial dose $\approx 0.5\,UI/Kg/j$. - $50\%$ slow analogue. - $50\%$ rapid analogue (split into $1/3$ for each meal). - Functional Insulin Therapy (IF): Centered on the patient; doses adjusted based on carbohydrate intake, sensitivity, weighting, and activity.

2. Limited Objective Regimen

Indications: Short life expectancy ($< 10$ years/elderly); patients refusing constraints (adolescents in denial).
Objectives: Avoid acute metabolic complications. GAJ $< 1.60\,$g/l, GPP $\approx 2\,$g/l, HbA1c $< 9\%$.
Modality: Two injections of Premix (before breakfast and dinner).

3. Survival Regimen

Indications: Very limited; elderly with very short life expectancy, physical/psychological handicap, or transient refusal in DT1.
Objectives: Only to avoid acute metabolic complications.
Modality: One single injection of a slow insulin.

Surveillance and Monitoring

Accidents and Incidents

Hypoglycemia: Most frequent and feared. Prevented by education on causes, signs, and treatment.
Lipodystrophies: - Lipoatrophy: Loss of fatty tissue (depression in skin). - Lipohypertrophy: Hypertrophy of subcutaneous tissue due to repeated injections in one site.
Allergy: Rare with human insulins; mostly mild local reactions.

Monitoring Tools

Capillary Glycemia: Daily self-monitoring (ASG) cycle including GAJ, preprandial, postprandial, and bedtime values.
Surveillance Log: Must record insulin doses, glycemia results, urine chemistry, hypoglycemia events, and dietary slips.
Urinary Strips: Primarily used for detecting ketone bodies.
Glycated Protein Markers: - HbA1c: Reflects average glycemia over the last $3$ months. - Fructosamine: Glycosylated proteins representing the last $15$ days. Useful during pregnancy, therapeutic changes, or when HbA1c is unreliable (e.g., severe anemia, beta-thalassemia major).

Special Case: Ramadan and ASG

Self-monitoring should occur $6$ to $7$ times daily:

Before dawn (Suhoor).
Morning.
Midday.
Mid-afternoon.
At breaking of the fast (Iftar).
Two hours after Iftar.
At any symptom of malaise or glycemic fluctuation.