Δ40 Isoform of p53 Controls β-Cell Proliferation and Glucose Homeostasis in Mice

OBJECTIVE-Investigating the dynamics of pancreatic beta-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that beta-cell proliferation and glucose homeostasis were controlled by Delta 40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice. RESEARCH DESIGN AND METHODS-We phenotyped metabolic parameters in Delta 40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine beta-cell proliferation. RESULTS-Transgenic mice with an ectopic p,53 gene encoding Delta 40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from similar to 14 months of age. Consistent with a dramatic decrease in beta-cell mass and reduced beta-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased. CONCLUSIONS-These data indicate a significant and novel role for Delta 40p53 in beta-ell proliferation with implications for the development of age-dependent diabetes. Diabetes 60:1210-1222, 2011