Salsalate Improves Glycemia and Inflammatory Parameters in Obese Young Adults

Abstract

OBJECTIVE -Sedentary lifestyle and a western diet promote subacute-chronic inflammation, obesity, and subsequently dysglycemia. The aim of the current study was to evaluate the efficacy of the anti-inflammatory drug salsalate to improve glycemia by reducing systemic inflammation in obese adults at risk for the development of type 2 diabetes.RESEARCH DESIGN AND METHODS -In a double-masked, placebo controlled trial, we evaluated 20 obese nondiabetic adults at baseline and after 1 month of salsalate or placebo.RESULTS -Compared with placebo, salsalate reduced fasting glucose 13% (P Ͻ 0.002), glycemic response after an oral glucose challenge 20% (P Ͻ 0.004), and glycated albumin 17% (P Ͻ 0.0003). Although insulin levels were unchanged, fasting and oral glucose tolerance test C-peptide levels decreased in the salsalate-treated subjects compared with placebo (P Ͻ 0.03), consistent with improved insulin sensitivity and a known effect of salicylates to inhibit insulin clearance. Adiponectin increased 57% after salsalate compared with placebo (P Ͻ 0.003). Additionally, within the group of salsalate-treated subjects, circulating levels of C-reactive protein were reduced by 34% (P Ͻ 0.05).CONCLUSIONS -This proof-of-principle study demonstrates that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in overweight individuals. These data support the hypothesis that subacute-chronic inflammation contributes to the pathogenesis of obesity-related dysglycemia and that targeting inflammation may provide a therapeutic route for diabetes prevention. Diabetes Care 31:289-294, 2008

Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRβ/IRS-1 and Akt

“…This proof-ofprinciple study demonstrates that salsalate reduces glycaemia and may improve inflammatory cardiovascular risk indexes in overweight individuals [32]. In addition, aspirin treatment improved glycaemic control of diabetic patients, in parallel with reductions in inflammatory response, including reduced levels of serum nitrite, which at least in part may be secondary to reduced iNOS activation [33].…”

Inflammation and adipose tissue macrophages in lipodystrophic mice

“…This suggested an inability to respond to challenge, akin to anergy or LPS tolerance, despite the fact that the Tg mice had never before been challenged with LPS. Given our interest in using the antiinflammatory drug salicylate to treat insulin resistant states related to inflammation (8,22,24,25), we also analyzed the ability of this drug to suppress LPS-induced cytokine gene expression. Mice were chronically treated with salicylate in their diet (4 g/kg), as we typically do to treat insulin resistance in obese C57BL/6J mice.…”

“…Two methods are available to conveniently target inflammation in obese mice as a way of improving insulin resistance. The first is the antiinflammatory drug salicylate, an effective pharmacologic inhibitor of NF-κB and insulin sensitizer in rodents and humans (8,(22)(23)(24)(25). The other uses Cre-Lox technology to genetically delete IκB kinase β (IKKβ) and thus inhibit NF-κB, in myeloid cells (Ikkβ Δmye ), including macrophages (26).…”

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

“…The first clinical trials with high dose (≥3 g) salsalate or the salicylate derivative trifusal indeed showed that fasting glucose levels decreased in nondiabetic, mostly obese, persons while insulin concentrations increased in the context of reduced insulin clearance [90][91][92]. In a pilot trial of 7 g aspirin/day for 2 weeks in nine patients with type 2 diabetes, similar changes were observed, with mean fasting plasma glucose levels falling from 9.1 to 6.9 mmol/l [93].…”