Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of the insulin-producing pancreatic β-cells, leading to absolute insulin deficiency and manifested by the sudden onset of severe hyperglycemia leading to lifelong dependence on exogenous insulin [1]. Over the past few decades, the incidence of T1D has risen significantly worldwide and cannot be explained by genetic changes alone; it is most likely attributable to environmental influences as well [2,3]. Although lifestyle and behavioral factors are known to contribute to health and disease [4-6], growing evidence suggests that other environmental exposures may also play a critical role in the risk of chronic diseases and associated complications such as diabetes [7,8].

Emerging research highlights the complex role of the exposome, defined as the totality of environmental exposures experienced by an individual from conception onwards [9]. This exposome includes various dimensions that interact over time to influence individuals’ health. It comprises the general external exposome (eg, built environment, social environment, physicochemical exposures), the specific external exposome (eg, diet, pollutants, financial status), and the internal exposome (eg, metabolic processes, microbiome). These domains are interconnected, with overlapping exposures acting cumulatively to drive disease risk and progression throughout life [10-12].

Many studies have provided valuable insights into the exposome's significant role in developing and managing chronic diseases [13]. For instance, a review found that cardiometabolic risk factors and cardiovascular disease have been linked primarily to poor air quality [14] and a wide range of other elements of the exposome [15]. In another review, ischemic heart disease progression has been linked to several dimensions from the exposome, such as air, light, acoustic pollution, soil pollution, water contamination, climate change, social stress, and infectious diseases [16]. The effect of components from the exposome such as pollutants, industrial and agricultural chemicals, toxins, lifestyle and social factors, diet, microbiome, and infection have also been reported for Alzheimer disease as well as other major neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis [17-19]. Similarly, some studies have identified links between air pollution and heavy metals and susceptibility to the development and progression of chronic kidney disease, while associations with other dimensions from the exposome, such as chemicals and the built environment, remain understudied [20]. In the diabetes field, research has predominantly focused on type 2 diabetes (T2D) and gestational diabetes mellitus. Studies have shown exposure to ambient air pollution, persistent organic pollutants, and endocrine-disrupting chemicals play a critical role in the development of gestational diabetes mellitus [21], as well as air pollution, residential noise, and socioeconomic deprivation in the alteration of β-cells, leading to an increased risk of T2D [11,22].

Despite these interesting findings, the role of the exposome in T1D remains largely unexplored. We performed an explanatory search in relevant databases such as MEDLINE, Cochrane Database of Systematic Reviews, Open Science Framework, and PROSPERO. We did not identify current or underway scoping reviews on the exposome and its relationship to the development of T1D and its outcomes such as glycemic variability, long-term complications, and quality of life. Previous reviews have focused on specific exposures such as prenatal pollutants, diet, or viral infections [23-26]. However, the overall knowledge of the exposome remains dispersed. Even less is known about how these environmental factors impact individuals already living with T1D. Such a comprehensive understanding is essential for the identification of new strategies for disease prevention and management.

Conducting a scoping review is well-suited for this broad research question, as it allows for an exhaustive exploration, particularly for a fragmented research area. Unlike systematic reviews, scoping reviews map existing knowledge, identify research gaps, and comprehensively synthesize the available evidence [27-29]. This approach is beneficial for investigating the various environmental exposures in T1D development and its association with T1D disease outcomes, which remain underexplored.

The purpose of this protocol study is to describe the methodology for a scoping review assessing the current understanding of the role of the exposome in T1D development and complications. In the scoping review study, we aim to describe the main components of the exposome linked to T1D, report the most effective ways to collect exposome data, and highlight the existing gaps linked to this research question.

This protocol was previously registered using the Open Science Framework Registries platform [30]. The scoping review will follow the Joanna Briggs Institute (JBI) methodology for scoping reviews [29,31] and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews) guidelines, shown in Multimedia Appendix 1 [32]. In addition, we will follow the guidance of the free web-based tool CADIMA (Client-Server Application for Documentation and Integrated Management of All Steps of a Systematic Review), which will be used to perform this review. CADIMA is designed to assist in conducting systematic reviews and evidence syntheses, including scoping reviews. It provides a structured workflow to manage and document the review process, facilitate collaboration, and ensure transparency and reproducibility. For a scoping review, CADIMA allows the importation of a reference list from a preliminary literature search and deduplicates records, defines eligibility criteria, screens studies (based on titles and abstracts, and full texts), extracts relevant data, and generates visual reports such as PRISMA diagrams [33].

JBI proposes the PCC (Population/Concept/Context) framework to determine the key notions of the research question [29,31,34]. It has been determined based on the elements in Table 1 and defined as follows: which and how could environmental exposures lead to the development of the disease or complications of the disease for those who already have T1D?

Before using the CADIMA tool, an exhaustive search for studies in various databases will be performed to identify a comprehensive corpus of relevant studies: PubMed, Embase (Elsevier), CINAHL (EBSCO), Web of Science (Clarivate), and Google Scholar, based on the key concepts of T1D and exposome. Key concepts and further ones will be associated using the classic syntactic techniques provided by PubMed. The search strategy, including all identified keywords and index terms, will be adapted for each database after several attempts to provide the most efficient source of information. An example of what will be done in PubMed as well as the strings adapted to other databases is shown in Multimedia Appendix 2. There will be no selection by language. Studies available only in the original language other than English will be translated using artificial intelligence tools and verified with native speakers when needed. Each time a paper will have to be translated in English, a native-speaking scientist from our institution will be involved to check the relevance of the translation. Additional search strategies will be employed for additional sources by using backward and forward snowballing approaches, citations from review studies, and alerts for new studies from the different database queries.

Following the literature search, all identified studies concerning the impact of environmental exposures on the development or outcomes of T1D will be collected. All studies will be uploaded to the CADIMA tool, and duplicates will be removed. Two independent reviewers will perform the screening for titles and abstracts. After that, 2 independent researchers will select the studies by full text before extracting the data and summarizing all the relevant findings. The study eligibility criteria will be defined as follows.

As this work will focus on T1D, we will exclude studies on T2D or those where it is impossible to distinguish between T1D and T2D. For mixed populations, only results concerning T1D will be extracted. Studies that do not distinguish between T1D and T2D may introduce confounding factors, given their distinct etiology and pathophysiology [35-37]. The same applies to alterations in glucose levels caused by medication, which may lead to a bias in the interpretation of results, as they are not representative of the typical glycemic variability in people with T1D [38]. Finally, review studies will be excluded as they do not provide original data or specific methodologies. The same applies to case studies with limited scope for generalization [39].

Following a pilot test (consistency check to determine the agreement between reviewers when applying the selection criteria), 2 independent reviewers will screen titles and abstracts to assess them according to the study eligibility criteria defined for the review. CADIMA automatically and randomly allocates the studies to team members. The preliminary eligibility of the studies will be assessed at this stage. The selected studies by title and abstract will be evaluated for eligibility by full text. Authors of studies for which the full text is unavailable will be contacted using various communication channels (ResearchGate, email, LinkedIn) to maximize the chances of accessing the full text. During this stage, full texts will be excluded based on the eligibility criteria and for other reasons, such as being inaccessible or not presenting primary data/summary statistics. Any disagreements between the reviewers at each stage of the selection process will be solved through discussion among the reviewers, or if no consensus is reached, by involving a third reviewer. The search results and the study selection process will be fully documented in the final scoping review and presented as a PRISMA flow diagram.

Data will be extracted from eligible papers selected for the scoping review by 2 independent reviewers by using a data extraction sheet developed with the CADIMA tool. A draft of the data to be gathered is detailed in Multimedia Appendix 3. The data extracted will include comments, article ID, study ID, author, year of publication, title, data location, and study name as predefined by the CADIMA tool (columns 1 to 8, Multimedia Appendix 3) and additional columns defined by team members according to the research question (columns 9 to 62, Multimedia Appendix 3). This draft data extraction tool will be modified and revised as necessary during the data extraction process for each eligible study. Any disagreements between the reviewers will be solved through discussion.

The quality of the selected papers will be assessed by 2 independent reviewers by using JBI Critical Appraisal Tools [40] when provided for the specific study designs (eg, analytical cross-sectional, case-control, cohort studies, qualitative research, quasi-experimental, randomized controlled trials) and other relevant tools validated in the literature for study designs not covered by JBI, such as the National Institutes of Health and STROBE (Strengthening the Reporting of Observational studies in Epidemiology) checklists [41,42].

We will perform an analytical approach based on the following PCC (JBI) approach [34].

To ensure that the findings respond correctly to the review question and objectives and to organize and interpret the data, we will use numerical summaries and thematic synthesis [43]. To provide an overview of the included studies, we will describe the data with numerical summaries. We will present the sample characteristics such as the year of publication, geographical location, study design, and population. The exposures will be detailed in terms of exposure type (eg, environmental pollutants, occupational exposures, lifestyle factors) and exposure period (eg, in utero, childhood, adulthood). This summary will help identify current trends and gaps in the existing literature. We will also classify using thematic synthesis. This classification will provide key dimensions of the exposome based on its consensual definition about the general external exposome, specific external and internal exposome, and its associations with T1D. The results will be presented according to the outcome definition (development of T1D in the general population vs complications and outcomes in people living with T1D). We will use descriptive tables to summarize the characteristics of the studies and figures or diagrams to illustrate the distribution of the exposome dimensions related to T1D and the development and complications of T1D.

This scoping review aims to discuss in detail the current knowledge of the impact of the exposome in the context of T1D by exploring its role in the development of the disease and its subsequent complications. We expect that the principal findings will mainly concern aspects from the specific external exposome (eg, diet, infectious agents, pollutants). We expect to find more studies on the development of T1D (in young populations and possibly in utero exposure) rather than research on T1D complications. Indeed, several reviews and meta-analyses have already highlighted specific components of the exposome and their role in the development and the evolution of the disease [44-47]. Moreover, the current research seems to focus on a single impact of specific exposures rather than the combined effect, acting as a trigger at an early stage of the disease, particularly during onset. Although these studies have led to a better understanding of how the environment can affect diabetes, further aspects of the exposome and its relationship with T1D remain underexplored. To our knowledge, this is the first literature review to explore the role of the exposome in both the development of T1D and its complications in individuals living with T1D.

The principal strength of this review lies in its comprehensive scope. It will provide an in-depth examination of a recent and evolving concept while covering stages of the disease. However, this approach also implies that some limitations are expected. First, as the exposome concept is new and evolving, its dimensions are not always well-defined. Additionally, the measurement methods for environmental exposures could vary a lot from objective to subjective methods, and because of this heterogeneity, it could make it challenging to summarize and define the most effective ways to collect them. Lastly, it could be difficult to interpret the findings due to the different outcomes studied in this review, including the development of the disease or its complications.

In conclusion, this review protocol aims to establish a methodology for a comprehensive examination of the impact of the exposome in T1D and to highlight the existing gaps in the current research. The findings are expected to provide a valuable resource for future research projects in the development of personalized strategies for the prevention and management of T1D. In order to give the broadest possible access to this research work, the results of this scoping review will be disseminated via several channels such as an open-access paper, presentations at congresses or conferences on the topic, or press releases aimed at the scientific community and the general population.