Balasenthilkumaran, N. V. | bioRxiv Science

bioRxiv2025

Role of GLP1-receptor-mediated α-β-cell communication in functional β-cell heterogeneity.

While islet {beta}-cells were first viewed as a singular functional entity, since the 1970s findings reveal that individual {beta}-cells differ in their insulin secretion. More recently distinct functional subpopulations based on differential calcium dynamics have been demonstrated to drive islet function. Here, we investigate how paracrine signaling, specifically glucagon-like peptide receptor (GLP-1R)-mediated -{beta}-cell communication shapes functional {beta}-cell heterogeneity. To address this, we utilized confocal imaging of calcium responses in isolated islets from GCaMP6s mice and in islets from pancreatic slices of C57BL/6 mice, both before and after a GLP-1R antagonist (exendin-9) treatment. Inhibiting -{beta}-cell communication prolonged response time, increased 1st phase heterogeneity, and decreased the 1st phase response peak. Additionally, it reduced 2nd phase oscillation frequency and heterogeneity, thereby enhancing 2nd phase coordination across {beta}-cells. These changes were more pronounced in -neighboring {beta}-cells. Moreover, addition of exendin-9 disrupted the temporal consistency and -cell proximity of hub-cells and (to a lesser degree) 1st responder {beta}-cells. Together, these findings underscore the importance of engineering islets containing both - and {beta}-cells for stem cellderived islet replacement therapies for Type-1diabetes. Article Highlights{whitebullet} Role of GLP-1R mediated -{beta} cell communication in functional {beta}-cell heterogeneity was unclear. {whitebullet}Does GLP-1R inhibition affect all {beta}-cells uniformly, or will -neighboring cells be affected more? Is existence of 1st responder and hub cell subpopulations shaped by GLP-1R signaling? {whitebullet}GLP-1R inhibition decreases multiple metrics or {beta}-cell responsiveness - especially in -neighboring {beta}-cells. It diminishes spatiotemporal consistency of hub {beta}-cells and (to a lesser degree) 1st responders. {whitebullet}Islet-local GLP-1R communication in absence of exogenous GLP-1 is sufficient for significant control of {beta}-cell function. Incorporating -cells into the engineered islets can improve islet replacement outcomes.

bioengineering↗

bioRxiv2024

Network approach reveals preferential T-cell and macrophage association with α-linked β-cells in early stage of insulitis in NOD mice.

One of the challenges in studying islet inflammation - insulitis - is that it is a transient phenomenon. Traditional reporting of the insulitis progression is based on cumulative, donor-averaged values of leucocyte density in the vicinity of pancreatic islets, that hinders intra- and inter-islet heterogeneity of disease progression. Here, we aimed to understand why insulitis is non-uniform, often with peri-insulitis lesions formed on one side of an islet. To achieve this, we demonstrated applicability of network theory in detangling intra-islet multi-cellular interactions during insulitis. Specifically, we asked the question "what is unique about regions of the islet which interact with immune cells first". This study utilized the non-obese diabetic mouse model of type one diabetes and examined the interplay among -, {beta}-, T-cells, myeloid cells, and macrophages in pancreatic islets during the progression of insulitis. Disease evolution was tracked based on T/{beta} cell ratio in individual islets. In the early stage, we found that immune cells are preferentially interacting with -cell-rich regions of an islet. At the islet periphery -linked {beta}-cells were found to be targeted significantly more compared to those without -cell neighbors. Additionally, network analysis revealed increased T-myeloid, and T-macrophage interactions with all {beta}-cells.

bioengineering↗