Monograph of Insulin

Introduction/Overview

Insulin remains the cornerstone of glycaemic management for individuals with diabetes mellitus. Its pivotal role in regulating carbohydrate, lipid, and protein metabolism has been confirmed through decades of clinical research. In contemporary practice, the breadth of insulin preparations—ranging from human recombinant variants to analogues with distinct kinetic profiles—has expanded therapeutic flexibility. Understanding the pharmacological nuances of insulin is essential for medical and pharmacy professionals to optimize patient outcomes, minimize complications, and tailor regimens to individual needs.

Learning Objectives

• Identify the pharmacodynamic and pharmacokinetic properties that distinguish insulin formulations.
• Elucidate the molecular mechanisms underlying insulin action at the cellular level.
• Apply knowledge of insulin pharmacology to clinical decision‑making, including dosing strategies and monitoring.
• Recognise major adverse effects, drug interactions, and special population considerations associated with insulin therapy.
• Integrate evidence‑based principles to formulate safe and effective insulin regimens.

Classification

Drug Classes and Categories

Insulin preparations are categorised primarily by onset and duration of action, reflecting their suitability for basal, prandial, or mixed therapeutic approaches. The major classes include:

• Rapid‑acting analogues (e.g., insulin lispro, aspart, glulisine)
• Short‑acting human insulin (regular insulin)
• Intermediate‑acting analogues (e.g., insulin detemir, degludec) and intermediate‑acting human insulins (NPH)
• Long‑acting analogues (e.g., insulin glargine, detemir, degludec)
• Ultra‑long‑acting analogues (insulin degludec with a duration exceeding 42 hr)
• Premixed formulations combining basal and prandial components

Chemical Classification

All insulin molecules are polypeptide hormones composed of two chains linked by disulfide bonds. Human recombinant insulin (human insulin) retains the native amino‑acid sequence, whereas analogues contain single or multiple amino‑acid substitutions that modify receptor affinity or proteolytic stability. Chemical modifications can be summarised as follows:

• Substitution at the B-chain amino‑acid position 3 or 21 to accelerate or prolong absorption.
• Addition of fatty acid chains (e.g., detemir) to enhance albumin binding and prolong action.
• Glycosylation or acylation (e.g., glargine) to shift isoelectric point and influence precipitation kinetics.

Mechanism of Action

Pharmacodynamics

Insulin exerts its effects by binding to the transmembrane insulin receptor (IR), a receptor tyrosine kinase expressed on virtually all metabolically active tissues. Receptor binding initiates autophosphorylation of specific tyrosine residues, creating docking sites for intracellular substrates such as insulin receptor substrates (IRS‑1, IRS‑2). Subsequent phosphorylation cascades activate phosphatidylinositol 3‑kinase (PI3K), leading to downstream signalling that promotes glucose transport, glycogen synthesis, and lipogenesis, while inhibiting gluconeogenesis and lipolysis.

In hepatocytes, insulin signalling enhances glucokinase activity and glycogen synthase while suppressing phosphoenolpyruvate carboxykinase, thereby reducing hepatic glucose production. In adipocytes, insulin stimulates the translocation of GLUT‑4 transporters to the plasma membrane, increasing fatty acid uptake, and activates acetyl‑CoA carboxylase to favour fatty acid synthesis.

Receptor Interactions

Human insulin binds the IR with high affinity, whereas rapid‑acting analogues exhibit slightly altered binding kinetics that facilitate faster onset. Long‑acting analogues are designed to minimise proteolytic degradation and maintain steady receptor occupancy. The receptor affinity profile can influence the magnitude and duration of downstream signalling, thereby shaping the clinical action profile.

Molecular/Cellular Mechanisms

Key cellular events include:

• Activation of IRS‑1/IRS‑2 → PI3K → Akt → GLUT‑4 translocation.
• Suppression of glycogenolysis via inhibition of glycogen phosphorylase kinase.
• Modulation of transcription factors (e.g., FOXO1, SREBP‑1c) that regulate gluconeogenic and lipogenic genes.
• Inhibition of hormone‑sensitive lipase, reducing free fatty acid release from adipose tissue.

Pharmacokinetics

Absorption

Subcutaneous insulin absorption is variable and influenced by injection site, depth, and local blood flow. Rapid‑acting analogues achieve C_max within 15–30 min, while long‑acting analogues display a gradual rise over 1–2 hr. Absorption can be delayed by lipohypertrophy or excessive subcutaneous fat. The absorption profile of each formulation dictates clinical scheduling decisions.

Distribution

Insulin distribution is largely confined to the extracellular fluid compartment. The volume of distribution approximates total body water (≈0.6 L/kg). Binding to plasma proteins is minimal; however, long‑acting analogues with fatty acid chains exhibit transient albumin binding, contributing to sustained release.

Metabolism

Insulin is primarily metabolised in the liver and kidneys via proteolytic cleavage. The rate of degradation correlates with receptor binding and internalisation; analogues with modified receptor affinity may exhibit altered metabolic clearance. The hepatic first‑pass effect is negligible due to subcutaneous administration.

Excretion

Renal excretion is a minor pathway, accounting for less than 10 % of insulin elimination. In patients with severe renal impairment, clearance is modestly reduced, but dose adjustments are rarely required unless concomitant hepatic dysfunction is present.

Half‑Life and Dosing Considerations

Rapid‑acting analogues have a t_1/2 of ~2–3 hr; short‑acting regular insulin has a t_1/2 ≈ 3–4 hr. Intermediate‑acting insulins such as NPH have a t_1/2 of ~5–8 hr, whereas long‑acting analogues (glargine, detemir) maintain a flat action profile for 24 hr. Ultra‑long‑acting degludec provides a t_1/2 ≈ 25 hr, enabling once‑daily dosing with minimal variability.

Dosing regimens are individualized based on glycaemic targets, carbohydrate intake, physical activity, and comorbidities. The basal‑bolus approach typically involves a basal insulin dose of 0.3–0.5 units/kg/day, divided into prandial injections of 0.2–0.4 units/kg. Premixed formulations simplify administration but reduce flexibility.

Therapeutic Uses/Clinical Applications

Approved Indications

Insulin therapy is indicated for:

• Type 1 diabetes mellitus (T1DM) requiring insulin replacement.
• Type 2 diabetes mellitus (T2DM) when oral agents fail to maintain glycaemic control.
• Gestational diabetes mellitus (GDM) to prevent fetal hyperglycaemia.
• Acute insulin deficiency states such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS).

Off‑Label Uses

Insulin is occasionally employed off‑label for:

• Severe hyperinsulinaemic hypoglycaemia in congenital disorders of carbohydrate metabolism.
• Management of hypertriglyceridaemia associated with pancreatitis when triglyceride levels exceed 10 mmol/L.
• Adjunctive therapy in oncology to counteract tumour‑induced insulin resistance, although evidence remains limited.

Adverse Effects

Common Side Effects

• Hypoglycaemia (most frequent, ranging from mild to severe).
• Injection‑site reactions: erythema, induration, lipohypertrophy.
• Weight gain secondary to anabolic effects.

Serious/Rare Adverse Reactions

• Hypersensitivity reactions, including anaphylaxis, primarily associated with bovine or porcine insulin preparations.
• Insulin‑induced edema in susceptible individuals.
• Rare cases of insulin resistance leading to marked hyperglycaemia.

Black Box Warnings

The predominant warning concerns the risk of severe hypoglycaemia, particularly in patients with impaired counter‑regulatory responses such as the elderly, those with renal dysfunction, or individuals on concomitant agents that lower blood glucose.

Drug Interactions

Major Drug‑Drug Interactions

Co‑administration of insulin with the following agents may necessitate dose adjustments:

• Oral hypoglycaemics (sulfonylureas, meglitinides) – additive hypoglycaemic effect.
• Glucocorticoids – increase insulin resistance, requiring higher doses.
• Thiazolidinediones – potentiate insulin sensitivity, potentially reducing required insulin.
• Digoxin – may potentiate hypoglycaemia through sympathetic activation.
• Beta‑blockers – mask hypoglycaemic symptoms, increasing risk of severe episodes.

Contraindications

Insulin is contraindicated in:

• Patients with known hypersensitivity to any insulin component.
• Pregnancy in the first trimester if the patient has a history of severe hypoglycaemic episodes in response to insulin.
• Acute hypoglycaemic states with compromised consciousness, where intravenous glucose is preferred.

Special Considerations

Use in Pregnancy/Lactation

Insulin remains the treatment of choice for diabetes during pregnancy due to its safety profile. The insulin dose should be titrated to maintain target glucose ranges to mitigate fetal complications. Lactation is not contraindicated; insulin does not significantly affect breast milk composition, and breast‑fed infants tolerate maternal insulin therapy without adverse effects.

Pediatric/Geriatric Considerations

Children require weight‑based dosing, typically 0.5–1 units/kg/day, with careful monitoring of growth parameters. In older adults, the risk of hypoglycaemia increases due to diminished counter‑regulatory capacity and variable renal function; thus, basal insulin doses may be reduced, and monitoring intervals extended.

Renal/Hepatic Impairment

In moderate renal impairment (creatinine clearance 30–60 mL/min), insulin clearance is reduced by ~10–15 %; dose adjustments are usually unnecessary but vigilance for hypoglycaemia is advised. Severe hepatic dysfunction may prolong insulin action due to decreased metabolic capacity, warranting cautious titration.

Summary/Key Points

• Insulin’s therapeutic efficacy stems from its precise modulation of glucose homeostasis via receptor‑mediated signalling.
• Formulation selection should align with patient lifestyle, glycaemic goals, and tolerability of injection‑site reactions.
• Hypoglycaemia remains the principal safety concern; patient education and regular glucose monitoring are essential.
• Drug interactions, particularly with agents affecting glucose metabolism, necessitate dose recalibration.
• Special populations—including pregnant women, children, and patients with renal or hepatic impairment—require individualized dosing strategies to minimise adverse outcomes.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.