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

Open Journal of Molecular and Integrative Physiology 2012年第3期2卷 51-60页

作者： Ernest Beaudelaire Tsiaze Ya-Chi Huang Lidija Krizancic Bombek Shi-Bing Yang Marko Jevsek Susumu Seino Marjan Slak Rupnik European Neuroscience Institute GottingenGermany Institute of Medical Science University of TorontoTorontoCanada Institute of Physiology Faculty of MedicineUniversity of MariborMariborSlovenia Howard Hughes Medical Institute San FranciscoUSA Division of Diabetes and Endocrinology Department of Internal MedicineKobe University Graduate School of MedicineKobeJapan

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.

关键词： Islets of Langerhans Insulin Hyperinsulinism persistent hyperinsulinemia hypoglycemia of infancy Ion Channels Patch-Clamp Techniques

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