Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance

  1. Jonathan D. Schertzer1,2,*
  1. 1Department of Biochemistry and Biomedical Sciences,
  2. 2Department of Pediatrics,
  3. 3Department of Medicine, McMaster University, Hamilton, ON, Canada
  1. *Corresponding Author: Jonathan D. Schertzer, E-mail: schertze{at}mcmaster.ca

Abstract

Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor family, pyrin domain containing (NLRP)3/caspase-1 inflammasome promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased IL-1β secretion from macrophages, characteristic of NLRP3 inflammasome activation. This effect was dose-dependent, absent in NLRP3-/- mice and prevented by caspase-1 inhibition or the diabetes drug, glyburide. Chronic fluvastatin treatment of obese mice impaired insulin stimulated glucose uptake in adipose tissue. Fluvastatin-induced activation of the NLRP3/caspase-1 pathway was required for the development of adipose tissue insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in LPS primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β. Our results define an NLRP3/caspase-1-mediated mechanism of statin-induced insulin resistance in adipose tissue and adipocytes, which may be a contributing factor to statin-induced development of type 2 diabetes. These results warrant scrutiny of insulin sensitivity during statin use and suggest combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome may be effective in preventing the adverse effects of statins.

  • Received September 9, 2013.
  • Accepted March 31, 2014.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

This Article

  1. Diabetes
  1. All Versions of this Article:
    1. db13-1398v1
    2. db13-1398v2 most recent