title: Accounting for near-normal glucose sensitivity in Kir6.2[AAA] transgenic mice.
abstract: K(ir)6.2[AAA] transgenic mouse islets exhibit mosaicism such that approximately 70% of the beta-cells have nonfunctional ATP-sensitive potassium (K(ATP)) channels, whereas the remainder have normal K(ATP) function. Despite this drastic reduction, the glucose dose-response curve is only shifted by approximately 2 mM. We use a previously published mathematical model, in which K(ATP) conductance is increased by rises in cytosolic calcium through indirect effects on metabolism, to investigate how cells could compensate for the loss of K(ATP) conductance. Compensation is favored by the assumption that only a small fraction of K(ATP) channels are open during oscillations, which renders it easy to upregulate the open fraction via a modest elevation of calcium. We show further that strong gap-junctional coupling of both membrane potential and calcium is needed to overcome the stark heterogeneity of cell properties in these mosaic islets.
authors.affiliation: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Krasimira
authors.initials: K
authors.lastname: Tsaneva-Atanasova
authors.forename: Arthur
authors.initials: A
authors.lastname: Sherman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001703:Biophysics / Q000379:methods; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008962:Models, Theoretical; D009991:Oscillometry / Q000379:methods; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism*; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D002118:Calcium; D005947:Glucose; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel