The loss of functional beta cells and their ability to produce insulin underlies both T1D and T2D. However, the mechanisms of beta cell loss and dysfunction are still not fully understood. To better understand the fate of beta cells under physiologic “stressful” conditions such as aging and pregnancy, Dr. Domenico Accilli and his team at Columbia University generated mice without a specific pancreatic beta cell gene called Fox01. Fox01 is a gene that integrates beta cell proliferation with adaptive beta cell function and insulin secretion under conditions of increased metabolic demand such as in pregnancy. These mice were then subjected to repeated stresses including multiple pregnancies and aging. As expected, the mutant mice were unable to respond to these stresses appropriately and became diabetic as a result of decreased functional beta cell numbers and lower insulin production. When the researchers examined the pancreas of these animals to determine the fate of the lost beta cells, they were surprised to find that the majority of the beta cells did not die, but instead had regressed to an immature stem- or progenitor-cell-like state unable to produce insulin. The research team also found evidence of beta cell regression as the primary driver of loss of functional beta cells in other mouse models of T2D. Thus, this phenomenon of beta cell regression is not limited or unique to mutant beta cells but appears to have broader implications for beta cell loss in diabetes.
Ramifications for Individuals with T1D:
This exciting, early stage, exploratory research has identified a novel and previously unappreciated mechanism underlying the loss of beta cells in diabetes. This work opens up an entirely new potential therapeutic strategy to protect and restore beta cells in T1D. Further research is required to determine if a similar process is active in patients with T1D and to determine if drug therapies could be used to reverse the process and increase beta cell numbers and insulin production.
Investigators and Institutions:
This work was led by Dr. Domenico Accilli at Columbia University in New York.
Chutima Talchai, Shouhong Xuan, Hua V. Lin, Lori Sussel and Domenico Accili (2012), Pancreatic Beta Cell Dedifferentiation as a Mechanism of Diabetic Beta Cell Failure, Cell 150, 1223–1234.