Mechanism of Action of Insulin

Introduction

Insulin is a peptide hormone produced by pancreatic β‑cells. It belongs to the class of anabolic hormones. It plays a vital role in maintaining blood glucose homeostasis. Insulin therapy is crucial for managing type 1 diabetes and advanced type 2 diabetes.

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Step-by-Step Mechanism of Action

1. Receptor Binding
   • Insulin binds to the α‑subunits of the insulin receptor, a tetrameric receptor tyrosine kinase (RTK) on cell membranes (liver, muscle, adipose) 
2. Autophosphorylation
   • Binding triggers receptor β‑subunit autophosphorylation on tyrosine residues 
3. IRS Activation
   • Phosphorylated receptor recruits IRS proteins, activating PI3K → PIP3 cascade .
4. AKT Activation
   • PIP3 activates AKT (PKB), a key mediator of insulin action.
5. GLUT4 Translocation
   • AKT promotes GLUT4 translocation to the plasma membrane in muscle and adipose tissue, increasing glucose uptake 
6. Glycogen Synthesis
   • AKT inhibits GSK‑3, activating glycogen synthase and enhancing glycogenesis.
7. Hepatic Effects
   • Insulin reduces gluconeogenesis and glycogenolysis by regulating key enzymes
8. Lipogenesis & Protein Synthesis
   • Insulin promotes lipogenesis, protein synthesis and inhibits lipolysis and proteolysis .

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Pharmacokinetic Parameters

Parameter	Details
Absorption	Administered SC or IV; absorption varies by insulin formulation
Distribution	Remains extracellular; rapid portal to systemic gradient with endogenous insulin
Half‑life	4–6 minutes in plasma
Metabolism	Degraded via receptor-mediated endocytosis; primarily in liver and kidneys
Excretion	Broken into amino acids; renal elimination of fragments

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Clinical Uses

• Type 1 diabetes mellitus
• Advanced type 2 diabetes
• Diabetic ketoacidosis and hyperosmolar hyperglycemic states
• Hyperkalemia (promotes cellular K⁺ uptake)

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Adverse Effects

• Hypoglycemia – sweating, tremors, confusion
• Weight gain – due to anabolic effects
• Hypokalemia – from increased cellular K⁺ uptake
• Injection‑site reactions – lipodystrophy, erythema
• Allergic reactions – rare; often due to excipients

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Comparative Analysis

• Short‑acting (regular): Onset ~30 min; duration ~6–8 h
• Rapid‑acting analogues (e.g., lispro): Onset <15 min; better postprandial control
• Long‑acting analogues (e.g., glargine): Provide basal coverage (~24 h); lower hypoglycemia risk

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MCQs Section

1. Which receptor class does insulin bind?
   Receptor tyrosine kinase.
2. What effect does AKT have on GLUT4?
   Promotes translocation of GLUT4 to cell membrane.
3. Which enzyme does AKT inhibit to promote glycogen synthesis?
   Glycogen synthase kinase‑3 (GSK‑3).
4. Main organs responsible for insulin metabolism?
   Liver and kidneys.
5. What is the main risk of insulin overdose?
   Hypoglycemia.
6. Which insulin type is optimal for post-prandial glucose control?
   Rapid‑acting analogues.
7. Why does insulin therapy cause weight gain?
   Due to increased lipogenesis and protein anabolism.
8. Which electrolyte disturbance may insulin induce?
   Hypokalemia.
9. Best insulin for basal coverage?
   Long‑acting analogues (e.g., glargine).
10. Why isn’t insulin given orally?
    It degrades in the gastrointestinal tract, hence no bioavailability.

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FAQs

1. Can insulin treat type 2 diabetes?
   Yes, especially in later stages or during pregnancy.
2. How do you treat insulin-induced hypoglycemia?
   Fast-acting carbohydrates; IV glucagon or dextrose for severe cases.
3. Why rotate injection sites?
   To prevent lipodystrophy and ensure consistent absorption.
4. Why might insulin dose need adjustment during illness or stress?
   Stress hormones can increase insulin resistance, requiring dose adjustments.
5. Can patients develop antibodies to insulin?
   Yes; rare immune reactions may require changing the insulin formulation.

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References

• KD Tripathi, Essentials of Medical Pharmacology (Insulin chapter) 
• Goodman & Gilman, The Pharmacological Basis of Therapeutics (Pharmacokinetics of insulin) 
• Petersen & Shulman, “Mechanisms of Insulin Action and Insulin Resistance,” Physiol Rev (NCBI) pmc.ncbi.nlm.nih.gov+1journals.physiology.org+1