title: Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Changting
authors.initials: C
authors.lastname: Xiao
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001786:Blood Glucose; D004721:Endoplasmic Reticulum / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000503:physiopathology*; D050177:Overweight / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects*; D010654:Phenylbutyrates / Q000494:pharmacology*; D011863:Radioimmunoassay
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D010654:Phenylbutyrates