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

Brault, Marilyne; Ray, Jessica L.; Gomez, Yessica-Haydee; Mantzoros, Christos S.; Daskalopoulou, Stella S.

doi:10.1016/j.metabol.2014.02.014

Cited by 201 publications

(180 citation statements)

References 93 publications

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“…2014; Robinson 2015). Interestingly, nearly two decades of randomized, control trials and meta‐analyses have revealed that the risk is not the same among statins with atorvastatin, simvastatin, and rosuvastatin being the most diabetogenic, lovastatin and fluvastatin having an intermediate risk, and pravastatin and pitavastatin having the lowest diabetogenicity (Millan Nunez‐Cortes et al.…”

Section: Discussionmentioning

confidence: 99%

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Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

et al. 2017

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Insulin action and glucose disposal are enhanced by exercise, yet the mechanisms involved remain imperfectly understood. While the causes of skeletal muscle insulin resistance also remain poorly understood, new evidence suggest excess plasma membrane (PM) cholesterol may contribute by damaging the cortical filamentous actin (F‐actin) structure essential for GLUT4 glucose transporter redistribution to the PM upon insulin stimulation. Here, we investigated whether PM cholesterol toxicity was mitigated by exercise. Male C57BL/6J mice were placed on low‐fat (LF, 10% kCal) or high‐fat (HF, 45% kCal) diets for a total of 8 weeks. During the last 3 weeks of this LF/HF diet intervention, all mice were familiarized with a treadmill for 1 week and then either sham‐exercised (0 m/min, 10% grade, 50 min) or exercised (13.5 m/min, 10% grade, 50 min) daily for 2 weeks. HF‐feeding induced a significant gain in body mass by 3 weeks. Sham or chronic exercise did not affect food consumption, water intake, or body mass gain. Prior to sham and chronic exercise, “pre‐intervention” glucose tolerance tests were performed on all animals and demonstrated that HF‐fed mice were glucose intolerant. While sham exercise did not affect glucose tolerance in the LF or HF mice, exercised mice showed an improvement in glucose tolerance. Muscle from sham‐exercised HF‐fed mice showed a significant increase in PM cholesterol, loss of cortical F‐actin, and decrease in insulin‐stimulated glucose transport compared to sham‐exercised LF‐fed mice. These HF‐fed skeletal muscle membrane/cytoskeletal abnormalities and insulin resistance were improved in exercised mice. These data reveal a new therapeutic aspect of exercise being regulation of skeletal muscle PM cholesterol homeostasis. Further studies on this mechanism of insulin resistance and the benefits of exercise on its prevention are needed.

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Section: Discussionmentioning

confidence: 99%

“…Also of interest are data suggesting statin diabetogenicity may be more coupled to defects in pancreatic β ‐cell insulin secretory and not peripheral insulin action(Brault et al. 2014; Robinson 2015; Salunkhe et al. 2016).…”

Section: Discussionmentioning

confidence: 99%

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

et al. 2017

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“…Brault et al has recently reviewed studies demonstrating the impact statins have on pathways mediated by intermediates of the cholesterol synthesis pathway. 46 This discussion focuses on the potential of statins to directly impact the delicate balance of cellular cholesterol. It has also been found that skeletal muscle LDL-C uptake is increased in statin-treated mice overexpressing LPL in skeletal muscle.…”

Section: Challenges Opportunities and Lessons From Statin Therapymentioning

confidence: 99%

New Aspects of Cellular Cholesterol Regulation on Blood Glucose Control—Review and Perspective on the Impact of Statin Medications on Metabolic Health

Grice

Elmendorf

2017

US Endocrinology

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Cholesterol is an essential component of cell membranes, and during the past several years, diabetes researchers have found that membrane cholesterol levels in adipocytes, skeletal muscle fibers and pancreatic beta cells influence insulin action and insulin secretion. Consequently, it is thought that dysregulated cell cholesterol homeostasis could represent a determinant of type 2 diabetes (T2D). Recent clinical findings compellingly add to this notion by finding increased T2D susceptibility in individuals with alterations in a variety of cholesterol metabolism genes. While it remains imperfectly understood how statins influence glucose metabolism, the fact that they display an influence on blood glucose levels and diabetes susceptibility seems to intensify the emerging importance of understanding cellular cholesterol in glucose metabolism. Taking this into account, this review first presents cell system and animal model findings that demonstrate the negative impact of cellular cholesterol accumulation or diminution on insulin action and insulin secretion. With this framework, a description of how changes in cholesterol metabolism genes are associated with T2D susceptibility will be presented. In addition, the connection between statins and T2D risk will be reviewed with expanded information on pitavastatin, a newer statin medication that displays actions favoring metabolic health.

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“…The Mendelian randomization study showed that a common allele in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene (encoding the target of statins) associated with lower LDL-C was also associated with a higher risk of diabetes and that this risk is potentially mediated through a slight increase in BMI. The mechanism by which statins could increase the risk of diabetes is not known, but other theories include direct effects of statins on insulin secretion, reduced translocation of GLUT-4 to membranes in target tissues, and reduced intracellular signaling (7,8). …”

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confidence: 99%

Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes

et al. 2015

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The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (b = 20.12, P = 0.03) and T2D and genetically determined lower LDL-C (b = 20.21, P = 5 3 10 26 ) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.Type 2 diabetes is associated with dyslipidemia (i.e., higher circulating concentrations of triglycerides and small, dense LDL cholesterol [LDL-C] and lower concentrations of HDL cholesterol [HDL-C]), but the causal relationship between dyslipidemia and type 2 diabetes has been difficult to disentangle (1). Most evidence suggests that altered lipid concentrations are secondary to insulin resistance (2) or other factors associated with both lipids and diabetes (e.g., adiposity), but some studies suggest that dyslipidemia could contribute to the pathogenesis of type 2 diabetes (3) through mechanisms related to impaired protection of b-cells or endoplasmic reticulum stress (4). Other studies of carriers of loss-of-function mutations in the ABCA1 gene have demonstrated that altered cholesterol concentrations could affect insulin secretion in humans, although with conflicting results (5,6).The relationship between lipid levels and diabetes is further complicated by the apparently causal link between statin therapy and increased risk of type 2 diabetes. A meta-analysis of randomized controlled trials and Mendelian randomization analysis (7) showed that statin treatment results in a slightly increased risk of diabetes. The Mendelian randomization study showed that a common allele in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene (encoding the target of statins) associated with lower LDL-C was also associated with a higher risk of diabetes and that this risk is potentially ...

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

Cited by 201 publications

References 93 publications

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

New Aspects of Cellular Cholesterol Regulation on Blood Glucose Control—Review and Perspective on the Impact of Statin Medications on Metabolic Health

Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes

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