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

Abstract

Failure to expand pancreatic β-cells in response to metabolic stress leads to excessive workload resulting in β-cell dysfunction, dedifferentiation, death, and development of type 2 diabetes. In this study, we demonstrate that induction of Myc is required for increased pancreatic β-cell replication and expansion during metabolic stress–induced insulin resistance with short-term high-fat diet (HFD) in young mice. β-Cell–specific Myc knockout mice fail to expand adaptively and show impaired glucose tolerance and β-cell dysfunction. Mechanistically, PKCζ, 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 β-cell replication. We conclude that Myc is required for metabolic stress–mediated β-cell expansion in young mice, but with aging, Myc upregulation is not sufficient to induce β-cell replication by, at least partially, an epigenetically mediated resistance to Myc action.

CDK2 limits the highly energetic secretory program of mature β cells by restricting PEP cycle-dependent KATP channel closure

“…In addition to CDK2, CDK1 ( Gregg et al, 2019 ), CDK5 ( Wei et al, 2005 ), and CDK8 ( Xue et al, 2019 ) have been found to regulate glucose-stimulated insulin secretion. Additionally, the CDK regulator p16/INK4a ( Helman et al, 2016 ; Zheng et al, 2013 ) and the effector molecule c-MYC ( Puri et al, 2018 ; Rosselot et al, 2019 ) have demonstrated significant control over insulin secretion in addition to established canonical cell cycle control of proliferation. Our results provide further evidence that CDK2 can modify the metabolic and secretory state independent of maturation defects reflected by MAFA, GLUT2, or UCN3 ( Blum et al, 2012 ; Hang et al, 2014 ; van der Meulen et al, 2015 ).…”

The many lives of Myc in the pancreatic β-cell

“…4). This is the case, Myc deficiency in β-cells of young mice fed HFD impairs adaptive β-cell proliferation and mass expansion (33).…”

“…Unlike young mice, one-year-old mice fed the same HFD display an increase in both Myc expression and stability in β-cells, but do not induce Myc targets. Therefore, HFD increases Myc abundance in islets of young and old mice but impairs Myc action in old mouse β-cells (33). "Myc resistance" in the aged β-cell.…”

“…Critically, the normal physiological role of Myc in β-cell biology is barely known. Two recent studies using β-cell specific Myc knockout mice have provided the first in vivo evidence indicating that Myc plays a crucial role in the growth and function of the β-cell and that the destructive nature of Myc only develops after prolonged metabolic insult resulting in inappropriate chronic high levels of expression ( 32 , 33 ) ( Fig. 2 ).…”

“…The first study demonstrated that (i) Myc is required for postnatal β-cell proliferation and (ii) that mild, lifelong Myc overexpression in the mouse β-cell markedly enhances β-cell mass and leads to sustained mild hypoglycemia, without induction of tumorigenesis ( 32 ). The second study reported that in response to a 1-week hypercaloric diet, Myc protein levels increase in mouse β-cells independent of age and that Myc is necessary for the normal adaptive β-cell expansion that occurs in young mice ( 33 ). In total, these unique recent data and the available literature provide strong support for the idea that Myc is crucial for potential β-cell regenerative approaches as well as for the normal physiology of the β-cell under basal or metabolically stressed conditions.…”