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


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.
Goldfine
Allison B
AB
Joslin Diabetes Center & Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Silver
Robert
R
Aldhahi
Waleed
W
Cai
Dongsheng
D
Tatro
Elizabeth
E
Lee
Jongsoon
J
Shoelson
Steven E
SE