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Mechanisms and Predisposing Conditions for Statin-Induced New-Onset Type 2 Diabetes Mellitus: A Paradox Relative to
Ali Nosrati Andevari1, Mohsen Koolivand2
1Department of Clinical Biochemistry, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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.
Insights
Statins can induce type 2 diabetes mellitus (T2DM) by inhibiting isoprenoid synthesis, affecting insulin secretion and sensitivity. However, some statins like pravastatin may offer neutral or beneficial effects on glucose metabolism.
Area of Science:
- Biochemistry
- Endocrinology
- Pharmacology
Background:
- Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder characterized by impaired insulin secretion and sensitivity.
- Statins are widely prescribed for T2DM patients to prevent complications and reduce mortality, primarily by inhibiting HMG-CoA reductase and lowering cholesterol.
- Despite potential pleiotropic antidiabetic effects, the diabetogenic impact of statins remains a subject of debate.
Purpose of the Study:
- To elucidate the mechanisms underlying statin-induced T2DM development.
- To identify specific statins and conditions associated with adverse glucose metabolism effects.
- To explore the role of isoprenoid synthesis inhibition in statin's diabetogenic actions.
Main Methods:
- A comprehensive narrative review of existing literature.
- Literature search conducted across PubMed, Scopus, and Google Scholar databases.
- Identification and synthesis of studies evaluating statin effects on glucose metabolism and T2DM.
Main Results:
- Statin-induced T2DM is primarily mediated by the inhibition of isoprenoids (e.g., farnesyl pyrophosphate, geranylgeranyl pyrophosphate) in the mevalonate pathway.
- Insulin secretion impairment in pancreatic beta cells is linked to cholesterol synthesis inhibition affecting SNARE proteins and calcium channels.
- Suppression of isoprenoids like Cdc42, Rac1, and Rab significantly impacts insulin secretion and sensitivity, independent of cholesterol levels.
- Some statins also influence insulin sensitivity through pathways not directly related to isoprenoid inhibition.
Conclusions:
- Atorvastatin, simvastatin, and rosuvastatin exhibit the strongest diabetogenic potential.
- Lovastatin, fluvastatin, pitavastatin, and particularly pravastatin demonstrate neutral or beneficial effects on glucose metabolism.
- The choice of statin may influence the risk of developing T2DM or impact glucose control in patients.
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