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Observational Study
. 2025 Sep;68(9):1889-1898.
doi: 10.1007/s00125-025-06461-z. Epub 2025 May 29.

Prevention of diabetic ketoacidosis in relatives screened for islet autoantibodies and followed up in the TrialNet Pathway to Prevention study at a single institution in Italy

Sabina Martinenghi  1 , Aurora Merolla  2 , Pauline Grogan  1 , Eleonora Bianconi  1 , Elisa Senni  2 , Anastasia Goncharova  2 , Francesco Massara  2 , Francesca Ragogna  1 , Elena Bazzigaluppi  1 , Matteo R Pastore  1 , Riccardo Bonfanti  2 , Emanuele Bosi  3   4
Affiliations
Observational Study

Prevention of diabetic ketoacidosis in relatives screened for islet autoantibodies and followed up in the TrialNet Pathway to Prevention study at a single institution in Italy

Sabina Martinenghi et al. Diabetologia. 2025 Sep.

Abstract

Aims/hypothesis: Screening for islet autoantibodies is an effective method for identifying individuals with pre-symptomatic (stage 1 and 2) type 1 diabetes. This approach offers a valuable opportunity for education and monitoring, which can help to reduce the severity of clinical manifestations at clinical onset (stage 3), including diabetic ketoacidosis. The aim of the study was to evaluate the progression to stage 3 and the incidence of diabetic ketoacidosis in relatives of individuals with type 1 diabetes screened and followed up at a single institution in Italy.

Methods: This was a single-centre observational study conducted at San Raffaele Hospital, Milan, Italy, within the international multisite TrialNet Natural History Study-Pathway to Prevention. First-degree (aged 1-45 years) and second-degree (aged 1-20 years) relatives were screened primarily for GADA, IAA and IA-2A. In the event of a positive result, subsequent testing was conducted for ICA and ZnT8A. Periodic autoantibody testing, metabolic monitoring and educational support were offered to all autoantibody-positive participants. Participants were screened between July 2005 and February 2020, with the latest update obtained between January 2023 and June 2024.

Results: In total, 4046 relatives were screened at a median (IQR) age of 17.6 (7.9-38.0) years. At first screening, 4.9% were found to be positive, with 3.1% having a single autoantibody and 1.8% multiple autoantibodies. Follow-up data were available for 78.5% of the participants, with a median (IQR) follow-up time of 9.9 (6.5-13.5) years. Progression to stage 3 was observed in 51 (1.6%) participants. Disease onset occurred in 0.4% of autoantibody-negative, 6.5% of single-positive and 43.1% of multiple-positive participants after a median (IQR) time of 7.8 (5.4-10.4), 7.9 (2.1-11.8) and 2.9 (0.9-6.5) years, respectively (p=0.012). The Kaplan-Meier survival free of clinical diabetes at 15 years was 99.5% (95% CI 99.1, 99.7), 87.3% (95% CI 74.4, 94.0) and 45.9% (95% CI 31.1, 59.6), respectively (p<0.001). At the time of disease onset, no occurrences of diabetic ketoacidosis were documented. Median (IQR) HbA1c was 64 (52-86) mmol/mol (8.0 [6.9-10.0]%) and median (IQR) venous pH at onset was 7.37 (7.35-7.39). Hospitalisation occurred in 22 paediatric participants, as part of standard practice for newly diagnosed patients at our institution aiming to provide disease education and insulin therapy optimisation.

Conclusions/interpretation: The early identification of individuals at risk for type 1 diabetes through a single-centre approach, combining autoantibody screening and regular monitoring, completely prevented diabetes-associated ketoacidosis at disease onset in relatives of individuals with type 1 diabetes.

Trial registration: ClinicalTrials.gov NCT00097292.

Keywords: Autoantibody; Diabetic ketoacidosis; Monitoring; Prevention; Screening; Type 1 diabetes.

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Conflict of interest statement

Acknowledgements: The sponsor of the trial was the Type 1 Diabetes TrialNet Study Group. The authors would like to extend their gratitude to the thousands of participants and their families who generously contributed to the study, providing data, samples and information of invaluable importance for the advancement of knowledge about type 1 diabetes. Data availability: The data that support the findings of this study are available from the corresponding author. Restrictions apply to the availability of these data, which were used under license from the TrialNet (USA) for the current study and so are not publicly available. Data are, however, available from the corresponding author upon reasonable request and with permission from the TrialNet Consortium. Funding: We acknowledge the support of the Type 1 Diabetes TrialNet Study Group’s Pathway to Prevention Study for this TrialNet Ancillary Study. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through the cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180,U01 DK103153, U01 DK085476, U01 DK103266, U01 DK103282, U01 DK106984,U01 DK106994, U01 DK107013, U01 DK107014, U01 DK106993 and Breakthrough T1D (formerly JDRF). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or Breakthrough T1D (formerly JDRF). Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: EBo was a member of the TrialNet Study Group and had clinical and scientific responsibility for the conduction of TrialNet studies at the centre. PG was the Trial Coordinator. SM, MRP, RB were the physicians responsible for the contact with participants and families for screening and follow-up. EBi, PG, FR and EBa were responsible for the conduction of screening, follow-up and monitoring procedures, including periodic contact, administration of educational tools, execution of immunological and metabolic tests. ES, AG and FM were responsible for the phone and e-mail contacts during 2023 and 2024 with participants for whom there was no further contact after the first screening and those with no updated information during follow-up. SM, AM, ES and FM designed and conducted the statistical analysis. EBo, SM and AM wrote the manuscript. All authors contributed to discussion and reviewed/edited the manuscript and gave final approval for the paper to be published. EBo is responsible for the integrity of the work as a whole.

Figures

Fig. 1
Fig. 1
Participants’ flow diagram. Ab, autoantibody; T1D, stage 3 type 1 diabetes
Fig. 2
Fig. 2
Survival free of stage 3 type 1 diabetes after the first autoantibody screening test. Green line, autoantibody-negative; blue line, positive for a single autoantibody; red, positive for ≥2 autoantibodies. CIs are displayed around the survival curves. Statistical test used for comparison: logrank test (p value <0.001). Ab, autoantibody
See this image and copyright information in PMC

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