High doses of rosuvastatin induce impaired branched‐chain amino acid catabolism and lead to insulin resistance

Abstract

Accumulating evidence indicates that patients treated with rosuvastatin have an increased risk of developing new-onset diabetes. However, the underlying mechanism remains unclear. In this study, we administered rosuvastatin (10 mg/kg body weight) to male C57BL/6J mice for 12 weeks and found that oral rosuvastatin dramatically reduced intraperitoneal glucose tolerance. Rosuvastatin-treated mice showed considerably higher serum levels of branched-chain amino acids (BCAAs) than control mice. They also showed dramatically altered expression of BCAA catabolismrelated enzymes in white adipose tissue and skeletal muscle, including downregulated mRNA expression of BCAT2 and protein phosphatase 2Cm (PP2Cm) and upregulated mRNA expression of branched-chain ketoacid dehydrogenase kinase (BCKDK). The levels of BCKD in the skeletal muscle were reduced in rosuvastatin-treated mice, which was associated with lower PP2Cm protein levels and increased BCKDK levels.We also investigated the effects of rosuvastatin and insulin administration on glucose metabolism and BCAA catabolism in C2C12 myoblasts. We observed that incubation with insulin enhanced glucose uptake and facilitated BCAA catabolism in C2C12 cells, which was accompanied by elevated Akt and glycogen synthase kinase 3 β (GSK3β) phosphorylation. These effects of insulin were prevented by co-incubation of the cells with 25 μM rosuvastatin. Moreover, the effects of insulin and rosuvastatin administration on glucose uptake and Akt and GSK3β signaling in C2C12 cells were abolished when PP2Cm was knocked down. Although the relevance of these data, obtained with high doses of rosuvastatin in mice, to therapeutic doses in humans remains to be elucidated, this study highlights a potential mechanism for the diabetogenic effects of rosuvastatin, and suggests that BCAA catabolism could be a pharmacological target for preventing the adverse effects of rosuvastatin.

Duality of Branched-Chain Amino Acids in Chronic Cardiovascular Disease: Potential Biomarkers versus Active Pathophysiological Promoters

“…The initial event in the breakdown of the three aforementioned BCAAs is multifaceted. It involves the conversion of the amino acids to branched-chain α-keto acids (BCKAs) through transamination, a process catalyzed by the cytosolic or mitochondrial enzyme BCAA aminotransferase (BCAT) [ 17 ]. The transamination process involves the transfer of specific amino groups to α-ketoglutarate (α-KG), resulting in glutamate and the formation of corresponding BCKAs.…”

“…The phosphorylation–dephosphorylation mechanism regulates the BCKDH complex, with functional alterations in kinase activity producing a significant impact. BCKDK causes inactivation through phosphorylation, while mitochondrial phosphatase 2C (PP2Cm) catalyzes dephosphorylation, which activates the BCKDH complex [ 17 , 28 ]. The highest BCKDK activity is exhibited by the liver, followed by the kidneys and heart, while the muscles, adipose tissue, and brain have lower activity levels [ 13 , 23 ].…”

“…To differentiate the extent to which intrinsic disturbances in cardiac amino acid metabolism versus fluctuating plasma amino acid levels influence the physiopathology of HF, further studies were carried out employing dietary BCAA supplementation, pharmacological interventions targeting BCAA metabolism, and genetic animal models [ 17 , 85 ].…”

“…In Ppm1k-deficient mice, the allosteric inhibitor of BDK, known as 3,6 dichlorobenzo[b]thiophene-2-carboxylic acid (BT2), was used in an attempt to uncover the cardiac-specific metabolic BCAA dysfunction [ 56 ]. The administration of BT2 for one week resulted in the dephosphorylation and maximal activation of BCKDH in multiple sites, including the heart, skeletal muscle, kidneys, and liver of mice and rats, leading to normalizing plasma BCAA concentrations [ 17 , 90 , 96 , 97 ]. A fresh perspective was observed regarding Pp2cm and its interplay with the microbiome metabolite butyrate in the early stages of obesity-related heart failure with preserved ejection fraction (HfpEF) [ 98 ].…”

Can statin preventative treatment inform geroscience‐guided therapeutics?

“…Notably, however, statins have also been linked to adverse effects, including an increased risk for metabolic dysfunction (Abbasi et al, 2021 ; Bai et al, 2023 ; Centers for Disease Control and Pre‐ vention, n.d. ; Mansi et al, 2023 ; Sattar et al, 2010 ), albeit only minimally increasing glucose in the REPRIEVE study. The impact of statins on other pathways, may differ by population, dose and tissue effects.…”