Pancreatic islet regeneration through PDX-1/Notch-1/Ngn3 signaling after gastric bypass surgery in db/db mice.

In view of the compelling anti-diabetic effects of gastric bypass surgery (GBS) in the treatment of morbid obesity, it is important to clarify its enhancing effect on pancreatic islets, which is closely linked with diabetes remission in obese patients, as well as the underlying mechanisms. The present study evaluated the effects of GBS on glycemic control and other pancreatic changes in db/db mice. The db/db mice were divided into Control, Sham and GBS group. A significant improvement in fasting plasma glucose levels and glucose intolerance were observed post-surgery. At 4 weeks after surgery, further noteworthy changes were observed in the GBS group, including improved islet structure (revealed by immunohistochemical analysis), enhanced insulin secretion, pancreatic hyperplasia and a marked increase in the ratio of beta-cells to non-beta endocrine cells. Furthermore, notable changes in the levels of Notch-1, pancreatic and duodenal homeobox 1 (PDX-1) and neurogenin 3 (Ngn3) were observed in the GBS group, indicating a potential role of Notch signaling in pancreatic islet regeneration after surgery. In addition, results obtained in PDX-1 knockout (KO), Notch-1 KO and Ngn3 KO mouse models with GBS suggested that elevated PDX-1 resulted in the inhibition of Notch-1, further facilitated Ngn3 and thus promoted pancreatic beta-cell regeneration after GBS. The present findings demonstrated that GBS in db/db mice resulted in pancreatic islet regeneration through the PDX-1/Notch-1/Ngn3 signaling pathway, which also reflected the important role of the gastrointestinal system in metabolism control.