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Publications

Journal Article Epublish

PubMed: 40715470 DOI: 10.1038/s43856-025-01028-w

Altered branched chain ketoacids underlie shared metabolic phenotypes in type 1 diabetes and maple syrup urine disease.

Commun Med (Lond) 5(1):311

Authors: Domenico Roberti, Abby L Grier, Julie A Reisz, Fara Vallefuoco, Alicia Key, Shaun Bevers, Monika Dzieciatkowska, Travis Nemkov, Marcella Contieri, Angela Zanfardino, Philip J Norris, Michael P Busch, Vienna Kauffman, Holmes D Morton, Eric J Earley, Grier P Page, Pierluigi Marzuillo, Angelo D'Alessandro

Affiliations

  • Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • Vitalant Research Institute, San Francisco, CA, USA.
  • Central Pennsylvania Clinic, Belleville, PA, USA.
  • RTI International, Research Triangle Park, NC, USA.
  • Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Abstract

BACKGROUND

Diabetic ketoacidosis is an acute, potentially life-threatening, metabolic complication and often first presentation of type 1 diabetes (T1D) mellitus. Here, we investigated the metabolic and lipid profiles from pediatric patients with T1D, at initial diagnosis and after two weeks of insulin treatment, employing findings from patients affected by maple syrup urine disease (MSUD) and the Recipient Epidemiology and Donor Evaluation Study (REDS) III RBC Omics.

METHODS

27 patients with newly onset T1D were assessed at the University of Campania "L. Vanvitelli" at first diagnosis and 2 weeks after therapy with insulin. As part of the REDS-III RBC Omics, whole blood was collected from 13,091 healthy blood donors. Whole blood was also collected from 3 patients with MSUD by biallelic inactivating mutation of BCKDHA. Metabolomics and Lipidomics were performed via UHPLC-MS/MS.

RESULTS

Our findings highlight a newly identified associations among short-chain hydroxyacyl-carnitines, ketoacidosis, and hematological alterations in T1D. An associative linkage with SNPs in the regions coding for branched chain ketoacid dehydrogenase A and B (BCDHKA/B) is noted by leveraging measurements of the same metabolites in over 13,000 healthy genetically characterized donor volunteers. MSUD, a rare genetic disorder characterized by inactivating mutations of the BCDHKA gene leading to inability to metabolize branched-chain amino acids, manifests a strong association between the branched-chain amino acid-derived ketoacids, associated acyl-carnitines, and acidosis.

CONCLUSIONS

These results indicate that T1D hematological alterations at onset might act as biomarkers linked to circulating levels of short-chain acyl-carnitines, providing risk stratification for T1D and potentially for MSUD. Carnitine metabolism may be a promising therapeutic target for both diseases.

MeSH

Diabetes Mellitus, Carnitine, Genes, Insulin, Blood, Amino Acids, Phenotype, Maple Syrup Urine Disease, Diagnosis, Therapeutics, Mutation, Diabetes Mellitus, Type 1, Amino Acids, Branched-Chain, Ketosis, Acidosis