Dynamic Changes of BVRA Protein Levels Occur in Response to Insulin: A Pilot Study in Humans

Abstract

Biliverdin reductase-A (BVRA) is involved in the regulation of insulin signaling and the maintenance of glucose homeostasis. Previous research showed that BVRA alterations are associated with the aberrant activation of insulin signaling in dysmetabolic conditions. However, whether BVRA protein levels change dynamically within the cells in response to insulin and/or glucose remains an open question. To this aim, we evaluated changes of intracellular BVRA levels in peripheral blood mononuclear cells (PBMC) collected during the oral glucose tolerance test (OGTT) in a group of subjects with different levels of insulin sensitivity. Furthermore, we looked for significant correlations with clinical measures. Our data show that BVRA levels change dynamically during the OGTT in response to insulin, and greater BVRA variations occur in those subjects with lower insulin sensitivity. Changes of BVRA significantly correlate with indexes of increased insulin resistance and insulin secretion (HOMA-IR, HOMA-β, and insulinogenic index). At the multivariate regression analysis, the insulinogenic index independently predicted increased BVRA area under curve (AUC) during the OGTT. This pilot study showed, for the first time, that intracellular BVRA protein levels change in response to insulin during OGTT and are greater in subjects with lower insulin sensitivity, supporting the role of BVR-A in the dynamic regulation of the insulin signaling pathway.

Neuroprotective Roles of the Biliverdin Reductase-A/Bilirubin Axis in the Brain

“…In addition to the periphery, BVRA also regulates insulin receptor signaling in the brain and prevents the hyperphosphorylation of tau through the Akt pathway [41,77,82]. Furthermore, BVRA levels are dynamically altered in response to insulin, including intranasal administration used to alleviate brain insulin resistance in AD [77,109]. In agreement with these reports, the loss of BVRA causes elevated oxidative stress, abnormal tau pathology, and impaired autophagy [8,14,34,76,82].…”