Mechanisms and Predisposing Conditions for Statin-Induced New-Onset Type 2 Diabetes Mellitus: A Paradox Relative to Their Pleiotropic Metabolic Effects

Abstract

Introduction

Type 2 diabetes mellitus (T2DM) is one of the most common metabolic disorders arising from decreased insulin secretion and insulin sensitivity. Patients with T2DM take statins to prevent diabetic complications and mitigate mortality risk associated with this disease. Statins primarily function by blocking HMG-CoA, resulting in reduced cholesterol levels. Statins have been suggested to possess certain antidiabetic properties. However, the overall effects of statins remain controversial. The aim of this study was to investigate the mechanisms and triggering conditions for the development of statin-induced T2DM, despite their reported pleiotropic antidiabetic effects.

Methods

This paper is a narrative review. A thorough literature search was carried out across PubMed, Scopus and Google Scholar to identify studies relevant to the evaluation.

Results

In the cholesterol biosynthesis pathway (the mevalonate pathway), in addition to cholesterol, isoprenoids such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate are also produced. Inhibition of these metabolites largely mediates the diabetogenic action of statins. The effects of statins on insulin secretion appear to be largely independent of cholesterol. However, the inhibition of cholesterol synthesis in pancreatic beta cells reduces insulin secretion through impaired function of SNARE proteins and calcium channels. The most prominent effects of statins on insulin secretion and sensitivity are attributed to the suppression of isoprenoids, particularly Cdc42, Rac1 and Rab. Furthermore, studies have shown that statins directly affect the levels of some insulin-sensitivity-related factors, independent of the identification of isoprenoid-mediated pathways.

Conclusions

Atorvastatin, simvastatin and rosuvastatin possess the most pronounced diabetogenic properties. In contrast, lovastatin, fluvastatin, pitavastatin and most notably pravastatin exert either neutral or advantageous effects with respect to glucose metabolism.