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

作     者：Ernest Beaudelaire Tsiaze Ya-Chi Huang Lidija Krizancic Bombek Shi-Bing Yang Marko Jevsek Susumu Seino Marjan Slak Rupnik 

作者机构：European Neuroscience InstituteGottingenGermany Institute of Medical ScienceUniversity of TorontoTorontoCanada Institute of PhysiologyFaculty of MedicineUniversity of MariborMariborSlovenia Howard Hughes Medical InstituteSan FranciscoUSA Division of Diabetes and EndocrinologyDepartment of Internal MedicineKobe University Graduate School of MedicineKobeJapan 

出 版 物：《Open Journal of Molecular and Integrative Physiology》 (分子和综合生理学期刊（英文）)

年 卷 期：2012年第2卷第3期

页      面：51-60页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：the Growbeta EU grant (5th framework, No. QLG1-CT-2001-02233) The European Neuroscience Institute Gottingen (ENI-G) Gottingen University Medical School the Max-Planck-Society and Schering AG 

主　　题：Islets of Langerhans Insulin Hyperinsulinism Persistent Hyperinsulinemia Hypoglycemia of Infancy Ion Channels Patch-Clamp Techniques 

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.