Ricerc@Sapienza

Randomized clinical trials have shown that treatment with bempedoic acid is associated with improvement in fasting glucose and HbA1c in patients with type 2 diabetes. Additionally, new-onset diabetes mellitus was less frequently observed amongst individuals treated with bempedoic acid. These results are at odds with those observed in patients treated with statins as confirmed by a meta-analysis showing that the overall risk of incident diabetes is increased by 11% in these individuals. Bempedoic acid is converted to ETC-1002-CoA in the liver, which allosterically activates AMPK and inhibits ATP-citrate lyase (ACL), resulting in lower LDL-C and atherosclerosis in mice. The mechanisms by which ETC-1002-CoA directly activates AMPK are currently undefined but appear to involve direct interactions with the beta1 isoform. In the liver, AMPK controls glucose homeostasis mainly through the inhibition of gluconeogenic gene expression and hepatic glucose production. Metformin, the most commonly used drug for type 2 diabetes, also activates AMPK. Glucose production in primary cultured hepatocytes is suppressed by metformin, and in diabetic patients, the glucose lowering effect of metformin is at least partly attributed to its ability to suppress gluconeogenesis. It is still unknown whether bempedoic acid is able to reduce hepatic glucose production by activation of the AMPK signalling pathway thus resulting in improvement in glucose metabolism observed in clinical trials. The principal aims of the present project proposal are: 1) To evaluate if bempedoic acid is able to reduce hepatic glucose production in human hepatoma cells by activation of the AMPK signalling pathway involving phosphorylation of the transcriptional coactivators CBP and TORC2 resulting in the dissociation of the CREB-CBP-TORC2 complex. 2) To evaluate if bempedoic acid is able to reduce hepatic glucose production in hyperglycaemic mouse models by activation of the AMPK signalling pathway.