A recent DZD study has identified the protein Flattop as a marker to distinguish between mature beta cells and their precursors in the pancreas. (See figure: Flattop-positive beta cells (green), precursor cells without Flattop (red).)Approximately 80% of beta cells produce insulin; the remaining 20% form a highly proliferative reserve pool. Flattop is only present in mature beta cells. When blood glucose levels rise, these mature beta cells secrete insulin to keep glucose levels in equilibrium. In contrast, the cells without Flattop do not respond as well to glucose and secrete less insulin. Instead, they are capable of proliferating up to four times more often than beta cells expressing Flattop. They have a particularly high division rate during pregnancy and in the expansion phase during the neonatal period. This suggests that they are precursor cells of the beta cells that can serve as a reserve pool. By means of in vitro and in vivo genetic lineage tracing experiments, the DZD scientists confirmed that insulin-producing beta cells with Flattop develop from beta cells without Flattop. To carry out the study, the researchers introduced a genetic modification to cells and to a mouse line: The DZD scientists replaced the Flattop gene with a gene encoding a fluorescent reporter protein. When the gene was activated to express Flattop, the cells fluoresced green.Flattop itself is not causally involved in the maturation of beta cells. In mice that cannot generate Flattop, neither the maturation of beta cells nor the regulation of the glucose homeostasis is impaired. However, the DZD researchers showed that factors that regulate Flattop can also influence the maturation of beta cells and their activity.These findings provide an important basis for new therapeutic approaches in diabetes: First, they can contribute to the development of cell replacement therapy, in which mature beta cells are derived in the laboratory from stem cells. Second, they provide targets for new drugs that induce the regeneration of beta cell tissue by stimulating the conversion of immature precursor cells into insulin-secreting beta cells.

Original-Publication:
Bader, E. et al. (2016). Identification of proliferative and mature β-cells in the islet of Langerhans, Nature, DOI: 10.1038/nature18624