Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance.

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 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.

• Authors: Brandyn D Henriksbo, Trevor C Lau, Joseph F Cavallari, Emmanuel Denou, Wendy Chi, James S Lally, Justin D Crane, Brittany M Duggan, Kevin P Foley, Morgan D Fullerton, Mark A Tarnopolsky, Gregory R Steinberg, Jonathan D Schertzer
• Journal: Diabetes (Diabetes) Vol. 63 Issue 11 Pg. 3742-7 (Nov 2014) ISSN: 1939-327X [Electronic] United States
• PMID: 24917577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Diabetes Association. 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.

Chemical References

• 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

Topics

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