The importance of gap-junction coupling between β cells in pancreatic islets is well established in mouse. Suchultrastructural connections synchronize cellular activity, confine biological heterogeneity, and enhance insulinpulsatility. Dysfunction of coupling has been associated with diabetes and altered β-cell function. However, therole of gap junctions between human β cells is still largely unexplored. By using patch-clamp recordings of β cellsfrom human donors, we previously estimated electrical properties of these channels by mathematical modelingof pairs of human β cells. In this work we revise our estimate by modeling triplet configurations and largerheterogeneous clusters. We find that a coupling conductance in the range 0.005–0.020 nS/pF can reproduceexperiments in almost all the simulated arrangements. We finally explore the consequence of gap-junctioncoupling of this magnitude between β cells with mutant variants of the ATP-sensitive potassium channels involvedin some metabolic disorders and diabetic conditions, translating studies performed on rodents to the human case.Our results are finally discussed from the perspective of therapeutic strategies. In summary, modeling of morerealistic clusters with more than two β cells slightly lowers our previous estimate of gap-junction conductanceand gives rise to patterns that more closely resemble experimental traces.

Gap-junction coupling and ATP-sensitive potassium channels in human β -cell clusters: Effects on emergent dynamics

Loppini A;Filippi S
2017-01-01

Abstract

The importance of gap-junction coupling between β cells in pancreatic islets is well established in mouse. Suchultrastructural connections synchronize cellular activity, confine biological heterogeneity, and enhance insulinpulsatility. Dysfunction of coupling has been associated with diabetes and altered β-cell function. However, therole of gap junctions between human β cells is still largely unexplored. By using patch-clamp recordings of β cellsfrom human donors, we previously estimated electrical properties of these channels by mathematical modelingof pairs of human β cells. In this work we revise our estimate by modeling triplet configurations and largerheterogeneous clusters. We find that a coupling conductance in the range 0.005–0.020 nS/pF can reproduceexperiments in almost all the simulated arrangements. We finally explore the consequence of gap-junctioncoupling of this magnitude between β cells with mutant variants of the ATP-sensitive potassium channels involvedin some metabolic disorders and diabetic conditions, translating studies performed on rodents to the human case.Our results are finally discussed from the perspective of therapeutic strategies. In summary, modeling of morerealistic clusters with more than two β cells slightly lowers our previous estimate of gap-junction conductanceand gives rise to patterns that more closely resemble experimental traces.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12610/4227
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