Ca2+ controls slow NAD(P)H oscillations in glucose-stimulated mouse pancreatic islets

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 whethermetabolic 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 (ΔΨm). All three parameters responded
to 10mM 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 3mM glucose,
but often lowered NAD(P)H autofluorescence of islets exposed to 10mM glucose. Comparable
rises in [Ca2+]c depolarized ΔΨm. 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.

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