Slow oscillations of KATP conductance in mouse pancreatic islets provide support for electrical bursting driven by metabolic oscillations.
We used the patch clamp technique in situ to test the hypothesis that slow oscillations in metabolism mediate slow electrical oscillations in mouse pancreatic islets by causing oscillations in KATP channel activity. Total conductance was measured over the course of slow bursting oscillations in surface β-cells of islets exposed to 11.1 mM glucose by either switching from current clamp to voltage clamp at different phases of the bursting cycle or by clamping the cells to -60 mV and running two-second voltage ramps from -120 to -50 mV every 20 s. The membrane conductance, calculated from the slopes of the ramp current-voltage curves, oscillated and was larger during the silent phase than during the active phase of the burst. The ramp conductance was sensitive to diazoxide, and the oscillatory component was reduced by sulfonylureas or by lowering extracellular glucose to 2.8 mM, suggesting that the oscillatory total conductance is due to oscillatory KATP channel conductance. We demonstrate that these results are consistent with the Dual Oscillator model, in which glycolytic oscillations drive slow electrical bursting, but not with other models in which metabolic oscillations are secondary to calcium oscillations. The simulations also confirm that oscillations in membrane conductance can be well estimated from measurements of slope conductance and distinguished from gap junction conductance. Furthermore, the oscillatory conductance was blocked by tolbutamide in isolated β-cells. The data, combined with insights from mathematical models, support a mechanism of slow (∼5 min) bursting driven by oscillations in metabolism, rather than by oscillations in the intracellular free calcium concentration.
Department of Pharmacology and Brehm Diabetes Center, University of Michigan Medical School, Ann Arbor, Michigan;
Jianhua
J
Ren
Arthur
A
Sherman
Richard
R
Bertram
Paulette B
PB
Goforth
Craig S
CS
Nunemaker
Christopher D
CD
Waters
Leslie S
LS
Satin
D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D054086:KATP Channels / Q000378:metabolism*; D051379:Mice; D018408:Patch-Clamp Techniques
D054086:KATP Channels; D005947:Glucose
ATP-sensitive potassium channels; insulin; islets; oscillations