Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes

Abstract

Objectives: Chronic subacute inflammation is implicated in the pathogenesis of insulin resistance and type 2 diabetes. Salicylates were shown years ago to lower glucose and more recently to inhibit NF-kappaB activity. Salsalate, a prodrug form of salicylate, has seen extensive clinical use and has a favorable safety profile. We studied the efficacy of salsalate in reducing glycemia and insulin resistance and potential mechanisms of action to validate NF-kappaB as a potential pharmacologic target in diabetes.

Methods and results: In open label studies, both high (4.5 g/d) and standard (3.0 g/d) doses of salsalate reduced fasting and postchallenge glucose levels after 2 weeks of treatment. Salsalate increased glucose utilization during euglycemic hyperinsulinemic clamps, by approximately 50% and 15% at the high and standard doses, respectively, and insulin clearance was decreased. Dose-limiting tinnitus occurred only at the higher dose. In a third, double-masked, placebo-controlled trial, 1 month of salsalate at maximum tolerable dose (no tinnitus) improved fasting and postchallenge glucose levels. Circulating free fatty acids were reduced and adiponectin increased in all treated subjects.

Conclusions: These data demonstrate that salsalate improves in vivo glucose and lipid homeostasis, and support targeting of inflammation and NF-kappaB as a therapeutic approach in type 2 diabetes.

Keywords: adiponectin; glucose; inflammation; insulin resistance; salicylate; salsalate; type 2 diabetes.

Figure 1

Metabolic parameters in subjects prior to treatment (pre, grey boxes) and after 2‐week treatment with 4.5 g/d (n= 7) or 3.0 g/d (n= 9) salsalate (post, black boxes). Fasting data are displayed for (A) blood glucose (mg/dL × 0.0555 = mmol/L), (B) insulin (pM/6.945 =μU/mL), (C) C‐peptide (nM/0.333 = ng/mL), (D) triglyceride (TG, mg/mL × 0.0113 = mmol/L), (E) total cholesterol (mg/dL × 0.0259 = mmol/L), (F) free fatty acids (FFA, mM), (G) C‐reactive protein (CRP, mg/dL), (H) sCD40L (ng/mL), (I) adiponectin (mg/dL), (J) glycated albumin (%), (K) nitrites (μM), (L) NF‐κB activity (arbitrary units), and (M) energy expenditure (kcal/d). Data represent mean ± SEM; *p < 0.05, **p < 0.005.

Figure 2

Euglycemic‐hyperinsulinemic clamp data are shown for subjects treated for 2 weeks with 4.5 g/d or 3.0 g/d salsalate. (A) Exogenous glucose infusion rates (GIR) and (B) rates of total body glucose utilization (Rd) were determined during clamps before (grey boxes) and after (black boxes) 2‐week treatment with 4.5 g/d or 3.0 g/d salsalate. (C) Rates of oxidative (grey boxes) and nonoxidative glucose metabolism (non‐ox, hatched boxes) are shown before and after 2‐week treatment with 4.5 g/d salsalsate. (D) Insulin clearance rates are shown at baseline (pre, grey boxes) and after 2‐week treatment (post, black boxes) with 4.5 g/d or 3.0 g/d salsalate. (E, F) Insulin levels achieved during the clamps (pM/6.945 =μU/mL) are before (dashed grey lines) or after (solid black lines) 4.5 g/d and 3.0 g/d salsalate, respectively. Data represent mean ± SEM; A, *p= 0.02, **p= 0.002. B, *p < 0.009. C, *p= 0.006. D, **p= 0.01, *p= 0.05. E, ANOVA, p < 0.005. F, ANOVA, p < 0.02.

Figure 3

Intravenous glucose tolerance tests (IVGTT). (A, B) Glucose excursions (mg/dL × 0.0555 = mmol/L) and (C, D) insulin responses (pM/6.945 =μU/mL) during IVGTTs were before (pre, dashed grey lines) or after (post, solid black lines) 2‐week treatment with (A, C) 4.5 g/d or (B, D) 3.0 g/d salsalate. (E) The acute (0–10 minutes) and (F) delayed (10–180 minutes) insulin secretory responses to glucose, calculated as the area under the curve (AUC) C‐peptide, at baseline (pre, grey boxes) and after 2‐week treatment (post, black boxes) with 4.5 g/d or 3.0 g/d salsalate. Data represent mean ± SEM; *p= 0.04.

Figure 4

Metabolic parameters of subjects treated with salsalate at highest tolerated dose. (A, B) Fasting glucose levels (mg/dL × 0.0555 = mmol/L) are at baseline and after 2 or 4 weeks of treatment or placebo; (C) change in fasting glucose values are for the salsalate (Sal) and placebo (Pla) groups at 4 weeks. (D) Glycated hemoglobin (%) is shown at baseline and after 4‐week salsalate (Sal) or placebo (Pla). (E, F) Glucose excursions following a liquid meal are before (pre, dashed grey lines) or after (post, solid black lines) 4‐week salsalate or placebo. (G) Changes in glucose (area under the curve, AUC) following liquid meal for salsalate (Sal) and placebo (Pla). Data represent mean ± SEM. *p < 0.04, **p= 0.002

Figure 5

Metabolic parameters. Responses to the liquid meal for subjects treated with (A, C, E) highest tolerated salsalate dose or (B, D, F) placebo are before (pre, dashed grey lines) or after (post, solid black lines) 4‐week treatment. (G) Adiponectin (mg/dL) levels were determined before and after 4‐week maximum tolerated dose salsalate or placebo, **p= 0.001. Insulin, pm/6.945 =μU/mL; C‐peptide nM/0.333 = ng/mL. Data represent mean ± SEM.