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lüll Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans Xiao C; Giacca A; Lewis GFDiabetes 2011[Mar]; 60 (3): 918-24OBJECTIVE: Chronically elevated free fatty acids contribute to insulin resistance and pancreatic beta-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 beta-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 x S(I)), indicating that PBA prevented lipid-induced beta-cell dysfunction. CONCLUSIONS: These results suggest that PBA may provide benefits in humans by ameliorating the insulin resistance and beta-cell dysfunction induced by prolonged elevation of free fatty acids.|*Insulin Resistance[MESH]|Adult[MESH]|Analysis of Variance[MESH]|Blood Glucose[MESH]|Endoplasmic Reticulum/drug effects[MESH]|Humans[MESH]|Insulin Secretion[MESH]|Insulin-Secreting Cells/*drug effects/metabolism[MESH]|Insulin/metabolism[MESH]|Lipids/administration & dosage[MESH]|Male[MESH]|Middle Aged[MESH]|Obesity/*physiopathology[MESH]|Overweight/*physiopathology[MESH]|Oxidative Stress/*drug effects[MESH]|Phenylbutyrates/*pharmacology[MESH]|Radioimmunoassay[MESH] |