Insulin

1. Introduction

• Insulin is a peptide hormone produced by the β-cells of the pancreatic islets of Langerhans.

• Central regulator of glucose metabolism, controlling blood sugar levels by promoting cellular uptake, storage, and utilization of glucose.

• Deficiency or resistance to insulin leads to diabetes mellitus.

• In medicine, insulin also refers to pharmaceutical preparations used for the treatment of diabetes and certain hyperkalemic states.

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2. Structure and Biosynthesis

• Composed of two peptide chains:

  • A chain – 21 amino acids.

  • B chain – 30 amino acids.

  • Linked by two disulfide bridges.

• Synthesized as preproinsulin → converted to proinsulin in the endoplasmic reticulum → cleaved into insulin and C-peptide in the Golgi apparatus.

• Stored in secretory granules until released in response to stimuli.

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3. Physiological Secretion

• Stimulated by:

  • Elevated blood glucose (primary trigger).

  • Amino acids (arginine, leucine).

  • Gastrointestinal hormones (GLP-1, GIP).

• Inhibited by:

  • Low blood glucose.

  • Catecholamines via α2-adrenergic receptors.

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4. Mechanism of Action

• Binds to insulin receptor, a transmembrane receptor with intrinsic tyrosine kinase activity.

• Triggers autophosphorylation and activation of intracellular signaling pathways:

  • PI3K-Akt pathway – increases glucose transporter (GLUT4) translocation, glycogen synthesis, lipid synthesis, protein synthesis.

  • MAPK pathway – affects cell growth and differentiation.

• Overall effect: promotes anabolic metabolism and inhibits catabolic processes.

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5. Metabolic Actions

• Carbohydrate metabolism:

  • Increases glucose uptake in muscle and adipose tissue.

  • Stimulates glycogen synthesis in liver and muscle.

  • Inhibits hepatic gluconeogenesis and glycogenolysis.

• Lipid metabolism:

  • Promotes lipogenesis.

  • Inhibits lipolysis.

• Protein metabolism:

  • Stimulates amino acid uptake and protein synthesis.

  • Inhibits proteolysis.

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6. Pharmaceutical Preparations

A. Based on Onset and Duration of Action

• Rapid-acting (e.g., insulin lispro, insulin aspart, insulin glulisine) – onset 10–30 min; duration 3–5 h.

• Short-acting (e.g., regular insulin) – onset 30–60 min; duration 5–8 h.

• Intermediate-acting (e.g., NPH insulin) – onset 1–2 h; duration 12–18 h.

• Long-acting (e.g., insulin glargine, insulin detemir) – onset 1–2 h; duration up to 24 h.

• Ultra-long-acting (e.g., insulin degludec) – duration >42 h.

B. Mixtures

• Fixed combinations of short/rapid-acting and intermediate-acting insulin for convenience.

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7. Routes of Administration

• Subcutaneous injection – most common for chronic therapy.

• Intravenous infusion – for emergencies (e.g., diabetic ketoacidosis, hyperkalemia).

• Inhaled insulin – alternative for mealtime coverage in selected patients.

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8. Indications

• Type 1 diabetes mellitus (absolute requirement).

• Type 2 diabetes mellitus when oral agents are insufficient.

• Gestational diabetes not controlled with diet/oral drugs.

• Diabetic ketoacidosis and hyperosmolar hyperglycemic state.

• Hyperkalemia (with glucose to prevent hypoglycemia).

• Certain cases of stress-induced hyperglycemia in hospital settings.

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9. Contraindications

• Hypoglycemia.

• Known hypersensitivity to specific insulin formulation or excipients.

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10. Adverse Effects

Common

• Hypoglycemia – most important and potentially life-threatening.

• Weight gain.

• Local injection site reactions.

Less Common

• Lipodystrophy (lipoatrophy or lipohypertrophy) at injection sites.

• Edema.

Rare

• Insulin allergy (local or systemic).

• Insulin resistance (immune-mediated).

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11. Drug Interactions

• Hypoglycemia risk increased by: oral hypoglycemics, β-blockers (mask symptoms), ACE inhibitors, alcohol.

• Hyperglycemia risk increased by: corticosteroids, thiazide diuretics, sympathomimetics.

• Potassium-lowering effect enhanced by: combined use with β2-agonists or potassium-binding resins.

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12. Monitoring

• Blood glucose (self-monitoring and laboratory).

• HbA1c (every 3–6 months).

• Signs of hypoglycemia.

• Weight changes.

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13. Advantages

• Most effective agent for lowering blood glucose.

• Can be tailored in type, dose, and regimen for individual needs.

• Allows tight glycemic control, reducing risk of microvascular complications.

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14. Limitations

• Requires injections or special delivery systems.

• Hypoglycemia risk if dose, food intake, and activity are not balanced.

• Weight gain potential.