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Cellular |
1 Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
2 Department of Physics, Technical University of Denmark, Lyngby, Denmark
3 Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA
Exposure of pancreatic islets of Langerhans to physiological concentrations of glucose leads to secretion of insulin in an oscillatory pattern. The oscillations in insulin secretion are associated with oscillations in cytosolic Ca2+ concentration ([Ca2+]c). Evidence suggests that the oscillations in [Ca2+]c and secretion are driven by oscillations in metabolism, but it is unclear whether metabolic oscillations are intrinsic to metabolism or require Ca2+ feedback. To address this question we explored the interaction of Ca2+ concentration and islet metabolism using simultaneous recordings of NAD(P)H autofluorescence and [Ca2+]c, in parallel with measurements of mitochondrial membrane potential (
m). All three parameters responded to 10 mM glucose with multiphasic dynamics culminating in slow oscillations with a period of 
5 min. This was observed in 90% of islets examined from various mouse strains. NAD(P)H oscillations preceded those of [Ca2+]c, but their upstroke was often accelerated during the increase in [Ca2+]c, and Ca2+ influx was a prerequisite for their generation. Prolonged elevations of [Ca2+]c augmented NAD(P)H autofluorescence of islets in the presence of 3 mM glucose, but often lowered NAD(P)H autofluorescence of islets exposed to 10 mM glucose. Comparable rises in [Ca2+]c depolarized m. The NAD(P)H lowering effect of an elevation of [Ca2+]c was reversed during inhibition of mitochondrial electron transport. These findings reveal the existence of slow oscillations in NAD(P)H autofluorescence in intact pancreatic islets, and suggest that they are shaped by Ca2+ concentration in a dynamic balance between activation of NADH-generating mitochondrial dehydrogenases and a Ca2+-induced decrease in NADH. We propose that a component of the latter reflects mitochondrial depolarization by Ca2+, which reduces respiratory control and consequently accelerates oxidation of NADH.
(Received 11 November 2005;
accepted after revision 31 January 2006;
first published online 2 February 2006)
Corresponding author D. S. Luciani: Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3. Email: dan.luciani{at}gmail.com
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