Anaplerosis from glucose, α-ketoisocaproate, and pyruvate in pancreatic islets, INS-1 cells and liver mitochondria

• Published in: Molecular and cellular biochemistry Vol. 313; no. 1-2; pp. 195 - 202
• Main Authors: MacDonald, Michael J, Stoker, Scott W, Hasan, Noaman M
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.06.2008; Springer US
• Subjects: Animals; ATP Citrate (pro-S)-Lyase - metabolism; Biochemistry; Biomedical and Life Sciences; Carbon Dioxide - metabolism; Carbon Isotopes; Cardiology; Cell Line; Chemical Precipitation; Glucose - metabolism; Glucose - pharmacology; Islets of Langerhans - drug effects; Islets of Langerhans - enzymology; Islets of Langerhans - metabolism; Keto Acids - metabolism; Keto Acids - pharmacology; Life Sciences; Medical Biochemistry; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Oncology; Pyruvates - metabolism; Pyruvates - pharmacology; Rats; Rats, Sprague-Dawley; Subcellular Fractions - drug effects; Substrate Specificity - drug effects; Synergistic secretagogue combinations; Pancreatic islets; Methyl succinate; Anaplerosis; Acetoacetate
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-008-9757-x

Methyl succinate (MS) and α-ketoisocaproate (KIC) when applied alone to cultured pancreatic islets or INS-1 832/13 cells do not stimulate insulin release. However, when the two metabolites are combined together they strongly stimulate insulin release. Studying the possible explanations for this complementarity has provided clues to the pathways involved in insulin secretion. MS increased carbon incorporation of KIC into acid-precipitable material and lipid in INS-1 cells. In isolated mitochondria, MS alone increased malate, but MS plus KIC increased citrate, α-ketoglutarate, and isocitrate. These data and the known pathways of their metabolism suggest that MS supplies the oxaloacetate component of citrate and KIC supplies the acetate component of citrate. Other citric acid cycle intermediates can be formed from citrate enabling anaplerosis to supply precursors for extramitochondrial pathways. In addition, KIC, glucose and pyruvate can be metabolized to acetoacetate. In an INS-1 cell line deficient in ATP citrate lyase, incorporation of carbon from pyruvate into acid-precipitable material and lipid was not lowered. This negative result is in agreement with our recent discovery that citrate is not the only carrier of acyl groups from the mitochondria to the cytosol in the beta cell and that acetoacetate can also transfer acyl carbon to the cytosol.