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.

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.

FIG. 1.

Plasma concentrations of glucose (A), insulin (B), and C-peptide (C), and calculated insulin secretion rates (D) during the last 30 min of the hyperglycemic clamp. Clamps were performed on subjects in four randomized visits after a 48-h SAL infusion; a 48-h IH infusion; 2-week oral PBA (7.5 g/day), followed by a 48-h IH infusion; or 2-week oral PBA, followed by a 48-h SAL infusion. Data are means ± SE.

FIG. 2.

Plasma concentrations of glucose (A), glucose infusion rates (B), plasma concentrations of insulin (C), and calculated insulin clearance (D) during the last 30 min of the hyperinsulinemic-euglycemic clamp. Clamps were performed on subjects in four randomized visits after a 48-h SAL infusion; a 48-h IH infusion; 2-week oral PBA (7.5 g/day), followed by a 48-h IH infusion; or 2-week oral PBA, followed by a 48-h SAL infusion. Data are means ± SE. *P < 0.05 vs. SAL, †P < 0.05 vs. IH, ¶P < 0.01 vs. IH.

FIG. 3.

Insulin sensitivity index calculated from the last 30 min of the hyperinsulinemic-euglycemic clamp (A) and disposition index (B). Clamps were performed on subjects in four randomized visits after a 48-h SAL infusion; a 48-h IH infusion; 2-week oral PBA (7.5 g/day), followed by a 48-h IH infusion; or 2-week oral PBA, followed by a 48-h SAL infusion. Data are means ± SE. *P < 0.01 vs. SAL, ¶P < 0.05 vs. IH.