Intrinsic islet heterogeneity and gap junction coupling determine spatiotemporal Ca2+ wave dynamics

Richard K.P. Benninger, Troy Hutchens, W. Steven Head, Michael J. McCaughey, Min Zhang, Sylvain J. Le Marchand, Leslie S. Satin, David W. Piston

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Insulin is released from the islets of Langerhans in discrete pulses that are linked to synchronized oscillations of intracellular free calcium ([Ca2+]i). Associated with each synchronized oscillation is a propagating calcium wave mediated by Connexin36 (Cx36) gap junctions. A computational islet model predicted that waves emerge due to heterogeneity in β-cell function throughout the islet. To test this, we applied defined patterns of glucose stimulation across the islet using a microfluidic device and measured how these perturbations affect calcium wave propagation. We further investigated how gap junction coupling regulates spatiotemporal [Ca2+]i dynamics in the face of heterogeneous glucose stimulation. Calcium waves were found to originate in regions of the islet having elevated excitability, and this heterogeneity is an intrinsic property of islet β-cells. The extent of [Ca2+]i elevation across the islet in the presence of heterogeneity is gap-junction dependent, which reveals a glucose dependence of gap junction coupling. To better describe these observations, we had to modify the computational islet model to consider the electrochemical gradient between neighboring β-cells. These results reveal how the spatiotemporal [Ca2+]i dynamics of the islet depend on β-cell heterogeneity and cell-cell coupling, and are important for understanding the regulation of coordinated insulin release across the islet.

Original languageEnglish
Pages (from-to)2723-2733
Number of pages11
JournalBiophysical Journal
Volume107
Issue number11
DOIs
StatePublished - Dec 2 2014
Externally publishedYes

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