Statins — how they increase diabetes risk

Statins have been observed to increase the risk for type 2 diabetes; a study published recently in the journal Diabetes reveals a mechanism. The authors note their interest in an inflammatory immune response pathway:

"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."

Using statins including fluvastatin (Lescol®), they showed that the proinflammatory cytokine IL-1β was increased,  resulting in impaired nsulin signaling (long known to be worsened by inflammation):

"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."

 Clinical note: Knowing that statins activate the NLRP3/caspase-1 inflammasome that promotes inflammation and insulin resistance should caution practitioners to attend carefully to insulin sensitivity in patients taking statins. The authors conclude:

"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."