Myc Is Required for Adaptive β-Cell Replication in Young Mice but Is Not Sufficient in One-Year-Old Mice Fed With a High-Fat Diet

Failure to expand pancreatic beta-cells in response to metabolic stress leads to excessive workload resulting in beta-cell dysfunction, dedifferentiation, death, and development of type 2 diabetes. In this study, we demonstrate that induction of Myc is required for increased pancreatic beta-cell replication and expansion during metabolic stress-induced insulin resistance with short-term high-fat diet (HFD) in young mice. beta-Cell-specific Myc knockout mice fail to expand adaptively and show impaired glucose tolerance and beta-cell dysfunction. Mechanistically, PKC zeta, ERK1/2, mTOR, and PP2A are key regulators of the Myc response in this setting. DNA methylation analysis shows hypomethylation of cell cycle genes that are Myc targets in islets from young mice fed with a short-term HFD. Importantly, DNA hypomethylation of Myc response elements does not occur in islets from 1-year-old mice fed with a short-term HFD, impairing both Myc recruitment to cell cycle regulatory genes and beta-cell replication. We conclude that Myc is required for metabolic stress-mediated beta-cell expansion in young mice, but with aging, Myc upregulation is not sufficient to induce beta-cell replication by, at least partially, an epigenetically mediated resistance to Myc action.