A groundbreaking discovery by the University of California, Davis, could revolutionize diabetes treatment. Researchers have identified a previously unknown signaling pathway in the pancreatic islets of Langerhans that could protect diabetics from life-threatening hypoglycemia. The study, published on September 16, 2025, in the Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.250415112), shows how so-called delta cells interact with insulin-producing beta cells to prevent dangerous drops in blood sugar.
Feedback loop as a protective mechanism
The researchers, led by Professor Mark Huising and MD/Ph.D. student Mohammad Pourhosseinzadeh, discovered that delta cells in the islets of Langerhans become active in sync with beta cells. While beta cells release insulin to lower blood sugar levels, delta cells release the hormone somatostatin, which slows insulin production. This feedback loop prevents an excessive drop in blood sugar, which can lead to unconsciousness, coma, or even death in diabetics.
“Hypoglycemia is an acute danger for people with diabetes, especially for those taking insulin or other blood-sugar-lowering medications,” explains Pourhosseinzadeh. “Without prompt medical attention, the brain can be damaged by the lack of blood sugar.” The study shows that coordination between beta and delta cells is controlled via electrical connections (gap junctions made of connexin 36) and the hormone urocortin-3. These mechanisms ensure that insulin release is precisely regulated.
Delta cells: Solving a medical mystery
The role of delta cells, which make up only about 5% of the islets of Langerhans, has long been unclear. While beta cells have been known as insulin producers since the 1920s, delta cells have largely gone unnoticed. Huising and his team found that delta cells are activated by urocortin-3, a hormone released by beta cells during insulin secretion. Without this interaction, as shown in mice lacking delta cells, blood sugar levels remain permanently below normal, increasing susceptibility to hypoglycemia.
“The discovery of this signaling pathway opens up new possibilities for improving insulin regulation,” says Huising. “By strengthening the function of urocortin-3 and delta cells, we could optimize existing diabetes medications and prevent hypoglycemia.”
Cellular synchrony
The study shows that beta and delta cells work in a synchronous rhythm, similar to heart cells during a heartbeat. Calcium pulses originating in the beta cells spread to the delta cells via gap junctions, triggering somatostatin release. If this connection is disrupted, the system no longer responds effectively, causing insulin production to go haywire. "The interplay between fast electrical signals and the delayed urocortin-3 effect is like a double-tap that precisely controls insulin release," explains Pourhosseinzadeh.
Hope for diabetics
The findings could drive the development of new therapies that specifically promote coordination between beta and delta cells. This would be particularly important for patients with type 1 and type 2 diabetes who often struggle with hypoglycemia. "Our goal is to improve the quality of life for diabetics by preventing these dangerous drops in blood sugar," emphasizes Huising.
The research was funded by the National Institutes of Health and the UC Davis Training Program in Molecular and Cellular Biology. Other authors of the study include Jessica Huang, Donghan Shin, Ryan Hart, Luhaiza Framroze, Jaresley Guillen, Joel Sanchez, Ramir Tirado, and Kelechi Unanwa. The authors declare that there is no conflict of interest.
Source:
University of California, Davis
Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.250415112
