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bioRxiv · 10.1101/2025.03.03.641205

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

Kercmar, J.·Murko, N.·Krizancic Bombek, L.·Paradiz Leitgeb, E.·Pfabe, J.·Postic, S.·Huang, Y.-C.·Stozer, A.·Korosak, D.·Kozisek, X.·Perisic, M.·Muttenthaler, M.·Gruber, C. W.·Slak Rupnik, M.
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Abstract

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

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Kercmar, J., Murko, N., Krizancic Bombek, L., Paradiz Leitgeb, E., Pfabe, J., Postic, S., Huang, Y.-C., Stozer, A., Korosak, D., Kozisek, X., Perisic, M., Muttenthaler, M., Gruber, C. W., Slak Rupnik, M.. 2025-03-11. Effects of Arginine Vasopressin on Islet Cells in Pancreatic Tissue Slices: Glucose-Dependent Modulation of IP3 Receptor-Specific Responses. https://doi.org/10.1101/2025.03.03.641205

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