Exenatide is a GLP-1 receptor agonist used in T2DM. Its glucose-lowering effects are glucosedependent, meaning it does not cause hypoglycaemia in normoglycaemia. The reason for this glucosedependency is:

• A GLP-1 receptors on β-cells are internalised in the absence of glucose, preventing receptor activation
• B GLP-1 receptor stimulation increases cAMP, which potentiates KATP channel closure and insulin exocytosis ONLY when glucose is already depolarising the β-cell membrane ✓
• C Exenatide requires glucokinase activation (which occurs only at high glucose) to enter the β-cell
• D Exenatide stimulates somatostatin release at low glucose, which auto-inhibits insulin secretion

Explanation

GLP-1 receptor activation raises β-cell cAMP (via Gs-coupled pathway), which activates PKA and Epac2, potentiating the upstream glucose-sensing pathway. Specifically, GLP-1 enhances insulin secretion only when glucose is already metabolised by the β-cell, creating membrane depolarisation via KATP closure. Without glucose-triggered depolarisation, the cAMP signal alone is insufficient to trigger Ca2+ entry and exocytosis. This glucose-dependency makes GLP-1 agonists and DPP-4 inhibitors have a very low risk of hypoglycaemia as monotherapy.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.