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Metabolism. 2014 Jun;63(6):735-45. doi: 10.1016/j.metabol.2014.02.014. Epub 2014 Feb 25.

Statin treatment and new-onset diabetes: a review of proposed mechanisms.

Author information

1
Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
2
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
3
Division of Internal Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
4
Endocrinology Section, VA Boston Healthcare System and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
5
Division of Internal Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: stella.daskalopoulou@mcgill.ca.

Abstract

New-onset diabetes has been observed in clinical trials and meta-analyses involving statin therapy. To explain this association, three major mechanisms have been proposed and discussed in the literature. First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic β-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling. Other possible mechanisms implicated in the effect of statins on new-onset diabetes are: statin interference with intracellular insulin signal transduction pathways via inhibition of necessary phosphorylation events and reduction of small GTPase action; inhibition of adipocyte differentiation leading to decreased peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein which are important pathways for glucose homeostasis; decreased leptin causing inhibition of β-cells proliferation and insulin secretion; and diminished adiponectin levels. Given that the magnitude of the risk of new-onset diabetes following statin use remains to be fully clarified and the well-established beneficial effect of statins in reducing cardiovascular risk, statins remain the first-choice treatment for prevention of CVD. Elucidation of the mechanisms underlying the development of diabetes in association with statin use may help identify novel preventative or therapeutic approaches to this problem and/or help design a new generation statin without such side-effects.

KEYWORDS:

Adipocytes; Adiponectin; Ca(2+) channels; Cholesterol; Diabetes mellitus; GLUT4; HMG-CoA inhibitors; Isoprenoids; Lipophilicity

PMID:
24641882
DOI:
10.1016/j.metabol.2014.02.014
[Indexed for MEDLINE]

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