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Click to add/remove this article to your list of 'My Favorites' Accounting for Near-Normal Glucose Sensitivity in Kir6.2[AAA] Transgenic Mice

Year: 2006

Abstract Number: 1602-P


Institutions: Bethesda, MD; St. Louis, MO.

Results: We have previously reported that in Kir6.2[AAA] transgenic mice exhibhit islet mosaicism such that in 70% of the beta-cells the K(ATP) channels are rendered non-functional whereas the remainder have normal K(ATP) function (PNAS 99:16992, 2002). Further study of the response of insulin secretion has shown that the glucose dose response curve is only shifted modestly, by about 1 - 2 mM ( PLOS Biology, 2006, in press). Similarly, electrical activity, as assayed by fast (< 1 min) calcium oscillations, appears to be normal, with a shift in glucose sensitivity of again 1 - 2 mM. We have used a previously published mathematical model (Bull. Math. Biol. 66:1313 2004) to examine whether the observed shift in glucose sensitivity is compatible with known electrical properties of beta-cells. We found that in the model, reducing K(ATP) conductance by 2/3 could produce a shift of only about 1 mM glucose in the sensitivity of calcium oscillations, as assayed by either mean cytosolic calcium or plateau fraction of the bursting electrical oscillations. This result was favored by the assumption that only a small fraction of K(ATP) channels were open when cells were above threshold for oscillations. Thus, cells could maintain relatively normal electrical activity in the face of drastically reduced total K(ATP) conductance by up-regulating the open fraction in response to increased calcium influx, due to either reduced ATP production or increased ATP consumption. In conclusion, the presence of large numbers of "spare" K(ATP) channels and calcium feedback onto metabolism permits islets to function nearly normally when K(ATP) is genetically down-regulated.