OBJECTIVE: Chronically elevated free fatty acids contribute to insulin 
resistance and pancreatic β-cell failure. Among numerous potential factors, the 
involvement of endoplasmic reticulum (ER) stress has been postulated to play a 
mechanistic role. Here we examined the efficacy of the chemical chaperone, 
sodium phenylbutyrate (PBA), a drug with known capacity to reduce ER stress in 
animal models and in vitro, on lipid-induced insulin resistance and β-cell 
dysfunction in humans.
RESEARCH DESIGN AND METHODS: Eight overweight or obese nondiabetic men underwent 
four studies each, in random order, 4 to 6 weeks apart. Two studies were 
preceded by 2 weeks of oral PBA (7.5 g/day), followed by a 48-h i.v. infusion of 
intralipid/heparin or saline, and two studies were preceded by placebo 
treatment, followed by similar infusions. Insulin secretion rates (ISRs) and 
sensitivity (S(I)) were assessed after the 48-h infusions by hyperglycemic and 
hyperinsulinemic-euglycemic clamps, respectively.
RESULTS: Lipid infusion reduced S(I), which was significantly ameliorated by 
pretreatment with PBA. Absolute ISR was not affected by any treatment; however, 
PBA partially ameliorated the lipid-induced reduction in the disposition index 
(DI = ISR × S(I)), indicating that PBA prevented lipid-induced β-cell 
dysfunction.
CONCLUSIONS: These results suggest that PBA may provide benefits in humans by 
ameliorating the insulin resistance and β-cell dysfunction induced by prolonged 
elevation of free fatty acids.