A patient with type 2 diabetes is started on pioglitazone. After 3 months she complains of weight gain and ankle swelling. Which mechanism explains these side effects?
- A Increased appetite from central PPAR-gamma activation in the hypothalamus
- B Increased insulin secretion from pancreatic beta cells causing hyperinsulinemia
- C Activation of PPAR-gamma in adipocytes promoting differentiation and fat accumulation, plus renal collecting duct ENaC activation causing sodium and water retention ✓
- D Direct renal sodium retention via mineralocorticoid receptor activation
Explanation
Thiazolidinediones (pioglitazone, rosiglitazone) are PPAR-gamma agonists. Activation of PPAR-gamma in adipocytes promotes adipogenesis, increases fat storage (especially subcutaneous), and causes insulin sensitization. Fluid retention occurs via PPAR-gamma-mediated upregulation of sodium transporters (particularly ENaC) in the renal collecting duct, causing sodium and water retention independent of aldosterone. This leads to weight gain (fat + water) and edema. These drugs are contraindicated in heart failure (NYHA III-IV) and osteoporosis (PPAR-gamma also promotes osteoclast activity over osteoblast, increasing fracture risk).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.