Abstract
Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Several clinical reports have recently suggested an increased risk of type 2 diabetes associated with chronic use of these drugs. The pathophysiology of this effect remains to be fully elucidated but impaired β-cell function constitutes a potential mechanism. The aim of this study was to explore the effect of a chronic treatment with lipophilic and hydrophilic statins on β-cell function, using human pancreatic islets and rat insulin-secreting INS-1 cells; we particularly focused on the role of mitochondria and oxidative stress. The present study demonstrates, for the first time, that atorvastatin (lipophilic) but not pravastatin (hydrophilic) affected insulin release and mitochondrial metabolism due to the suppression of antioxidant defense system and induction of ROS production in pancreatic β-cell models. Mevalonate addition and treatment with a specific antioxidant (N-AcetylCysteine) effectively reversed the observed defects. These data demonstrate that mitochondrial oxidative stress is a key element in the pathogenesis of statin-related diabetes and may have clinical relevance to design strategies for prevention or reduction of statin induced β-cell dysfunction and diabetes in patients treated with lipophilic statins.
Highlights
Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention
To study the effects of statin treatment on insulin release, we firstly investigated acute glucose-stimulated insulin secretion in human pancreatic islets that had been chronically pre-exposed for 48 h to atorvastatin or pravastatin (10 or 100 ng/mL) (Fig. 1)
100 ng/mL (Panels C and D) and pravastatin 10 ng/mL (Panels E and F) or 100 ng/mL (Panels G and H). *P < 0.05, **P < 0.01 vs. control at 3.0 mM glucose; ##P < 0.01 vs. control at 11.1 mM glucose; §P < 0.05 vs. S.I. in control islets; n.s. not significant (1-way ANOVA followed by Bonferroni test, n = 9)
Summary
Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Mevalonate addition and treatment with a specific antioxidant (N-AcetylCysteine) effectively reversed the observed defects These data demonstrate that mitochondrial oxidative stress is a key element in the pathogenesis of statin-related diabetes and may have clinical relevance to design strategies for prevention or reduction of statin induced β-cell dysfunction and diabetes in patients treated with lipophilic statins. In the last few years, a growing body of evidence has highlighted a 10–12% increase in new-onset diabetes mellitus (NODM) among patients on statin therapy[4,5,6] This issue first came to light in the JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating rosuvastatin)[7, 8]; in March 2012, the US Food and Drug Administration (FDA) decided there was sufficient evidence to support the addition of a warning label about diabetes risk on statin packaging[9]. A high hepato-selectivity translates into minimal interference with cholesterol metabolism in tissues other than the liver and in a lesser diabetogenicity[11,12,13]
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