Age-dependent changes in the exocytotic efficacy in Kir6.2 ablated mouse pancreatic β-cells

摘要

In this study, we aimed to examine the electrophysio- logical properties of β-cells in Kir6.2-/- mice using fresh pancreatic tissue slice preparation. This prepa-ration is advantageous since it preserves socio-cellular context of the β-cells. Using this novel approach we revisited basic morphology and used whole-cell patch-clamp to study electrical excitability as well as to assess the modulation of the late steps of the exocy-totic activity of β-cells by cytosolic [Ca2+] changes in control and Kir6.2-/- mice. We found that young Kir6.2-/- mice (2 - 4 weeks old) were hypoglycaemic while aged Kir6.2-/- mice (5 - 60 weeks old) were normo- or even hyper- glycaemic. Membrane ca-pacitance measurements show- ed more efficient Ca2+-secretion coupling in young Kir6.2-/- mice, but this coupling is significantly reduced in older Kir6.2-/- mice. We have found increased exo- cytotic efficacy induced by repetitive trains of depo- larization pulses which may result from higher cyto- solic [Ca2+] due to hyperexcitability in Kir6.2-/- mice. This condition in turn resulted in the reduced β-cell number and func-tion in the following weeks. Detailed assessment of the efficacy of Ca2+ dependent exocyto- sis in β-cell from Kir6.2-/- mice may contribute to our understanding of the pathophysiology of persistent hyperinsulinemia hypoglycemia of infancy (PHHI) and suggest potential alternative therapeutic approaches for PHHI patients.