A patient with type 2 DM has HbA1c of 9.2% and is started on a GLP-1 receptor agonist. The weight loss observed is primarily mediated by which mechanism distinct from its glucose-lowering action?
- A Peripheral GLP-1 receptor activation in adipocytes increases lipolysis and thermogenesis via PKA-mediated HSL phosphorylation
- B Inhibition of ghrelin secretion from gastric fundal cells, reducing hunger signals to the brain
- C Central GLP-1 receptor activation in the hypothalamic arcuate nucleus increases POMC/CART signalling, decreasing appetite, combined with delayed gastric emptying reducing nutrient absorption rate ✓
- D Hepatic GLP-1 receptor activation increases FGF-21 release promoting fatty acid oxidation and adipose browning
Explanation
GLP-1 receptor agonists reduce body weight through two complementary mechanisms: (1) Central action — GLP-1 receptors in the hypothalamic arcuate nucleus (on POMC neurons) and brainstem nucleus tractus solitarius (NTS) reduce appetite and caloric intake by augmenting satiety signals. Semaglutide, for example, has enhanced CNS penetrance that likely explains its superior weight-loss efficacy. (2) Peripheral gastrointestinal action — GLP-1 receptors in vagal afferents and gastric myenteric plexus delay gastric emptying, slowing nutrient delivery, reducing postprandial glucose excursions, and prolonging satiety. The weight loss is dose-dependent and independent of glycaemic control, as demonstrated by STEP trials of semaglutide 2.4 mg in non-diabetic obese individuals achieving 15% body weight loss.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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