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.

Clinical and biological characteristics of diabetic patients under age 40 in Cameroon: Relation to autoantibody status and comparison with Belgian patients

“…There was no case of diabetic ketoacidosis as none of our patients showed the clinical pattern that characterizes ketosis prone diabetes from patients in the same unit [30,31]. Further steps towards improved diagnosis in this heterogeneous patient group may require both C-peptide and GADA determinations, while additional markers could be developed following the recently described alterations in amino acid metabolism [32], in combination with determination of PAX4 risk haplotypes [33]. …”

Ketosis Onset Type 2 Diabetes Had Better Isletβ-Cell Function and More Serious Insulin Resistance

“…KPD was divided into four subgroups according to the presence of glutamic acid decarboxylase (GAD) 65, GAD67, or IA-2 autoantibodies (A + or A − ) and β -cell functional reserve ( β + or β − ). The group distribution was A + β − , A − β + , A − β − , and A + β + [22, 23]. Choukem et al showed that β - and α -cell dysfunctions both contribute to the pathophysiology of KPD; in addition, KPD displays a defect in β -cell sensitivity to glucose and has reduced β -cell mass [24].…”

Metabolomics, Stable Isotopes, and A−β+ Ketosis-Prone Diabetes

“…In the current issue of Diabetes , Patel et al (12) studied KPD patients with metabolomic approaches and then quantified metabolic fluxes using in vivo stable isotope tracers. This approach harnessed the high-throughput and broad information content of a metabolomic platform to generate hypotheses without the bias of a priori assumptions about disease-related metabolic derangements.…”