title: Pathogenesis of A⁻β⁺ ketosis-prone diabetes.
abstract: 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.
authors.affiliation: Translational Metabolism Unit, Diabetes/Endocrinology Research Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sanjeet G
authors.initials: SG
authors.lastname: Patel
authors.forename: Jean W
authors.initials: JW
authors.lastname: Hsu
authors.forename: Farook
authors.initials: F
authors.lastname: Jahoor
authors.forename: Ivonne
authors.initials: I
authors.lastname: Coraza
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Dinakar
authors.initials: D
authors.lastname: Iyer
authors.forename: Ramaswami
authors.initials: R
authors.lastname: Nalini
authors.forename: Kerem
authors.initials: K
authors.lastname: Ozer
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
mesh_terms: D000328:Adult; D000465:Algorithms; D001323:Autoantibodies / Q000032:analysis*; D015992:Body Mass Index; D002952:Citric Acid Cycle; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D016883:Diabetic Ketoacidosis / Q000209:etiology*; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D008137:Longitudinal Studies; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D009765:Obesity / Q000150:complications
chemical_list: D001323:Autoantibodies