Molecular cross-talk via extracellular vesicles for the characterization of young subjects with type 1 diabetes unravels new potential markers of insulin resistance and double diabetes

  • Diabetol Metab Syndr. 2025 Dec 10;18(1):16. doi: 10.1186/s13098-025-02042-7.
Maria Concetta Cufaro  1  2 ,  Ilaria Cicalini  1 ,  Paola Irma Guidone  3 ,  Paola Lanuti  2  4 ,  Francesca D'Ascanio  2  4  5 ,  Maria Alessandra Saltarelli  6 ,  Lorenza Sacrini  6 ,  Anna Piro  7 ,  Domenico De Bellis  2  4 ,  Gessica Di Carlo  2  8 ,  Luca Natale  1  2 ,  Serena Veschi  7 ,  Damiana Pieragostino  1  2 ,  Piero Del Boccio  2  8 ,  Claudia Rossi  9  10 ,  Stefano Tumini  6
Affiliations
  • 1. Department of Innovative Technologies in Medicine and Dentistry, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100, Italy.
  • 2. Center for Advanced Studies and Technology (CAST), G. d'Annunzio University of Chieti-Pescara, Chieti, 66100, Italy.
  • 3. UOSVD Paediatrics Della Murgia Fabio Perinei Hospital, Altamura (BA), 70022, Italy.
  • 4. Department of Medicine and Aging Sciences, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100, Italy.
  • 5. Department of Humanities Law and Economics, Leonardo da Vinci University, Torrevecchia Teatina (CH), 66010, Italy.
  • 6. Department of Maternal and Child Health UOSD Regional Center of Paediatric Diabetology, Chieti Hospital, Chieti, 66100, Italy.
  • 7. Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100, Italy.
  • 8. Department of Science, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100, Italy.
  • 9. Center for Advanced Studies and Technology (CAST), G. d'Annunzio University of Chieti-Pescara, Chieti, 66100, Italy. [email protected].
  • 10. Department of Science, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100, Italy. [email protected].
PMID: 41372973 DOI: 10.1186/s13098-025-02042-7
Abstract

Background: Insulin Resistance (IR) is commonly calculated using a simple mathematical formula, the eGDR (estimated Glucose Disposal Rate), but in the paediatric type I diabetes (T1DM) population this value has provided contrasting information. We aimed to provide a clearer metabolic "fingerprint" in children with "double diabetes", focusing on the molecular cross-talk mediated by extracellular vesicles (EVs).

Methods: Paediatric patients were classified based on the eGDR value in: insulin-resistant (T1DM+, eGDR < 8 mg/Kg/min, n = 29) and non-insulin-resistant (T1DM-, eGDR > 8 mg/Kg/min, n = 35). Venous blood collected from them, and 30 healthy controls was used to obtain dried blood spots (DBS) for AAs and ACs analysis by FIA-MS/MS and for EV by a patented flow cytometry method. Then, EVs were subjected to shotgun proteomics analysis by LC-MS/MS.

Results: Our data showed that T1DM + EVs were packaged with proteins involved in fatty acid metabolism suppression through STAT3 inhibition and related to possible liver damage. ACs on DBS samples corroborated these data, demonstrating a significant increase in oleoylcarnitine (C18:1), linoleoylcarnitine (C18:2), and myristoylcarnitine (C14) in T1DM+. The combination of clinical and metabolic data led to the identification of a statistical model with an out-of-bag error of 0.115%, demonstrating that palmitoleoylcarnitine (C16:1) and C18:1 are the metabolites that best distinguish children with T1DM + from T1DM- ones. C16:1 correlated significantly with eGDR (p = 0.0023).

Conclusions: Combined "omics" approach allowed us to identify a new metabolic "photograph" in a complex context involving diabetes complications related to Obesity and IR in a paediatric population that is not yet fully characterized, identifying EVs as well-organized and functionalized shuttles.

Keywords
Acylcarnitines; Double diabetes; Extracellular vesicles; FACS-Proteomics; Insulin resistance.
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