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

Allison B. Goldfine, Robert Silver, Waleed Aldhahi, Dongsheng Cai, Elizabeth Tatro, Jongsoon Lee, Steven E. Shoelson

Research output: Contribution to journalArticle

187 Citations (Scopus)

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-κB 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-κB 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. Doselimiting 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-κB as a therapeutic approach in type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)36-43
Number of pages8
JournalClinical and Translational Science
Volume1
Issue number1
DOIs
StatePublished - 2008
Externally publishedYes

Fingerprint

Medical problems
Type 2 Diabetes Mellitus
Insulin Resistance
Insulin
Inflammation
Glucose
Tinnitus
Salicylates
Fasting
Therapeutics
Glucose Clamp Technique
Adiponectin
Clamping devices
Prodrugs
Nonesterified Fatty Acids
Action Potentials
salicylsalicylic acid
Labels
Homeostasis
Placebos

Keywords

  • Adiponectin
  • Glucose
  • Inflammation
  • Insulin resistance
  • Salicylate
  • Salsalate
  • Type 2 diabetes

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. / Goldfine, Allison B.; Silver, Robert; Aldhahi, Waleed; Cai, Dongsheng; Tatro, Elizabeth; Lee, Jongsoon; Shoelson, Steven E.

In: Clinical and Translational Science, Vol. 1, No. 1, 2008, p. 36-43.

Research output: Contribution to journalArticle

Goldfine, Allison B. ; Silver, Robert ; Aldhahi, Waleed ; Cai, Dongsheng ; Tatro, Elizabeth ; Lee, Jongsoon ; Shoelson, Steven E. / Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. In: Clinical and Translational Science. 2008 ; Vol. 1, No. 1. pp. 36-43.
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AB - 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-κB 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-κB 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. Doselimiting 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-κB as a therapeutic approach in type 2 diabetes.

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