Atorvastatin Targets the Islet Mevalonate Pathway to Dysregulate mTOR Signaling and Reduce β-Cell Functional Mass

Abstract

Statins are cholesterol-lowering agents that increase the incidence of diabetes and impair glucose tolerance via their detrimental effects on nonhepatic tissues, such as pancreatic islets, but the underlying mechanism has not been determined. In atorvastatin (ator)-treated high-fat diet-fed mice, we found reduced pancreatic b-cell size and b-cell mass, fewer mature insulin granules, and reduced insulin secretion and glucose tolerance. Transcriptome profiling of primary pancreatic islets showed that ator inhibited the expression of pancreatic transcription factor, mechanistic target of rapamycin (mTOR) signaling, and small G protein (sGP) genes. Supplementation of the mevalonate pathway intermediate geranylgeranyl pyrophosphate (GGPP), which is produced by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, significantly restored the attenuated mTOR activity, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) expression, and b-cell function after ator, lovastatin, rosuvastatin, and fluvastatin treatment; this effect was potentially mediated by sGP prenylation. Rab5a, the sGP in pancreatic islets most affected by ator treatment, was found to positively regulate mTOR signaling and b-cell function. Rab5a knockdown mimicked the effect of ator treatment on b-cells. Thus, ator impairs b-cell function by regulating sGPs, for example, Rab5a, which subsequently attenuates islet mTOR signaling and reduces functional b-cell mass. GGPP supplementation could constitute a new approach for preventing statin-induced hyperglycemia.

The Intestinal Effect of Atorvastatin: Akkermansia muciniphila and Barrier Function

“…However, a growing number of studies based on longitude cohorts with large populations indicate that statin-use increases the risk of new-onset type 2 diabetes mellitus (T2D) in a dose-dependent manner (Rajpathak et al, 2009;Sattar et al, 2010;Preiss et al, 2011;Cederberg et al, 2015). Studies have shown that atorvastatin (Ator) as well as other statins can deteriorate glucose tolerance and promote development of diabetes via increasing hepatic glycogenesis (Wang et al, 2015), delaying glucose clearance (Cheng et al, 2015), inducing mitochondrial dysfunction (Urbano et al, 2017), inflammation of adipocytes (Henriksbo et al, 2019), and inhibiting adipocyte browning (Balaz et al, 2019) as well as moderately reducing β-cell functional mass via disrupting the mevalonate pathway to inhibit mTOR signaling (Shen et al, 2020).…”

Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis

“…We next asked how statin up-regulates miR-495 expression and wanted to test the possible involvement of mevalonate pathway 24 , 25 . The ability of simvastatin to induce miR-495 expression and the consequent dysregulation of Sirt6-FoxO1-gluconeogenesis axis were significantly blocked by supplementation of GGPP, which is the intermediate metabolite produced by HMG-CoA reductase, but neither by FPP, cholesterol, nor 25-hydroxycholesterol ( Figures S6 A-S6C).…”

“…Several pathways have been identified as a potential mechanism involved in the effect of statin on insulin resistance 29 . Statin impairs the insulin-secreting ability of pancreatic beta cells 25 , 30 , 31 , decreases insulin signaling in skeletal muscle 32 , and exacerbates adipose inflammation while suppressing white fat browning 24 , 33 , 34 . Another potential mechanism of statin-mediated insulin resistance that has been suggested is an increase in hepatic gluconeogenesis.…”

Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study

“… 56 Statins, the current main hypolipidemia medication to reduce major adverse cardiovascular events (MACEs) in T2D patients, 3 exhibits unfavorable effects, such as increasing intestinal cholesterol absorption, blood glucose level and diabetes incidence, as well as the hepatoxicity and myotoxicity. These side effects (SE) have brought concerns to the clinical practice , 57 , 58 particularly in East Asia population, including the Chinese, who is more susceptible to the SEs of statins. 59 , 60 A cross-sectional survey in a nationally representative sample of 15,540 Chinese adults reports only 3.5% and 3.4% of men and women with a total cholesterol ≥200 mg/dL has been treated with any antilipidemic medicine.…”