Pathogenesis of A−β+ Ketosis-Prone Diabetes
- Sanjeet G. Patel1,
- Jean W. Hsu2,
- Farook Jahoor2,
- Ivonne Coraza1,
- James R. Bain3,4,
- Robert D. Stevens3,4,
- Dinakar Iyer1,
- Ramaswami Nalini1,5,
- Kerem Ozer1,5,
- Christiane S. Hampe6,
- Christopher B. Newgard3,4 and
- Ashok Balasubramanyam1,5⇓
- 1Translational Metabolism Unit, Diabetes/Endocrinology Research Center, Baylor College of Medicine, Houston, Texas
- 2Department of Pediatrics, Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas
- 3Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina
- 4Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
- 5Endocrine Service, Ben Taub General Hospital, Houston, Texas
- 6Department of Medicine, University of Washington, Seattle, Washington
- Corresponding author: Ashok Balasubramanyam, .
A−β+ ketosis-prone diabetes (KPD) is an emerging syndrome of obesity, unprovoked ketoacidosis, reversible β-cell dysfunction, and near-normoglycemic remission. We combined metabolomics with targeted kinetic measurements to investigate its pathophysiology. Fasting plasma fatty acids, acylcarnitines, and amino acids were quantified in 20 KPD patients compared with 19 nondiabetic control subjects. Unique signatures in KPD—higher glutamate but lower glutamine and citrulline concentrations, increased β-hydroxybutyryl-carnitine, decreased isovaleryl-carnitine (a leucine catabolite), and decreased tricarboxylic acid (TCA) cycle intermediates—generated hypotheses that were tested through stable isotope/mass spectrometry protocols in nine new-onset, stable KPD patients compared with seven nondiabetic control subjects. Free fatty acid flux and acetyl CoA flux and oxidation were similar, but KPD had slower acetyl CoA conversion to β-hydroxybutyrate; higher fasting β-hydroxybutyrate concentration; slower β-hydroxybutyrate oxidation; faster leucine oxidative decarboxylation; accelerated glutamine conversion to glutamate without increase in glutamate carbon oxidation; and slower citrulline flux, with diminished glutamine amide–nitrogen transfer to citrulline. The confluence of metabolomic and kinetic data indicate a distinctive pathogenic sequence: impaired ketone oxidation and fatty acid utilization for energy, leading to accelerated leucine catabolism and transamination of α-ketoglutarate to glutamate, with impaired TCA anaplerosis of glutamate carbon. They highlight a novel process of defective energy production and ketosis in A−β+ KPD.
- Received May 17, 2012.
- Accepted August 19, 2012.
- © 2013 by the American Diabetes Association.
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