The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study

Abstract

Aim/hypothesis: Low-grade inflammation may contribute to obesity-related insulin resistance and has been associated with increased risk of type 2 diabetes mellitus. The present study evaluated whether treatment with salsalate, a traditional anti-inflammatory medication, would improve insulin action in obese non-diabetic individuals.

Methods: The study was a randomised, double-blind, placebo-controlled, parallel trial conducted at the inpatient clinical research unit of the NIDKK (Phoenix, AZ, USA). Participants were 54 adults (18 to 45 years of age) with BMI >or= 30 kg/m(2). The intervention was salsalate (3 g/day, n = 28) or identical placebo (n = 26) for 7 days. The allocation was kept concealed by giving the investigator only a number corresponding to a vial of placebo or salsalate sequentially randomised in blocks by sex. Main outcomes were changes in insulin action assessed as rate of glucose disposal (R (d)) by euglycaemic-hyperinsulinaemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) and glucose tolerance by 75 g OGTT.

Results: The study was completed by 47 participants, of which 40 were analysed (salsalate n = 22, placebo n = 18). Salsalate treatment resulted in decreased fasting plasma glucose concentration (mean [SD]; 4.83 [0.28] vs 5.11 [0.33] mmol/l, p = 0.001) and glucose AUC during the OGTT (p = 0.01), and in increased R (d) (20 [8] vs 18 [6] micromol [kg estimated metabolic body size](-1) min(-1), p = 0.002), while there was no significant change in these variables with placebo (p > 0.3 for all). The effect of salsalate on R (d) disappeared (p = 0.9) after normalising to increased insulin concentrations (701 [285] vs 535 [201] pmol/l, p < 0.0001) measured during the clamp. No side effects of salsalate were observed during the study.

Conclusions/interpretation: The glucose-lowering potential of salicylates appears to be due to effects on insulin concentration rather than improved insulin action. Salicylate-based compounds may be useful for the treatment and prevention of type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00339833.

Figures

Fig. 1

Plasma glucose and insulin concentrations (means and SD) during an OGTT at baseline (white circles) and after 6 days of treatment (black circles) with placebo (a, c) or salsalate (b, d). Repeated-measures ANOVA was used to test for the effects of time (p<0.0001 all models) and visit (follow-up vs baseline; glucose: p=0.2 after placebo, p=0.01 after salsalate; insulin: p=1.0 both), and for the visit × time interaction within each treatment group (glucose: p=0.9 placebo, p=0.4 salsalate; insulin: p=1.0 both groups). Between-group comparison (ANCOVA): group (placebo vs salsalate) × visit, p=0.007; group × visit × time, p=0.8

Fig. 2

Changes in: a serum insulin concentration (ΔSSSI; p=0.6 placebo, p<0.0001 salsalate, follow-up vs baseline by paired t test; p<0.0001 placebo vs salsalate by ANCOVA); b GIR (ΔGIR; p=0.9 placebo, p=0.004 salsalate; p=0.04 placebo vs salsalate); c EGP (ΔEGP; p=0.3 placebo, p=0.5 salsalate; p=0.9 placebo vs salsalate); and d Rd (ΔRd, adjusted for steady-state glucose; p=0.7 placebo, p=0.003 salsalate; p=0.02 placebo vs salsalate) during euglycaemic hyperinsulinaemia after treatment with placebo or salsalate. Data boxes display median (solid line), mean (dotted line), quartiles (box), and 10th and 90th percentiles (error bars)

Fig. 3

Change in Rd and serum insulin concentration from fasting state to euglycaemic hyperinsulinaemia at baseline (white circles) and after 7 days of treatment (black circles) with placebo (a) or salsalate (b) demonstrating that the increase in Rd during the clamp is directly associated with the increase in insulin concentration. Fasting Rd was assumed to be equal to the Ra (steady-state assumption) and clamp Rd was equal to M normalised to steady-state plasma glucose concentration. Data are shown as means (SE)

Fig. 4

a Spearman correlation between NF-κB activity (expressed as activity of p65 subunit) and Rd at baseline (normalised to steady-state plasma glucose concentration). r=−0.56; p=0.009. b The effect of treatment on NF-κB activity (n=10 per group). c Spearman correlation of changes (follow-up minus baseline) in Rd (normalised to steady-state plasma glucose concentration) and (d) NF-κB activity with serum salicylate concentrations at follow-up. r=0.47, p=0.03 (c). Black circles/bars, salsalate; white circles/bars, placebo; solid line, linear regression line; dotted line, 95% CI. (To convert plasma salicylate values in mg/l to mmol/l multiply by 0.00724)