Amino acids and CART distinguishing A-B+ ketosis-prone diabetes from type 1 and type 2 diabetes during hyperglycemic crises

Authors: JAHOOR, FAROOK - Children'S Nutrition Research Center (CNRC); HSU, JEAN - Children'S Nutrition Research Center (CNRC); KEENE, KELLY - Baylor College Of Medicine; PEACOCK, W FRANK - Baylor College Of Medicine; HUANG, XIAOFANG - Baylor College Of Medicine; GUFFEY, DANIELLE - Baylor College Of Medicine; BYUN, JINYOUNG - Baylor College Of Medicine; BENNET, RASMUS - Lund University; LERNMARK, AKE - Lund University; TOSUR, MUSTAFA - Children'S Nutrition Research Center (CNRC); BALASUBRAMANYAM, ASHOK - Baylor College Of Medicine

Submitted to: Journal of Clinical Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/3/2025
Publication Date: 1/16/2025
Citation: Jahoor, F., Hsu, J.W., Keene, K.R., Peacock, W., Huang, X., Guffey, D., Byun, J., Bennet, R., Lernmark, A., Tosur, M., Balasubramanyam, A. 2025. Amino acids and CART distinguishing A-B+ ketosis-prone diabetes from type 1 and type 2 diabetes during hyperglycemic crises. Journal of Clinical Endocrinology and Metabolism. 2025(00):1-10. https://doi.org/10.1210/clinem/dgaf033.
DOI: https://doi.org/10.1210/clinem/dgaf033

Interpretive Summary: Diagnosing diabetes correctly during a medical emergency can be hard, especially when it comes to ketosis-prone diabetes (KPD), a form that presents like type 1 diabetes (T1D) but behaves more like type 2 diabetes (T2D) in the long run. This is especially important because T1D and KPD require different treatments, and delays in diagnosis can cause harm. In this study, we explored how a special pattern of blood substances—amino acids and hormones related to stress and energy—can help doctors quickly tell KPD apart from T1D and T2D in the emergency room. We found that even during severe illness like diabetic ketoacidosis (DKA), people with KPD still had some insulin function, unlike those with T1D. But their bodies broke down protein differently—mostly due to high levels of stress hormones like cortisol and glucagon. A unique mix of six specific blood markers could accurately differentiate who has KPD, T1D, or T2D. Since many KPD patients are overweight, this research also highlights how obesity and nutrition-related metabolism may play a role in how diabetes presents and progresses. Better tools to diagnose KPD early could lead to more personalized and effective treatment from day one.

Technical Abstract: When clinically stable, patients with A-B+ Ketosis-Prone Diabetes (KPD) manifest unique markers of amino acid metabolism. Biomarkers differentiating KPD from type 1 (T1D) and type 2 diabetes (T2D) during hyperglycemic crises would accelerate diagnosis and management. Compare serum metabolomics of KPD, T1D and T2D patients during hyperglycemic crises, and utilize Classification and Regression Tree (CART) modeling to distinguish these forms of diabetes. Urban hospital emergency center. Adults with KPD, T1D and T2D during hyperglycemic crises (with or without diabetic ketoacidosis (DKA), and healthy controls. Comparisons of serum metabolite and hormonal profiles, and CART analysis. Group differences in concentrations of amino acids, their metabolites and relationship to glucose counterregulatory hormones; C-peptide cutoffs and analytes to distinguish KPD, T1D and T2D. Concentrations of most amino acids were similar in KPD and T1D and lower compared to T2D (P<0.05). Glucagon and cortisol concentrations were correlated with 3-methylhistidine and blood urea nitrogen in KPD but not in T1D. A C-peptide cutoff of 0.496 ng/mL differentiated T1D from KPD during DKA. CART revealed that a regression model based on the concentrations of B-hydroxybutyrate, C-peptide, glucagon, alpha-keto-B-methylvalerate, cystine and myristoyl-L-carnitine distinguished KPD from T1D and T2D. During DKA, KPD and T1D patients have similarly altered amino acid profiles that differentiate them from T2D patients. Elevated protein catabolic hormones drive altered amino acid metabolism in KPD, rather than insulin deficiency as with T1D. A combination of 6 analytes differentiates KPD from T1D and T2D during hyperglycemic crises.