Control of Insulin Secretion by Cytochrome c and Calcium Signaling in Islets with Impaired Metabolism

• Published in: The Journal of biological chemistry Vol. 289; no. 27; pp. 19110 - 19119
• Main Authors: Rountree, Austin M., Neal, Adam S., Lisowski, Mark, Rizzo, Norma, Radtke, Jared, White, Sarah, Luciani, Dan S., Kim, Francis, Hampe, Christiane S., Sweet, Ian R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.07.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Calcium; Calcium Signaling; Calcium Signaling - drug effects; Cytochrome c; Cytochrome c Translocation; Cytochromes c - metabolism; Dose-Response Relationship, Drug; Energy Metabolism - drug effects; Fasting; Glucose - pharmacology; Glycolysis - drug effects; In Vitro Techniques; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Keto Acids - pharmacology; Metabolic Diseases - metabolism; Metabolic Diseases - pathology; Metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Metabolism; Oxidation-Reduction; Oxygen - metabolism; Oxygen Consumption; Pancreatic Islet; Protein Transport - drug effects; Rats; Rats, Sprague-Dawley; Cytochrome c; Pancreatic Islet; Calcium; Oxygen Consumption; Insulin Secretion; Cytochrome c Translocation; Calcium Signaling; Mitochondrial Metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.556050

The aim of the study was to assess the relative control of insulin secretion rate (ISR) by calcium influx and signaling from cytochrome c in islets where, as in diabetes, the metabolic pathways are impaired. This was achieved either by culturing isolated islets at low (3 mm) glucose or by fasting rats prior to the isolation of the islets. Culture in low glucose greatly reduced the glucose response of cytochrome c reduction and translocation and ISR, but did not affect the response to the mitochondrial fuel α-ketoisocaproate. Unexpectedly, glucose-stimulated calcium influx was only slightly reduced in low glucose-cultured islets and was not responsible for the impairment in glucose-stimulated ISR. A glucokinase activator acutely restored cytochrome c reduction and translocation and ISR, independent of effects on calcium influx. Islets from fasted rats had reduced ISR and cytochrome c reduction in response to both glucose and α-ketoisocaproate despite normal responses of calcium. Our data are consistent with the scenario where cytochrome c reduction and translocation are essential signals in the stimulation of ISR, the loss of which can result in impaired ISR even when calcium response is normal. Background: Intracellular calcium and metabolic signals mediate glucose-induced insulin secretion. Results: In metabolically compromised islets, calcium signaling was robust, whereas reduction and translocation of cytochrome c were diminished. Conclusion: Data are consistent with a rate-determining role at the level of cytochrome c for insulin secretion. Significance: Impairment of metabolic control preferentially affects cytochrome c versus calcium signaling.