NMDA receptor inhibition increases, synchronizes, and stabilizes the collective pancreatic beta cell activity: Insights through multilayer network analysis.

Marko Šterk,Lidija Križančić Bombek,Marko Gosak,Maša Skelin Klemen,Marko Marhl,Marjan Slak Rupnik,Andraž Stožer

doi:10.1371/journal.pcbi.1009002

Marko Šterk, Lidija Križančić Bombek + Show 5 more

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https://doi.org/10.1371/journal.pcbi.1009002

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Abstract

NMDA receptors promote repolarization in pancreatic beta cells and thereby reduce glucose-stimulated insulin secretion. Therefore, NMDA receptors are a potential therapeutic target for diabetes. While the mechanism of NMDA receptor inhibition in beta cells is rather well understood at the molecular level, its possible effects on the collective cellular activity have not been addressed to date, even though proper insulin secretion patterns result from well-synchronized beta cell behavior. The latter is enabled by strong intercellular connectivity, which governs propagating calcium waves across the islets and makes the heterogeneous beta cell population work in synchrony. Since a disrupted collective activity is an important and possibly early contributor to impaired insulin secretion and glucose intolerance, it is of utmost importance to understand possible effects of NMDA receptor inhibition on beta cell functional connectivity. To address this issue, we combined confocal functional multicellular calcium imaging in mouse tissue slices with network science approaches. Our results revealed that NMDA receptor inhibition increases, synchronizes, and stabilizes beta cell activity without affecting the velocity or size of calcium waves. To explore intercellular interactions more precisely, we made use of the multilayer network formalism by regarding each calcium wave as an individual network layer, with weighted directed connections portraying the intercellular propagation. NMDA receptor inhibition stabilized both the role of wave initiators and the course of waves. The findings obtained with the experimental antagonist of NMDA receptors, MK-801, were additionally validated with dextrorphan, the active metabolite of the approved drug dextromethorphan, as well as with experiments on NMDA receptor KO mice. In sum, our results provide additional and new evidence for a possible role of NMDA receptor inhibition in treatment of type 2 diabetes and introduce the multilayer network paradigm as a general strategy to examine effects of drugs on connectivity in multicellular systems.

Highlights

Type 2 diabetes mellitus (T2DM) has become the most common metabolic disease in the developed world, representing a substantial public health threat with high personal and healthsystem costs [1]
Information processing in tissues is regulated by networks of interacting cells and through crosstalk with their environment. This is true for islets of Langerhans in which several hundreds of beta cells are interconnected to ensure a proper secretion of insulin, a hormone crucial for the control of metabolic homeostasis
Since the loss of coordinated cellular activity is accompanied by a disruption of insulin secretion patterns, one of the main hallmarks of diabetes, it is of utmost importance to understand the underlying mechanisms that drive collective cellular activity in the islets and how these are affected in disease

Summary

Introduction

Type 2 diabetes mellitus (T2DM) has become the most common metabolic disease in the developed world, representing a substantial public health threat with high personal and healthsystem costs [1]. Current treatment strategies are aiming at enhanced insulin secretion, insulin replacement, pharmacological or dietary improvement of insulin sensitivity, and direct plasma glucose reduction. Insulin is produced and secreted from beta cells in pancreatic islets. They are the dominant endocrine cell type, occupying 60–80% of the islet volume [2]. The main condition for insulin secretion from beta cells is sufficient plasma glucose concentration. Glucose exerts pleiotropic effects on beta cells, leading to a raise in cytosolic Ca2+ concentration, which triggers and further regulates insulin release [4]. Additional neurohormonal pathways, involving protein-kinase A (PKA) and protein-kinase C (PKC)-dependent processes, can amplify the Ca2+-dependent pathway or independently activate insulin secretion [5,6]

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