Statin Exposure Increases Star (Steroidogenic Acute Regulatory Protein) Expression in Islets: A Novel Mechanism for ß-Cell Dysfunction and Increased Diabetes Risk?

While statin therapy reduces plasma cholesterol, it also impairs β-cell function and increases the risk of developing diabetes. We have shown that the cholesterol transport protein STAR is synthesized in β cells and its upregulation results in increased β-cell mitochondrial cholesterol content, producing β-cell dysfunction. Given statins’ role in cholesterol metabolism, we determined whether statin exposure increased expression of islet STAR, decreased expression of the downstream cholesterol metabolizing enzyme CYP27A1 and inhibited β-cell function.
Atorvastatin treatment of C57Bl/6 islets increased Star gene (4.51±1.12 vs. 1.00±0.19, n=5, p<0.05) and a 3.3-fold increase in relative protein levels (n=2, p<0.005) while decreasing expression of Cyp27a1 (0.55±0.14 vs. 1.00±0.18, n=5, p<0.05). As expected, inhibition of the enzyme HMG-CoA reductase (Hmgcr) with atorvastatin resulted in compensatory increases in expression of Hmgcr and the LDL receptor (Ldlr); (Hmgcr: 5.88±0.65 vs. 1.00±0.05; Ldlr: 3.22±0.58 vs. 1.00±0.12; n=5, p<0.05), and a 5.1-fold increase in relative LDLR protein (n=2, p<0.05). Atorvastatin decreased glucose-stimulated insulin secretion (fold insulin response to 20 mM over 2.8 mM glucose: 28.6±5.86 vs. 52.0±8.25, n=5, p<0.05), but did not change insulin content (51.0±5.64 vs. 47.2±3.51 pmol insulin/5 islets, n=5, p=0.90).
In summary, exposure of islets to atorvastatin increased Star expression, decreased Cyp27a1 expression and reduced β-cell secretory function. These findings suggest that increased Star and impaired cholesterol metabolism, leading to increased cholesterol accumulation and mitochondrial dysfunction, may be a novel mechanism mediating the effects of statins to impair β-cell function and increase risk of type 2 diabetes.

Disclosure
M. F. Hogan: None. N. Esser: None. A. T. Templin: None. J. J. Castillo: None. R. Akter: None. R. L. Hull: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. S. Zraika: None.

Funding
American Diabetes Association (1-18-PDF-174 to M.F.H.); U.S. Department of Veterans Affairs (BX001060)