Kercmar, J. | 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↗

bioRxiv2025

Effects of Arginine Vasopressin on Islet Cells in Pancreatic Tissue Slices: Glucose-Dependent Modulation of IP3 Receptor-Specific Responses

Arginine vasopressin (AVP) is well known for regulating fluid volume, osmotic balance, and vascular tone. Its role in the regulation of pancreatic and {beta} cell function has been reported, yet its effects are not fully understood, particularly regarding its interaction with plasma glucose levels. The osmotic and volume challenges posed by hyper- and hypoglycaemia in diabetes can be a significant complication of effective hormonal regulation of metabolism. In this study, we primarily investigated the effects of AVP and synthetic peptide receptor agonists and antagonists on and {beta} cells in pancreatic tissue slices using live confocal Ca2+ imaging. Our findings demonstrate that AVP exerts glucose-dependent effects on both cell types. At low glucose concentrations, AVP, in combination with physiologically or pharmacologically increased cAMP levels, selectively activated cells without significantly affecting {beta} cells. In contrast, at higher glucose concentrations and pharmacologically elevated cAMP levels, physiological levels of AVP enhanced {beta} cell activity, leading to increased Ca2+ oscillations and insulin release. In both cell types, AVP displayed a bell-shaped concentration dependence, with lower AVP concentrations stimulating hormone release and higher concentrations leading to diminished responses, consistent with inositol trisphosphate receptor (IP3R) activation and inactivation properties. Furthermore, our results indicate that AVP acts primarily through V1b receptors in {beta} cells, with no involvement of V1a, V2 or oxytocin receptors. These findings provide new insights into the modulation of glucose-dependent release of pancreatic hormones by AVP in the context of changed blood osmolality due to hyper- or hypoglycemia in diabetes. Importantly, our results emphasize the potential of targeting AVP signaling pathways as a therapeutic approach in diabetes research, aiming to improve hormone regulation and nutrient homeostasis. HighlightsO_LIHighly spatio-temporally resolved imaging of islet Ca2+ oscillations on pancreatic tissue slices provides an in situ-like model for physiological and pharmacological approaches. C_LIO_LIPhysiological glucose stimulation triggers non-linear {beta} cell collective responses that must be taken into account when interpreting single concentration pharmacological experiments. C_LIO_LIIn a high cAMP context, AVP acts through V1b receptors on islet and {beta} cells, exhibiting a bell-shaped dependence driven by the activation-inactivation properties of IP receptors. C_LIO_LIAVP modulates glucose-dependent effects on and {beta} cells in a physiological concentration range, in the presence of altered blood osmolality or volume due to hyperglycemia, or to the direct effects of hypoglycemia in diabetes. C_LI

physiology↗