The effects of glucagon and somatostatin on the microenvironment of the neogenic beta-cell in the adult Worood Sirhan, Yara Hamshawi, Daljeet Kaur, Ron Piran

Diabetes characterized by having an inadequate supply of functional β-cells over time.A possible approach for replenishing these β-cells is to induce endogenous regeneration. Three possible pathways for endogenous replenishment exist for β-cells:replication, neogenesis, and transdifferentiation.The question of whether β-cell regeneration occurs is a broad focus of interest and controversy.We previously showed that pancreatic injury induced by the pharmacological procedure of caerulein plus alloxan administration led to islet cell transdifferentiation, but the final outcome was a large amount of δ-cells resulting from α to β and then to δ-cell transdifferentiation.The finding that β-cells transdifferentiate directly into δ-cells demonstrates that the assumed standards of type-1 diabetes in which autoimmunity leads to β-cell destruction is inadequate and must be adjusted to take into consideration the process of endocrine cell transdifferentiation.We suggested two alternative models to prevent the subsequent β-to δ-cell transdifferentiation process:

I-By eliminating the possibility of a functional, mature δ-cell.To this end, we have obtained Somatostatin knockout-mice.

II-By desensitizing neogenic β-cells to glucagon signaling, in which the relative excess of α-cells is propagating the β-to δ-cell transdifferentiation process, as δ-cells inhibit glucagon secretion. To this end, we have generated conditional specific glucagon-receptor-knockout in neogenic β-cells.

All these mice underwent the alloxan plus caerulein treatments. Alloxan-mediated ablation of β-cells in mice led to severe hyperglycemia in all groups.

The experimental mice exhibited lower blood glucose levels and insulin independence whereas control-mice remained diabetic.These results highlight the possibility to cure diabetes if somatostatin secretion or glucagon sensing by β-cells is inhibited in diabetic patients.