NADH Shuttle and Insulin Secretion

NADH Shuttle and Insulin Secretion

In their report (1), Eto et al. hypothesize that
nicotinamide adenine dinucleotide (NADH)
is the signal for the coupling of glycolytic and
mitochondrial glucose metabolism that triggers
insulin secretion. Their conclusions,
based on their innovative and meticulous experiments,
do not consider the possibility that
the glycolytic end-product in the cytosol is
not pyruvate, but lactate. Thus, when lactate
enters the mitochondrial tricarboxylic acid
cycle, it must first be converted to pyruvate
by the lactate dehydrogenase (LDH) reaction
that also produces NADH. The LDH reaction
is an important source of NADH that allows
cellular utilization of lactate as the sole oxidative
energy substrate (2). Whether or not
the LDH-produced NADH plays a role in
triggering insulin secretion could be determined
by use of the well-designed system
described in the report (1). Incubation of
mGPDH2/2 islets with 22.2 mM glucose 1
aminooxyacetate (AOA) 1 (20 to 40 mM)
lactate should provide ample amounts of
LDH-produced NADH. Alternatively, incubation
of wild-type (WT) islets with 22.2 mM
glucose 1 iodoacetic acid (IAA) 1 AOA 1
(20 to 40 mM) lactate should work as well.
Instead of IAA, the use of a pharmacological
dose of the glucose analog 2-deoxy-D-glucose
might work. Performing these experiments,
one should be able to determine if the
LDH reaction produces an NADH signal and,
if so, whether or not such a signal is sufficient
to trigger insulin secretion…

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