A human pancreas typically contains about a billion beta cells, which are the primary producers of insulin. In individuals with diabetes, these cells are either missing or dysfunctional, prompting scientists to explore methods to replenish their numbers as a potential long-term treatment or cure. A team of researchers has made progress by genetically altering ductal cells, another type of pancreatic cell, to produce and release insulin in response to high blood sugar levels.
The researchers engineered ductal cells, which have been observed in previous studies to occasionally transform into beta cells. This phenomenon is uncommon among adult cells, which usually maintain their specific identities, suggesting that ductal cells could be a viable target for research.
Jian Li, a postdoctoral researcher at Harvard Medical School and the lead author of the study published in Science Translational Medicine, stated that scientists previously lacked knowledge about the genes responsible for this transformation. To investigate, the researchers employed a genetic screening approach, which involves disrupting various segments of DNA across the genome to identify those critical for specific biological processes.
Through this method, the team discovered that silencing a gene known as ALDH3B2 increased the rate at which ductal cells transformed into beta-like cells. Without this genetic alteration, fewer than 1 percent of ductal cells spontaneously adopted a beta-cell-like state, but when ALDH3B2 was silenced, this rate rose to approximately 8.5 percent.
These initial experiments were conducted on human cells in vitro, which were then transplanted into mice with diabetes. Following the transplant, human insulin was detected in the mice, and their glucose levels decreased to near-normal levels, effects that lasted for six weeks.
Previous research has explored various gene therapies for diabetes aimed at providing long-term relief. For instance, a clinical trial initiated earlier this year is investigating the use of muscle cells equipped with genetic instructions to produce insulin. Other emerging therapies focus on generating new insulin-producing cells in the laboratory for transplantation into patients.
However, these approaches carry risks, particularly concerning immune system activation. The current study suggests an alternative strategy: utilizing existing pancreatic cells and modifying their function by deactivating certain genetic switches that define their identity.
This method presents challenges, particularly ensuring that only the intended cells are modified. Since ALDH3B2 is utilized by various cell types beyond the pancreas, precision is crucial to avoid unintended complications.
A significant question remains regarding the specific role of this gene in the conversion of ductal cells into beta cells. Li emphasized the need to verify this aspect first, with the next steps involving either gene therapy or identifying specific small molecules to inhibit this gene to achieve similar or improved effects.
Even partial advancements in this area could significantly impact the lives of the estimated 830 million individuals living with diabetes worldwide, many of whom face life-threatening complications each year.