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J Biol Chem, Vol. 273, Issue 33, 20770-20778, August 14, 1998

Desensitization of Mitochondrial Ca²⁺ and Insulin Secretion Responses in the Beta Cell

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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