Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance

Diabetes. 2014 Nov;63(11):3742-7. doi: 10.2337/db13-1398. Epub 2014 Jun 10.


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 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased interleukin-1β (IL-1β) secretion from macrophages, which is 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. Long-term 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 insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in lipopolysaccharide-primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β secretion. 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 that combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome, may be effective in preventing the adverse effects of statins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism*
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Fatty Acids, Monounsaturated / adverse effects
  • Fatty Acids, Monounsaturated / therapeutic use*
  • Fluvastatin
  • Glyburide / therapeutic use
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Indoles / adverse effects
  • Indoles / therapeutic use*
  • Inflammasomes / drug effects*
  • Inflammasomes / metabolism*
  • Insulin Resistance
  • Interleukin-1beta / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Obesity / drug therapy
  • Obesity / metabolism


  • Carrier Proteins
  • Fatty Acids, Monounsaturated
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indoles
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Fluvastatin
  • Caspase 1
  • Glyburide