image: Rnase4 regulates the proliferation of pancreatic islet β cells and blood glucose homeostasis through the Axl-PI3K/Akt/FoxO1/Pdx1 signaling pathway
Credit: ©Science China Press
Recently, a research team led by Professor Zhengping Xu of Zhejiang University School of Medicine and its affiliated Sir Run Run Shaw Hospital published a paper in Science Bulletin titled "Ribonuclease 4 is a pancreatic endogenous β cell proliferation factor". This study reveals that ribonuclease 4 (Rnase4), which is derived from pancreatic islet β cells themselves, plays a pivotal role in β cell proliferation and blood glucose homeostasis regulation.
Pancreatic islet β cells are the primary source of insulin, and their proliferative capacity directly influences islet function and blood glucose regulation. While a number of growth factors and hormones have been reported to promote β cell proliferation, they mainly respond to glucose stimulation or insulin resistance, and often originate from extra-pancreatic organs such as the liver and intestines. To date, no endogenous factor derived from β cells, expressed in the pancreas during development, and physiologically promoting β cell proliferation has been identified.
In this study, the team found that ribonuclease Rnase4, highly enriched in the pancreas, is specifically expressed in islet β cells. Its level exhibits dynamic changes after mice are born, closely aligning with the rapid proliferation phase of β cells, suggesting a strong association between Rnase4 and islet development. By generating Rnase4 knockout mouse models, the researchers confirmed that β cell-specific knockout of Rnase4 reduces β cell proliferation and number, leading to smaller islets. Mechanistic investigation showed that β cell-secreted Rnase4 binds to the cell surface receptor Axl, activating the PI3K/Akt/FoxO1/Pdx1 signaling pathway to promote β cell proliferation. Further studies on blood glucose regulation demonstrated that Rnase4 deficiency in mice lowers insulin levels and impaired glucose homeostasis (IMAGE); notably, Rnase4 supplementation effectively reverses β cell disruption and restores normal glucose metabolism caused by Rnase4 deficiency, as well as by streptozotocin or caerulein treatment.
This work clarifies the vital function of β cell-derived Rnase4 in promoting β cell proliferation, islet development, and glucose metabolism, and further demonstrates that supplementing Rnase4 can reverse β cell disorders triggered by genetic defects, chemical damage, or inflammatory stress. These findings provide a key theoretical basis for exploring targeted delivery of Rnase4 to the pancreas or islets to treat β cell loss-related diseases.
Dr. Chen Muxiong, a researcher from Sir Run Run Shaw Hospital affiliated with Zhejiang University School of Medicine, and Dr. Liu Yaxin, a postdoctoral fellow in Liangzhu Laboratory of Zhejiang Province, are co-first authors of this publication. Professor Xu Zhengping and Dr. Bai Rongpan, also a researcher in Sir Run Run Shaw Hospital, serve as co-corresponding authors. This research received support from the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang, and the Leading Innovation and Entrepreneur Team of Hangzhou.