9238 Application of DREADD Tools Offers New Insights About the Paracrine Cellular Crosstalk in the Islet of Langerhans

Abstract Disclosure: R. Rodriguez: None. A. Tamayo: None. D. Hakim Rodriguez: None. O. Alcazar: None. E. Pereira: None. M. Makhmutova: None. J. Almaca: None. L. Goncalves: None. The δ-cell is envisioned as a main suppressive component in the islet of Langerhans, which provides functional negative feedback to its neighboring α- and β-cells by secreting somatostatin. Considering that changes in the dynamics and amount of insulin and glucagon are associated to the natural history of Diabetes, more knowledge about the role that δ-cell and somatostatin play in the deregulation of islet glucoregulatory hormone secretion is of remarkable importance. Here we aimed to revisit the kinetics of the cellular crosstalk between β- and α-cell with the δ-cells and vice versa by taking advantage of a chemogenetic tool allowing the specific activation of any cell subset genetically modified to express DREADD (Designed Receptors Exclusively Activated by Designed Drugs). We bred mice that expressed the activator-DREADD (hM3Dq) in either α-, β-, or δ-cells. Immunohistochemical staining of pancreas sections confirmed the great cellular specificity and the effective translocation of the DREADD to the membrane of each targeted cell. Perifusion assays showed that α-, β-, and δ-cells bearing DREADD secreted glucagon, insulin and somatostatin respectively in a dose-response manner upon simulation with CNO; and as expected, the targeted stimulation of every specific cell type generated subsequent co-stimulatory or rebound responses in the other neighboring cell subsets. The data evidenced the complex network of paracrine cellular crosstalk within the islet, however the dynamics of hormone secretion in several instances did not fit into the current way we think α-, β- and δ-cells interact with each other’s. The data showed an overall increase of hormone secretion in instances we expected lessening of secretion resulting from inhibitory paracrine cellular crosstalk, such as 1) the burst of glucagon responses in non-permissive 16 mM glucose following the activation of either β- or δ-cells, and 2) net increment of insulin secretion following δ-cell activation. The results suggested more complex insights about the notion of inhibitory paracrine crosstalk within the Islet of Langerhans, where inhibition-mediated excitatory rebound responses might have more physiological relevance and be more significant for islet biology. Presentation: 6/3/2024