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J Biol Chem, Vol. 273, Issue 33, 20770-20778, August 14, 1998
From the Division of Clinical Biochemistry, Department of Internal
Medicine, University Medical Center,
CH-1211 Geneva 4, Switzerland
The role of mitochondria in the desensitization
of insulin secretion was investigated. In rat pancreatic beta cells,
both insulin secretion and mitochondrial [Ca2+]
increases were desensitized following two challenges with the mitochondrial substrate methyl succinate. In the beta cell line INS-1,
similar results were observed when a 5-min interval separated two 5-min
pulses. In contrast, ATP generation monitored in luciferase-expressing INS-1 cells was stimulated to the same extent during both exposures to
methyl succinate. Succinate, like 
-glycerophosphate, activates the
electron transport chain at complex II. As a consequence, the
mitochondrial membrane hyperpolarizes, promoting ATP synthesis and
Ca2+ influx into the mitochondria through the uniporter.
The mitochondrial desensitization was further studied in permeabilized
INS-1 cells. Increasing extramitochondrial [Ca2+] from
100 to 500 nM enhanced succinate oxidation 4-fold. At 500 nM Ca2+, 1 mM succinate caused a
blunted mitochondrial [Ca2+] increase upon the second,
compared with the first, stimulation. These effects were mimicked by
-glycerophosphate, and there was cross-desensitization between the
two compounds. Succinate hyperpolarized the mitochondrial membrane
during both the first and second applications. This suggests that the
uniporter itself, rather than the respiratory chain, is desensitized.
These results emphasize the key role of the mitochondria not only in
the stimulation of insulin secretion, but also in its
desensitization.
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