Interactions between Atorvastatin and the Farnesoid X Receptor Impair Insulinotropic Effects of Bile Acids and Modulate Diabetogenic Risk

Abstract

Bile acids such as chenodeoxycholic acid (CDC) acutely enhance insulin secretion via the farnesoid X receptor (FXR). Statins, which are frequently prescribed for patients with type 2 diabetes who suffer from dyslipidemia, are known for their diabetogenic risk and are reported to interact with the FXR. Our study investigates whether this interaction is relevant for beta cell signaling and plays a role for negative effects of statins on glycemic control. Experiments were performed with islets and islet cells from C57BL/6N wild-type and FXR-knockout (KO) mice. Culturing islets with atorvastatin (15 mM) for 24 hours decreased glucose-stimulated insulin secretion by approximately 30% without affecting ATP synthesis. Prolonged exposure for 7 days lowered the concentration necessary for impairment of insulin release to 150 nM. After 24-hour culture with atorvastatin, the ability of CDC (500 nM) to elevate [Ca 21 ] c was diminished and the potentiating effect on insulin secretion was completely lost. Mevalonate largely reduced the negative effect of atorvastatin. Nuclear activity of FXR was reduced by atorvastatin in a mouse FXR reporter assay. The atorvastatin-induced decrease in insulin release was also present in FXR-KO mice. Although not a prerequisite, FXR seems to influence the degree of damage caused by atorvastatin depending on its interaction with CDC: Preparations responding to CDC with an increase in insulin secretion under control conditions were less impaired by atorvastatin than preparations that were nonresponsive to CDC. Extended stimulation of FXR by the synthetic agonist GW4064, which is suggested to induce translocation of FXR from the cytosol into the nucleus, increased the inhibitory effect of atorvastatin. In conclusion, atorvastatin inhibits insulin release and prevents positive effects of bile acids on beta cell function. Both interactions may contribute to progression of type 2 diabetes mellitus. SIGNIFICANCE STATEMENTThis study shows that the diabetogenic risk of statins is coupled to the activity of farnesoid X receptor (FXR)-dependent signaling pathways in beta cells. On the one hand, statins abolish the insulinotropic effects of bile acids and on the other hand, FXR determines the level of impairment of islet function by the statin.

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“…This metabolite of cholesterol, which occurs naturally in human blood [ 37 ], is formed extrahepatically and has been observed to accumulate in human subdural hematomas in correlation with the time from bleeding to sample collection, and it has also been proposed as a diagnostic marker for dysfunctional blood–brain barrier [ 38 ]. This metabolite is taken up by the liver, where it is further oxidized into bile acids, mainly chenodeoxycholic acid [ 39 ], which have been shown to acutely enhance insulin secretion [ 40 ], explaining the accumulation of this precursor in our T2DM group.…”

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“…The mechanism of the FXR-dependent insulinotropic effect of BAs includes a block of potassium channels, membrane depolarization, and increased calcium concentration. For the stimulation of insulin secretion, the cytosolic localization of FXR and the BAs-induced interrelation with potassium channels are indispensable (25) .…”