Metabolomics Profiling of Patients With A-β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis

Authors

Farook Jahoor
Jean W Hsu
Paras B Mehta
Kelly R Keene
Ruchi Gaba
Surya Narayan Mulukutla
Eunice Caducoy
W Frank Peacock
Sanjeet G Patel
Rasmus Bennet
Ake Lernmark
Ashok Balasubramanyam

Publication Date

8-1-2021

Journal

Diabetes

DOI

10.2337/db21-0066

PMID

34021044

PMCID

PMC8385613

PubMedCentral® Posted Date

5-21-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adult, Amino Acids, Branched-Chain, Autoantibodies, Carnitine, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetic Ketoacidosis, Female, Humans, Male, Metabolome, Metabolomics, Middle Aged

Abstract

When stable and near-normoglycemic, patients with “A−β+” ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A−β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones—a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A−β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism.