SIRT1 Is Critical for Pdx1 Transcription and β‐Cell Formation

Mammalian SIRT1, a homolog of yeast Sir2, is implicated in many important biological processes, including metabolic regulation, animal aging, and cancer. A study of β cell‐specific SIRT1‐overexpressing transgenic mice showed that increased dosage of SIRT1 in β‐cells improves glucose tolerance and enhances insulin secretion in response to glucose. This observation prompted us to hypothesize that SIRT1 may also play a role in regulating pancreas development. To overcome the lethality of SIRT1 null mice, we applied a cre‐loxp approach for specifically deleting SIRT1 in pancreas by crossing Sirt1flox5‐6/flox5‐6 mice with Pdx‐cre mice (Sirt1PKO). Sirt1PKO mice displayed diminished PDX1 and islet agenesis. Consequently, Sirt1PKO mice developed progressive hyperglycemia, glucose intolerance, impaired insulin secretion, and type II diabetes, which directly correlate with the extent of SIRT1 deletion. We further show SIRT1 positively regulates Pdx1 transcription. Thus, SIRT1 acts as an upstream regulator of β‐cell formation by maintaining expression of PDX1 and its downstream genes. These results uncover an essential role of SIRT1 in β‐cell formation and identify SIRT1 pancreas‐specific mutant mice as a relevant model for studying diabetes. Research support for this study is from NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) intramural program to Dr. Chuxia Deng.