Diabetogenic effect of pravastatin is associated with insulin resistance and myotoxicity in hypercholesterolemic mice

• Published in: Journal of translational medicine Vol. 17; no. 1; p. 285
• Main Authors: Lorza-Gil, Estela, García-Arevalo, Marta, Favero, Bianca Cristine, Gomes-Marcondes, Maria Cristina C, Oliveira, Helena C F
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.08.2019; BioMed Central; BMC
• Subjects: AKT protein; Anticholesteremic agents; Antilipemic agents; Apoptosis; Bax protein; Biochemistry; Body weight; Cardiovascular agents; Cardiovascular diseases; Care and treatment; Caspase; Caspase-3; Cell death; Cell viability; Cholesterol; Chymotrypsin; Diabetes mellitus; Diabetes research; Diabetes therapy; Gastrocnemius muscle; Glucose; Glucose intolerance; Glucose tolerance; HMG-CoA reductase inhibitors; Homeostasis; Hydroxymethylglutaryl-CoA reductase; Hypercholesterolemia; Insulin; Insulin resistance; Insulin secretion; Intolerance; Mice; Muscle proteolysis; Muscles; Myopathy; Myotoxicity; Oxidative stress; Pancreas; Pravastatin; Protein biosynthesis; Protein synthesis; Protein turnover; Proteolysis; Reductases; Secretion; Statins; Studies; Superoxides; Testing; Type 2 diabetes; Viability; Brazil; Insulin resistance; Muscle proteolysis; Myotoxicity; Statins
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-019-2045-6

HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs widely used to treat hypercholesterolemia and prevent cardiovascular disease. Statins are generally well tolerated, but adverse reactions may occur, particularly myopathy and new onset of diabetes. The exact mechanism of statin-induced myopathy and diabetes has not been fully elucidated. We have previously shown that treatment of hypercholesterolemic (LDLr ) mice with pravastatin for 2 months decreased pancreatic islet insulin secretion and increased oxidative stress and cell death, but no glucose intolerance was observed. The purpose of the current work was to study long-term pravastatin effects on glucose homeostasis, insulin sensitivity, muscle protein turnover and cell viability. LDLr mice were treated with pravastatin for 3, 6 and 10 months. Glucose tolerance, insulin resistance and glucose-stimulated insulin secretion were evaluated. The rates of protein synthesis and degradation were determined in gastrocnemius muscle after 10 months of treatment. Insulin signalling, oxidative stress and cell death were analysed in vitro using C2C12 myotubes. After 6 and 10 months of treatment, these mice became glucose intolerant, and after 10 months, they exhibited marked insulin resistance. Reduced islet glucose-stimulated insulin secretion was observed after the 3rd month of treatment. Mice treated for 10 months showed significantly decreased body weight and increased muscle protein degradation. In addition, muscle chymotrypsin-like proteasomal activity and lysosomal cathepsin were markedly elevated. C2C12 myotubes exposed to increasing concentrations of pravastatin presented dose-dependent impairment of insulin-induced Akt phosphorylation, increased apoptotic markers (Bax protein and cleaved caspase-3) and augmented superoxide anion production. In addition to reduced insulin secretion, long-term pravastatin treatment induces insulin resistance and muscle wasting. These results suggest that the diabetogenic effect of statins is linked to the appearance of myotoxicity induced by oxidative stress, impaired insulin signalling, proteolysis and apoptosis.