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Background <p>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).</p> Methods <p>Paediatric patients were classified based on the eGDR value in: insulin-resistant (T1DM+, eGDR &lt; 8&#xa0;mg/Kg/min, <i>n</i> = 29) and non-insulin-resistant (T1DM-, eGDR &gt; 8&#xa0;mg/Kg/min, <i>n</i> = 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.</p> Results <p>Our data showed that T1DM + EVs were packaged with proteins involved in fatty acid metabolism suppression through <i>STAT3</i> 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 (<i>p</i> = 0.0023).</p> Conclusions <p>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.</p>

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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

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  • 发表日期：

    2025年12月10日

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  • Maria Concetta Cufaro,
  • Ilaria Cicalini,
  • Paola Irma Guidone,
  • Paola Lanuti,
  • Francesca D’Ascanio,
  • Maria Alessandra Saltarelli,
  • Lorenza Sacrini,
  • Anna Piro,
  • Domenico De Bellis,
  • Gessica Di Carlo,
  • Luca Natale,
  • Serena Veschi,
  • Damiana Pieragostino,
  • Piero Del Boccio,
  • Claudia Rossi,
  • Stefano Tumini

摘要

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.