It has been only demonstrated that early derangements are predictive of T1D development since prophylactic strategies are not available at the moment. The outcome of the at-risk status might lay downstream to the maturation of previously mentioned T1D-driving exogenous factors during the critical window, corresponding to the period of subject food and bacterial exposition, especially till early life. Epidemiologically identified T1D indicators have been frequently hypothesized as potentially responsible for the T1D increase phenomenon, although the correct answer to this important question must be awaited due to the fact of difficulties involving T1D incidence and the necessity for very long follow-up studies in a large number of individuals to that end [1]. The environmental triggers supposed to be responsible for accelerating T1D development have different characteristics. They are characterized by specificities, which distinguish them as very complex factors able to diverge diversely from the temporal, geographic and ethnic points of view. These facts could be extremely useful to elucidate the correct contribution of single etiological factors in T1D development and to provide preventive strategies [2]. Because of these uncertainties, the interest of scientists involved in the study of T1D pathogenesis is mainly focused on collecting more and more data on T1D indicators and etiological factors, also given being able to develop effective early diagnosis and especially preventive strategies [3]. To date, the physiopathology of Type 1 Diabetes Mellitus (T1D) has been almost fully elucidated, involving genetic, immunological and environmental determinants. T1D results from genetic susceptibility, mainly conferred by the HLA complex and by more than 50 additional genes only partially shared by different populations. The high worldwide incidence of T1D, together with the strong increase in various autoimmune disorders in the last few decades, arouses the competition to identify one or multiple environmental determinants responsible for this rise [4]. The fact that the pace of T1D development is recent and that the percentage of increase is following the pace of worldwide environmental changes suggests an epigenetic model in T1D pathogenesis. This model supports the acceleration in T1D incidence acting through the fast change exogenous factors. However, this phenomenon prevails only in the presence of a genetic predisposition and the development pace is likely delayed in subjects who carry T1D protective alleles. Indeed, metabolism and lifestyle of T1D families and of T1D patients during their early life or even before their birth might greatly influence T1D incidence [5].

Background and Significance

Most recent data show that T1DM has no sex preponderance, while its incidence varies across the world. Multiple factors, including genetic and non-genetic factors, have been investigated and at least 50 genetic risk factors and many environmental risk factors for T1DM have been established. Although progress has been made, the ultimate question remains unsolved, particularly the effect of environmental factors [6]. It seems that new parameters, such as the use of antibiotics, the mode of delivery and neonatal feeding could be added to the list shortly. Moreover, most of the updated prevention strategies continue to be of limited clinical use. It is paramount to know these data to establish new preventive strategies and to diagnose T1DM in its preclinical stage, instead of its classical stage [7]. Diabetes mellitus is a chronic illness that has a considerable impact on the quality of life of children and adolescents. It represents a significant cause of morbidity and mortality in this age group. Both major types of diabetes mellitus (types 1 and 2) are present in the pediatric group. However, type 1 diabetes mellitus (T1DM) is the most common type of diabetes in children, where approximately 90-95% of diagnosed cases are type 1 [8]. The onset of T1DM typically occurs in adolescence, although there is an increasing prevalence of T1DM in the pediatric group [8].

Purpose of the Review

Type 1 diabetes mellitus is a frequent chronic disease diagnosed in children and adolescents. Several risk factors have been associated with the onset of this endocrine disorder. The aim of this review is to summarize the latest updates on risk factors for type 1 diabetes in children and adolescents and to propose balanced and healthy nutritional interventions to prevent the development of this nosologic entity. The evidence supports the role of vitamin D, the feeding of neonates with breast milk, the repression in gut microbiota and the protective role of omega-3. In addition, factors that may exert a negative effect in the control of type 1 diabetes are described, such as tobacco use. A brief but closely related to diabetes mellitus in general and to type 1 diabetes mellitus in particular is the use of alcohol and marijuana [9].

Epidemiology of Type 1 Diabetes in Children and Adolescents

Interpolations of other factors, such as a reduction in adherence to preventive behavior and the increase in risk factors of T1DM, have led to an increase in T1DM incidence. The global increased incidence of T1DM among children requires a solution and such causal risk factors can be involved in potential primary preventive measures. Factors that increase the overall risk of T1DM and lead to a particular vulnerability of a type of pediatric population can be called T1DM risk factors and, including endogenous, exogenous and non-modifiable factors, make an important contribution to the development of primary T1DM prevention [10]. At the same time, exogenous T1DM preventive risk factors are modifiable to some extent and should be the focus of attention for healthcare professionals. In this review, the exogenous risk factors of T1DM that clinically act at various stages of the disease in children and adolescents are presented [11]. The prevalence of type 1 diabetes mellitus, including both annually diagnosed and total prevalent cases, increases globally. The total number of children and adolescents with type 1 diabetes mellitus increased by 3.4% annually in 2020. According to the current data of some countries, the annual incidence of type 1 diabetes mellitus varies from 5 to 42 per 100,000 and the prevalence varies from 69 to 198.4 per 100,000. The highest rates of T1DM incidence are usually seen in racial/ethnic groups including Finnish, Sardinian, North Asian and Northern European countries. Such a significant heterogeneity of T1DM incidence in children and adolescents of different populations and regions demonstrates the complexity of this process. The epidemiological studies provide a comprehensive description of the magnitude, clinical characteristics, outcomes, determinants, prevention and control/management of T1DM [12].

Global Prevalence

In Northern America, there is estimated to be one case of T1DM every 700 children and adolescents, mainly in Canada. The lowest prevalence is found in children aged 0–4 years (<1:6000). Therefore, T1DM is less frequent than Type 2 Diabetes Mellitus (T2DM) in obesity [13]. However, the increase of T2DM in the 0–19 years group ages may be changing the difference between the incidences, depending on legislation and social behavior in some countries. Overall, the number of T1DM cases is increasing. As for the EU's reason, there are many different ways to explain this. In fact, the lack of prevention, the rapid increase of unhealthy altered lifestyle and the increase of pollutants in the environment with genetic influences can contribute [14]. All over the world, T1DM is one of the most common chronic diseases in children and adolescents. The number of people with newly diagnosed T1DM is increasing and this affects all age populations, different social and ethnic groups. The global prevalence of T1DM in children and adolescents aged 0–19 years is increasing over the years. In 2021, there were an estimated 576,220 cases of children and adolescents with T1DM in the world, giving a global prevalence of 1 case every 800 children and adolescents. This prevalence is the highest in the 10–14 age group and in the Northern Europe region. However, it has to be taken into account that these regions are more impacted due to the larger number of existing studies and registries [15].

Trends and Patterns

The increasing incidence of the disease is affecting all age classes <15 years and a significant trend towards the diagnosis of younger and younger children has become evident over the years; indeed, it is conceivable to expect the doubling of the costs linked to children with diabetes over the next 15 years. Considering trends in time, a recent descriptive study examined the hospitalization records of patients hospitalized for the diagnosis of diabetes in Spain prior to the onset of the COVID-19 pandemic and found a consistent increase, in both the cumulative incidence of type 1 diabetes and the means of length of stay and in-hospital mortality throughout the length of the clinical series [16]. From the birth period 1970 to 1990, two (2) forms can be recognized here; in the last form, there is a faster progression with greater symptoms, slightly more females and a seasonal occurrence in the distribution of birth dates, with a peak in October. Recently, a shift towards an earlier presentation has been reported in temporal trends of newborn CD in the United States; the overall increase appears to be attributed to a greater number of asymptomatic children, perhaps explained by the long-term decline in population antibody levels, rather than a faster progression of disease in those with symptoms. This surprising increase in the incidence of type 1 diabetes has naturally brought with it an increase in the prevalence of the disease, as is demonstrated by the finding that the prevalence in Sweden, Italy and the United Kingdom is approximately 300 cases per 100,000 children [17].

For some time now, type 1 diabetes has experienced a "mysterious" expansion in industrialized countries; the incidence seems to have increased almost twofold in the last 20 years. This tendency has already been observed for quite a long time in the British Isles, in the Scandinavian countries and in the United States of America. Nowadays, an undeniable augmentation of the incidence of type 1 diabetes in children aged between 0 and 14 years is documented in Europe and even greater increments exist in the youngest children; a distinct geographical corridor can be identified from the United Kingdom to the western borders of the Russian Federation. According to data from different national registers, examinations carried out in hospital settings and reports from regional and local areas, Europe, with about 94,000 new cases each year, has the highest incidence of type 1 diabetes in the world; the countries with the largest number of cases and the highest incidence (over 30 or even 40 cases per 100,000 children) are located in the northern part of Europe, including Sweden, Norway, Iceland and Finland and in Western Europe (i.e., the United Kingdom, Belgium and the Netherlands) [18].

Genetic Risk Factors

The strongest genetic risk factors for T1DM are encoded by the genes that control the human leukocyte antigen (HLA) complex on chromosome 6p21.3. The other reported genes are not exclusively specific in these populations. Class II genes, such as HLA-DQ, located within the major histocompatibility complex (MHC), encode the most significant T1DM genetic risk factors that have long been known. The most interesting and consistent genetic risk factor is the class II HLA-DR and -DQ, located on chromosome 6. There are two segments of DNA encoding this highly polymorphic antigen, one of them encoding the DR antigen, while the other codes for the DQ antigen. T1DM is strongly and specifically linked to human leukocyte antigen genes. Approximately 90% of Caucasian patients with T1DM, ¼ of their first-degree relatives and 40% of children with autoimmune disorders carry the DQ2 and/or DQ8 heterodimer [19]. T1DM is largely inherited and there is a general agreement that it is caused by complex genetic predisposition, probably due to interaction between a large number of susceptibility genes. The strongest genetic factors and best studied are located within the HLA region on chromosome 6p21.3. The specific HLA class II alleles are responsible for the major genetic risk associated with T1DM. Other non-HLA genes have been reported that confer a much smaller risk. As our understanding of genetic factors associated with T1DM is increasing, we expect to be able to identify those children who are at high risk of developing the disease and who will benefit from altered risk factor exposure. Currently, several regions and genes have been associated with T1DM located outside the HLA region, including insulin (INS), CTLA4, PTPN22, IL2RA and the vitamin D receptor [20].

HLA Genes

The different heritability and gene-environment interactions may explain the reason why the identified risk factors of T1DM in literature exist. T1DM has a very strong familial clustering that consists of a 15-fold risk for first-degree relatives of diabetic probands and a 50- to 100-fold risk in monozygotic twins when a twin pair shares homozygous HLA haplotypes. In contrast, T2DM has a 2-7-fold risk for first-degree relatives and an 80% higher risk in male relatives and a 230% higher risk in female relatives with a diabetic mother of diabetic probands. Such an increase in concordance rates between monozygotic twins provoked premature reports that T1DM is a classical monogenic disease. The situation was clear in the 1980s that a single MHC region accounts for approximately 50% of genetic predisposition and the inheritance of T1DM depended on the number of shared alleles at the HLA-DR and HLA-DQ loci. These discoveries were confirmed by studies in multiplex diabetes families and other populations. From then on, dozens of additional susceptibility loci were identified through the genome-wide approach, secondary pathway approach, fine mapping and candidate gene approach [21].

Type 1 diabetes mellitus (T1DM) is a clinically and genetically heterogeneous disease that is characterized by the autoimmune destruction of pancreatic β-islet cells, leading to an absolute insulin deficit. The genetic factors in this context influence the immune system itself and are the key drivers of T1DM pathogenesis, while the environmental factors add their own influences to the disease. Genetically, T1DM is closely connected to type 2 diabetes mellitus (T2DM) and shares genes that regulate the development of endocrine pancreas and insulin function. T2DM is a polygenic disorder that gradually develops because of the interactions between genetic and environmental factors, leading to insulin resistance in the muscle and liver, pancreas β cell dysfunction and relative insulin deficit. Similar to T1DM, genetic factors influence the immune system, subsequently leading to T2DM manifestations [22].

Non-HLA Gene

It was proved that gene-encoded regulatory effects are crucial for the prevention of T1DM. The distal promoter and enhancer-like elements regulate the expression of CD25 molecule in cells. It was proved that HLA gene polymorphisms increase the risk of T1DM occurrence in their alleles. The use of anti-CD4 monoclonal antibody aglycon or chimeric proteins containing it, such as VNAR-Fcα, can help Treg cells. These cells interact with autoantigen-specific T-cells and prevent their activation. Treg proliferation and alteration to CD25- T conv population in the pancreatic lymph nodes eliminates activated effector or effector memory T cells, minimize islet cells death and normalize hyperglycemia. In order to prevent the T1DM from taking its course, the use of modified mAbVNAR-CD4 or mAb L6 mu might be useful. The aim is to ably combine suppression of human T-effector memory growth and effector T-cells of receptor specificity engaging CD4 in TDM. Resecting of the ITNVAR-CD4 to act via the CD4 on T reg to promote an anti-islet inhibitory effect [23].

Apart from DR and DQ genes from the HLA locus, other genes can also affect the risk of T1DM. Concerning these genes, ROS has conducted nine WHO-ILAR Diabetes System studies in eight regions around the world. Among children with newly diagnosed diabetes, a significant association was identified for the two SNPs from INS (rs689 and rs384, which are, in fact, the same SNP) and CTSH – cathepsin H gene. Data about polymorphism rs2476601, located in the PTPN22 gene, are controversial. The polymorphism, also known as 1858C > T, when homozygous for a minor allele (in this case, C allele), increases predisposition to T1DM. It was stated that this PTPN22 variant increases the risk of T1DM up to 5 times and the presence of heterozygosity has an effect of 2 times higher risk of disease development. The located amino acid change from arginine to tryptophan diminishes the activation of the lymphocytes and contributes to insufficient insulin production. These cells are necessary for host-protect immune responses using a T-cell regulating mechanism [24].

Environmental Risk Factors

Mumps and Coxsackie B viruses were cited as etiological factors in the pathogenesis of pancreatic beta-cell damage. However, despite progress in finding various viral substances in the affected tissue, the role of viruses as an etiological factor in type 1 diabetes (T1D) is not finally determined. Rotavirus was suggested as a precipitating factor by Kiess et al. and a meta-analysis by Honeyman and colleagues showed that T1D risk was elevated 4–6 weeks after rotavirus vaccination. Human enteroviruses were found to be the most relevant viral serotype by a nested case–control study where 100% of subjects showed seroconversion for enterovirus vs. 28% of controls [25]. This paper pointed out that some combinations of illness-making serotypes are more important than others; however, it was relatively small (n = 129). There were also papers suggesting maternal nutritional factors and hyperglycemia in pregnancy sexual selection for T1D susceptibility genotypes due to a changing environment, which is characterized by a growing incidence of T1D and a decreasing incidence of maternal stress [26].

Infectious Agents

Viral Infections: It is known that rotavirus infection often precedes the development of T1DM and after vaccination against rotavirus, the risk of the disease decreases. The vaccination mechanism is most likely associated with the introduction of exogenous antigens that have significant amino acid homology with antigens of the pancreatic islets. At the same time, the immune system of the body recognizes and memorizes these endogenous antigens, due to which the risk of developing T1DM and other autoimmune diseases is reduced. Other less frequent infections that can contribute to the development of the disease are adenovirus and mumps. Data on the role of herpesviruses in the development of T1DM are ambiguous; some authors associate the disease with HHV-6, a virus that causes common rash diseases, whereas, according to other researchers, this relationship is not fully proven [27].

Viral infections in childhood play an important role in the development of autoimmune diseases, including T1DM and are considered a risk factor. About 40 viruses from 4 groups can provoke the development of T1DM; these include enteroviruses, rubella and rotaviruses. Enteroviruses, namely coxsackieviruses A and B, are the leading agents of a T1DM trigger and are observed in 50-80% of patients one month before the onset of the disease. Enterovirus can enter the human body through the oral-fecal route and is found in the intestine, inflammatory foci in the nervous system and excretory organs. Pancreatic cells in severe cases are also affected. When entering pancreatic cells, the virus is replicated in them, the cell structure is disturbed and apoptosis of beta cells is initiated. In addition, the formation of viral proteins stimulates the development of autoantibodies that contribute to the death of pancreatic cells [28].

Dietary Factors

In recent years, the introduction of gluten-containing solid food during the first 3 months of life has specifically been implicated as an environmental risk factor for the development of islet autoantibodies and type 1 diabetes. This hypothesis emerged from the observations of a large prospective birth cohort study performed in three European countries. A higher number of islet autoantibodies in at-risk children were found and their appearance depended on both the dosage (grams of protein per week) and the timing of increased gluten intake. Other studies carried out in other European countries analyzed the relationship between gluten consumption (on a daily, weekly and monthly basis) and the onset of islet autoantibodies. These children had regular contact with the study team and samples were collected at home and in clinics every 3 to 6 months from birth up to 3 years of age and every 3 months from age 3 to 6 years [29].

Children's dietary habits are among the main environmental factors that determine the risk of developing type 1 diabetes. Some controversial evidence is available about the role of breastfeeding in this respect. Observations from a European multicenter trial reported a protective effect of early and long-term breastfeeding in the development of islet cell autoimmunity, especially in girls. Several other studies have yielded inconclusive results. The findings of a new large German study indicated an increased risk of diabetes-related autoantibodies associated with short or absent breastfeeding. Moreover, the presence of these antibodies earlier during life seems to be of greater importance in the etiopathogenesis of diabetes than the disease onset in childhood. It was previously suggested that an age-appropriate introduction of cereal products into the infant's diet might be an important dietary factor that modulates the onset of type 1 diabetes [30].

Immunological Factors

A family history of T1DM or another autoimmune disease, the presence of type 1-associated autoantibodies and certain immunogenetic markers are the best available estimate for diabetes risk. Should we consider determining the genetic predisposition of children and even future generations to T1DM? The identification of T1DM juveniles at an increased risk based on demonstrating genetic predisposition and exposure to significant environmental factors allows the accumulation of relevant skills and the development of prevention strategies for the disease. Currently, there are three main strategies to prevent T1DM: HLA class I or II genes for autoantigens to desensitize the immune system toward autoantigen via the use of monoclonal antibodies (teplizumab, rituximab and avexxin). Strategically educate the newborn immune system regarding an autoreactive immune cell [31].

Several studies have found a strong genetic association with an HLA haplotype predisposing to autoimmune diseases, in particular, HLA class II haplotypes that are strongly associated with susceptibility to T1DM: DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2, 15). This haplotype, also called the DR3-DQ2-D4, is present in more than half of Caucasians with T1DM. It confers a relative risk of approximately 16. The next most prominent susceptibility haplotype is DRB1*0401-DQA1*0301-DQB1*0302 (DR4), present in approximately 40% of Caucasian patients and conferring a relative risk of approximately 6. About 90% of patients with T1DM have an HLA haplotype DR3 or DR4. The main alleles known to protect from the development of T1DM are DRB1*1501-DQA1*0102-DQB1*0602 (DR15-DQ6,2 homozygotes, for example, are especially protective), DRB1*0701-DQA1*0201-DQB1*0303 and DRB1*1102-DQA1*0501-DQB1*0301, which has a strong negative association with T1DM and suppresses the risk among non-DR3 and non-DR4 individuals [32].

Autoantibodies

The frequency of autoantibodies is high in children and adolescents with newly diagnosed type 1 diabetes, with the majority having ICA 69-90%. The first to appear is IAA. The most important family of T1D prediction is the HLA genotype. According to one study, HLA-DR3-DQ2 and DR4-DQ8 in early life enhanced the likelihood of developing 2-4 autoantibodies. In the most recent international analysis of the Diabetes Autoimmunity Study in The Young (DAISY) and TrialNet cohort, the presence of two or more islet autoantibodies and anti-GAD with anti-ZnT8R alone reduced the risk of type 1 diabetes compared with children without diabetes-associated autoantibodies. This combination will have high sensitivity and specificity and enhance the prediction of T1D. High levels of ICA or insulin autoantibodies at any time increased the risk. Levels of autoantibodies to positively seroconvert and high levels of IAA were shown to increase the risk [33]. The associations between a decline in β-cell function and the development of established autoantibodies to β-cells are well known. have suggested that a rise in T1D is associated with the detection of islet cell autoantibodies by radiobinding assay (RBA) or by an immunoperoxidase method. Various combinations of autoantibodies have been identified and reported to be associated with the onset of clinical type 1 diabetes. The risk of diabetes increases with the number of positive autoantibodies. The standardization of the methods to measure autoantibodies and the development of new antibodies over the past few years has helped to strengthen the prediction and provided improved understanding of the natural history of diabetes. Various antibodies to different β-cell autoantigens have been detected at different stages of the development of the disease [34].

Immune Cell Dysregulation

On the other hand, Tregs cells are pivotal in maintaining self-tolerance and immune homeostasis. Tregs are a subset of lymphocytes derived from CD4+ T cells and play a crucial role in maintaining peripheral self-tolerance and excessive production of Tregs may lead to autoimmunity while their deficiency is more often associated with immune-related diseases such as T1DM. Tregs present in T1DM inhibit cellular dysfunction and reduce insulin autoantibody production. Tregs form a Th1 suppressive loop, enhance the expression of several immune checkpoint inhibitory receptors, mainly programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and forkhead box protein P3 (Foxp3), suppress the activation and expansion of Teff cells and their infiltration into target tissues while promoting the activity of pro-inflammatory macrophages (M1) and cytotoxic NK cells, ultimately attenuating pro-inflammatory responses and tissue destruction [35]. 

Immune cell dysregulation is known to be associated with T1DM. Thus, it seems that T1DM is a result of the balance of immune cells such as CD4+ T, CD8+ T and Tregs cells and cytokines excreting from them. Several studies emphasize the destruction of CD4+ and Tregs cells, which are responsible for immune tolerance in T1DM pathogenesis. The increased frequencies of CD4+ T cells promote pro-inflammatory conditions and result in beta cell damage. Furthermore, Kim et al. reported an increased CD4:CD8 ratio in pediatric T1DM compared to the control group. The activated Th1 cells increase destructive autoimmunity and they increase the CD4:CD8 ratio [36].

Psychosocial Factors

Psychosocial factors were defined as psychological or emotional states, individual and familial life-related variables and relationships between the child and parents/peers. Understanding these is important for defining the child/adolescent treatment adherence and realization of glycemic metabolism. Consequently, their control and application can be effective to improve the patient's glycemic regulation. The investigation of relationships between demographic characteristics, familial life-related variables and psychological, emotional states in patients with T1DM helps to present the real patient's psychosocial position and to organize specific interventions under the T1DM treatment strategy [37].

Psychosocial factors explain 2%–7% of T1DM variance and they can address the differences in glycemic control and HbA1c levels. Among other risks, they can include family's low income, father's/both parents' unemployment, mother's low education, single-parent households, family-related stressors, maternal depressive symptoms/stress/distress, insecure attachment to the family and stressful life events, including traumatic events, negative life changes and long-term problem situations. Adolescents with T1DM can experience a higher rate/level of diabetes distress, peer victimization, insecure attachment to friends, low peer support and low self-esteem. Negative emotions including a state of acute anxiety, frustration and embarrassment should be considered as the reasons for acute glycemic deteriorations and diabetes burnout may increase the risk for severe glycemic levels by 2–4 times [38].

Stress and Coping Mechanisms

Hyperglycemia can accompany any episode of physical or emotional stress, no matter how acute the episode. T1DM in both children and adolescents is a large source of physical and psychosocial stress for both patients and families. In fact, HPA axis dysfunction has been reported in T1DM. Data from both animal models and human studies suggest that recurrent stress-induced hyperglycemia affects glycemic variability and can be pro-atherogenic [39].

Although there is no consensus regarding the influence of stress on the appearance of T1DM, some authors have described stress as a trigger for the disease. Certain sudden, traumatic stressors such as the loss of a friend, divorce of parents, or moving to a different school have been implicated. Chronic stressors, such as family changes, illness of a family member, low socioeconomic level and lack of emotional support are likely to be associated with late diagnosis or poor diabetes management. This includes noncompliance with the diet or with strict management of their therapy [40]. Many studies have reported that children with T1DM exhibit more stress than their healthy peers due to daily living in monitoring, continual checking of blood glucose, self-injecting insulin and the need to follow a specific diet. They also experience psychological issues associated with the disease. Therefore, stress in DM is a direct result of the physiological demand imposed by the disease as the patient faces tension between their needs and the demands of the diabetic regimen [41]. Stress is an experience that is manifested in both physiological and psychological terms. It involves the central nervous system, the endocrine system and the activation of the autonomic nervous system. The presence of a stressful situation makes people aware of discomfort and/or insecurity. The more stressful the situation, the greater the degree of reaction [42].

Family Dynamics

Families go through critical developmental stages that affect the child’s future. Adapting to changes, role distribution, communication, absence of grandparents, parenting styles, the number of children, socioeconomic level, conflict resolution and adaptive strategies among its members are factors that have been associated with the onset of diseases. Factors that have the ability to generate high levels of stress would increase the levels of risk. The associations found show the internal dynamics of the family and its effects have significant implications for the development of the growing family members. The family context plays an important role in the lives of people, since from the moment of conception it accompanies the person’s evolutionary process. Throughout the life cycle, the family provides the child with protection, love, care, attention, food, shelter, clothing, affection and education. With the basic needs met, the child has the essentials to have the best basic conditions of life [43].

Clinical Presentation and Diagnosis

In the majority of cases, the onset of T1DM is characterized by a rapid and sudden appearance of generalized symptoms, often with severe diabetic ketoacidosis (DKA). A substantial proportion of patients may remain asymptomatic for a long period, frequently diagnosed by routine health screening of associated autoimmune diseases. Initial death in diabetic ketoacidosis, as well as death related to the diagnosis of T1DM, often represents potential missed diagnoses. Fasting hyperglycemia and glycosuria are the first signs that may be followed by all the classical symptoms of diabetes, due to insulin deficiency and metabolic derangement including osmotic diuresis, metabolic acidosis and, finally, ketonuria. In these cases, the rapid appearance of the clinical symptoms leads to the immediate diagnosis of T1DM, although sometimes with a few days of delay [44]. Type 1 diabetes mellitus is the most common chronic endocrinopathy of childhood and its autoimmune nature is well documented. A variety of tests are available, which help define the autoimmune phenotype and the stage of disease progression. Repeat testing may be required if autoimmune diabetes is initially ruled out but remains a clinical concern. Clinically, a wide spectrum of disease severity ranging from severe diabetic ketoacidosis to mild glucose intolerance characterizes the at-risk population and treatment is individualized. Glycemic management is difficult and time-consuming, but it has potential benefits for all aspects of autoimmune diabetes. Ongoing clinical studies offer hope not only for further understanding of this complex disease but also for finding ways to prevent the inevitable progression to exogenous insulin requirement. At this time, identification of at-risk individuals through appropriate laboratory studies, education and prompt referral of affected children to pediatric diabetes specialists are appropriate [45].

Symptoms in Children and Adolescents

It is easier to notice signs of diabetes even in children 6-10 years of age. They may notice more frequent urination, increased thirst and they may be tired. Teenagers themselves are also able to draw attention to their increased thirst, urination, fatigue, feelings of thirst and poor physical condition. In any case, if parents, teachers, sports coaches, or other caregivers have noticed more frequent urination, increased thirst, or increased urination at night, it would be advisable to check if this is not an unexplained early sign of diabetes mellitus on the child or adolescent. If a young person still has enough insulin, diabetes can only be identified by testing for sugar and sugar is excreted in the urine and some of the diagnostic signs of diabetes have not yet occurred [46]. Type 1 diabetes can be diagnosed at any age. In infants and toddlers, it is common to develop it quickly, even in a week. At this age, there may be electrolyte changes, which can lead to diabetic ketoacidosis. In preschool children, the most characteristic symptoms of diabetes are often associated with changes in behavior (being irritable and unhappy with diapers). As childhood progresses, children's ability to express the symptoms of diabetes mellitus increases. In 20-45% of preschool children with newly diagnosed diabetes mellitus, the disease is advanced and leads to the development of diabetic ketoacidosis [47].

Diagnostic Criteria

Since diabetic ketoacidosis that develops as a result of high blood glucose levels is the most common cause of childhood mortality and morbidity, a risk group under the age of five is identified. It can be difficult to perform oral glucose tolerance testing in young children. Moreover, there is still no consensus concerning the optimal testing method (300 mL of glucose, 1.75 g of glucose per kg of body weight, or 2 g of glucose per kg of body weight), so it is important to consider the clinical applicability of general blood glucose measurements. Counteraction is recommended if fasting or two-hour glucose values are impaired or glucose levels are marginal to prevent the development of type 1 diabetes cardiometabolic diseases (hypertension, obesity and dyslipidemia) [48]. The potential effects on shielding the mounting beta cell should be pursued with care. If the patient has no clinical symptoms, daily testing of blood glucose concentration and hemoglobin A1c is preferred. Counteraction with anti-insulin and oral glucose tolerance should be performed. Glucose testing should be performed yearly if the test is inconspicuous unless an unusual situation exists [49]. The diagnostic criteria for type 1 diabetes mellitus that have been modified by the International Society for Pediatric and Adolescent Diabetes (ISPAD) are based on the presence of classical symptoms of diabetes and elevated blood glucose levels. Fasting blood glucose is defined as being ≥126 mg/dL, blood glucose is defined as being ≥200 mg/dL at 2 hours after a glucose tolerance test, or random blood glucose is defined as being >200 mg/dL in the presence of classic diabetes symptoms such as polyuria, polydipsia, unexplained weight loss, or recurrent nocturnal enuresis. If a child presents atypically or asymptomatically and diabetes is diagnosed incidentally on the basis of risk factors, the diagnostic process must be applied carefully. Pancreatic autoantibodies can be used for differential diagnosis in these patients. The low sensitivity of classical blood or plasma glucose measurements may lead to delays in diagnosis. Therefore, there is no need to intervene in patients considered as having type 1 diabetes who subsequently test glucose negative on the oral glucose tolerance test or have fasting glucose negative results [50].

Complications and Comorbidities

The authors declare that they have no competing interests.

Competing Interest

Type 1 diabetes mellitus is a chronic disorder of childhood. The age of onset of the disease affects the formation of complications. Therefore, the early diagnosis of the disease is very important in terms of prevention. If left untreated, life-threatening complications and comorbidities develop in children who present with symptoms related to hyperglycemia and are delayed in receiving medical attention [51]. These complications can be classified as short and long term. Short-term complications are often related to a metabolic imbalance in diabetes and usually develop in a short period of time. Long-term complications are related to the effects of chronic hyperglycemia on the microvascular, macrovascular and nervous systems. The microvascular complications of diabetes include retinopathy, nephropathy and neuropathy disorders. Diabetes is also a risk factor for cardiovascular disease, which is the leading cause of mortality [7]. Diabetic children may develop comorbidities related to the association of type 1 diabetes with increased body weight, such as dyslipidemia, hypertension and non-alcoholic fatty liver disease. There are also some endocrine effects. These children can also develop growth or pubertal delays. Another comorbidity is celiac disease. Compliance with the therapeutic regimen is crucial in terms of preventing these complications [52].

Acute Complications

Hyperglycemic hyperosmolar nonketotic coma: The mortality rate is higher, especially in young children. The predisposing causes include prolonged dehydration, vomiting, diarrhea, infection, lack of insulin and inappropriate attempts to treat. Relying solely on oral medication may cause high levels of hyperglycemia and osmotic symptoms (such as polyuria, polydipsia, enuresis, low-grade fever, non-specific symptoms, vomiting, diarrhea and deep respiratory tracts) [53]. Hypoglycemia: The peak incidence is in the preschool years and young primary school years. The reasons are many and include variable income, fasting, improved emotional instability, insulin overdose, over-reaction to the treatment of acute febrile diseases [54]. Diabetic ketoacidosis: The incidence rate is highest in the first 5 years of diabetes. The predisposing factors are poor metabolic control, psychosocial factors, puberty and inadvertent omission of insulin. Glucose levels, moderate or severe ketosis (3-hydroxybutyrate acid) and acidosis (pH) are characteristic. Infection, improper insulin administration, psychiatric illness and true negligence may be the reasons why juvenile patients suddenly begin to have type 1 diabetes manifesting as ketoacidosis and are found to have long-term complications of diabetes. Most cases of ketoacidosis are preventable [55].

Long-Term Complications

The risk of these complications is higher if these diseases occurred at a young age. The development of target programs to identify and diagnose type 1 diabetes in the preclinical period can significantly reduce both social and economic costs and improve the quality of life of patients with severe autoimmune diabetes. The ability to predict the future development of the disease is the foundation for the development of such programs. Such predictions can be based only on the interaction of genetic predisposition and a complex network of environmental influences on the immune system of genetically susceptible individuals. Data from research will help in better predicting whether a child with a relative with autoimmune diabetes develops this type of disease and to have the ability to manage it before overt manifestations of clinical symptoms [56]. Both overt and latent autoimmune type 1 diabetes are at risk of long-term complications. It can be microvascular ones, such as kidney disease, neuropathy, macroangiopathy, which can lead to heart attacks, strokes and lower limb amputations and eye problems, including macular edema, cataracts, glaucoma and retinopathy, which is the leading cause of blindness in the working population. Type 1 diabetes is also associated with a wide range of psychological problems, including poor quality of life, distress related to the disease and the development of eating disorders, particularly in adolescence. In addition, there are problems in the transition period, a rare and expensive access to diabetes care in many countries of the world [57].

Preventive Strategies

There are no effective strategies to prevent T1DM, but attempts can be undertaken to modify T1DM risk through influencing early-life exposures. It is evident that infants who are at a high risk of T1DM would benefit from being breastfed, especially being breastfed at the time of introduction of solid foods, which should be introduced no earlier than at 17 weeks of age. The most important effects are seen in infants with a high-risk HLA genotype. Cow's milk and solid foods should be introduced to the infant's diet after 17 weeks of age and cereals or pablum with or without gluten and fruit are typically acceptable first choices. However, as this approach has not been tested in infants with increased genetic susceptibility, the general recommendation on solid food introduction for the neonate remains valid. The appropriate time openings are between 4-6 months of age in infants who are not breastfed (the ESPGHAN panel suggests the age of 17 weeks for the introduction of complementary feeding, without considering which type of food is involved) [58].

Primary Prevention

Primary prevention is aimed at preventing the disease at the earliest stages of development. Among the main mechanisms of development of type 1 diabetes are the activation of the autoimmune process and β-cell death. Preventing the main risk factors of the disease is important, such as viral and bacterial agents, cow's milk and hypovitaminosis of 25 (OH) D. Viral and bacterial agents are involved in the initiation of the autoimmune response. The risk of diabetes depends on the intensity of the infection and is closely related to the age of the infection. The results of the studies indicate that the majority of β-cells in children have an important criterion for the recognition of bacteria in the cytoplasm, which determines them as the main antigens for the activation of Caspase-1 from a melittin-suppressing surface receptor. The ENTRY-Coupled pattern recognition receptor NLRP3, by the way, is the stronger subordination which is entitled to subordinate the aforementioned secondary diabetes [59].

Secondary Prevention

The Ongoing Prevent Autoimmune Diabetes (OPAD) cohort enrolled relatives with β cell autoantibodies of pro-bands with newly diagnosed T1DM, randomized the subjects into the oral insulin therapy group or the placebo group and follow up for 7 years. 8-doses oral insulin was needed in order to obtain a 4.5-year delay in clinical T1DM onset in patients with the highest diabetes risk. After 15 years, within the previous 2 years, the insulin therapy + nicotinamide cohort had a longer delay in diabetes clinical onset than the previous insulin therapy cohort. When the metabolic condition improved, the recurrence of the islet autoimmune response should be noted. And the former children with metabolic syndrome, adiponectin and leptin antibody had a decreased recurrence risk. During the repeated therapy, there are several of the memory CD8 T effector cells directed against previously unrecognized antigens and/or control the effector CD8 T cells recognizing known autoantigen remained in a quiet (Anergic-low stimulatory) state. These anergic-like CD8 T cells had a therapeutic effect that weakened the pathogenic T cells function and regression autoimmunity. These data reveal a highly suitable and consistent platform to test the future protection strategies in stage 1 T1DM patients. Mercapturic acids including 3-MMPA (Ethacrynic), MPA (Probenecid) and 2-MMPA (Finasteride) therapy with Histone deacetylase inhibitors may also be valid options [60]. Other immunosuppressive therapies, such as cyclosporine, MTX, anti-CD3 monoclonal antibody (hOKT3g1 (Ala-Ala)), Rituximab (anti-CD20 monoclonal antibody), have had an effect in T1DM animal models, but only a few types of clinical trials, the effects were not ideal, the study and the clinical applications are rare. DNFB therapy used keratin capsules with 2,4-Dinitro-1-fluorobenzene thrown into the skin which can induce the perisisphere performance of GAD65-tolerance mice, but the wear process is unpleasant and this method has not carry out successful victims. Oral Nicotinamide (Vitamin B3) therapy is the best current secondary prevention method. The median Immunotherapy with 0.29 g/kg of nicotinamide per dose decrease by 31% [61]. In T1DM, secondary prevention means that GADs are present and the immunological reaction is ongoing. There are various intervention strategies, considering the low efficiency and the long-term outcome of immunosuppressive therapy, which includes steroid therapy, cyclosporine therapy and monoclonal anti-CD3 antibody. Steroid therapy is the most widely studied and widely used immunosuppressive therapy for human T1DM. It is cheap and easy to operate, but therapeutic effects are mild and the side effects are severe. The duration of the systemic steroid therapy is 3 months and the insulin requirement reduction rate is approximately 10%-30%. The long-term (>6 years) outcome showed that 24% achieved partial remission, including decreased insulin requirement and 9% became a noninsulin window. By contrast, 76% of the patients had no warning. The general toxicity includes hypertension, psychiatric changes and avascular bone necrosis [62].

Management and Treatment

Cognitive and behavioral strategies, developmentally appropriate educational methods and teaching materials should be used for empowerment, education and support to manage diabetes. Unfortunately, psychological and emotional problems are often overlooked especially in children and adolescents. In accordance with the vulnerability of this group, mental health should become within the coverage of essential support services for diabetes care as early as in the pre diagnosis period. In particular, parents of new diabetic children should be informed about the risk of psychiatric treatment. Furthermore, problems such as body perception, self-esteem, rebellion, depression, insomnia are defined in the adolescents [63]. Despite the great advancements in insulin formulation, delivery devices, self-monitoring devices and other diabetes supplies that have given patients greater choices, patients, particularly the younger age groups, have difficulty following systematic and regular monitoring. Families, especially the mothers, need to be supported. It is known that diabetes management is directly related to the knowledge and skills of the families about diabetes. A well-planned and adequate dietary program is essential in addition to medical nutritional therapy. Physical activity is an essential adjunct to the diet and medication regimens for all people with diabetes. The effect of regular physical activity on blood glucose control, heart protection, weight control, blood pressure, lipid and cholesterol regulation, bone development, reduction of stress and improved concentration is known. However, the positive effect of regular physical activity on weight control and glucose use can cause hypoglycemia during exercise and there may be a relative risk of weight loss [64].

Insulin Therapy

Nutritional therapy: Another important component of the treatment is nutritional therapy. The nutrition clinic will define the number of meals per day (three main ones and two or three snacks) and the Eating Well Plate. Counting carbohydrates is the most adaptable system and it is a fundamental part of nutritional therapy and it should not be mistaken for traditional quantitative measurements of proteins, fats, or carbohydrates. The individualized quantitative recommendations will have to take into account the needs of each child, the dietary habits of the family unit, individual preferences, energy expenditure and the influence of psycho-affective limitations [65]. The type of diabetes and the degree of metabolic control determine the insulin therapy regimen. However, daily dietary habits, day-to-day life and variations in insulin sensitivity will indicate small daily adjustments in the dose and type of insulin. Insulin therapy: The goal is to achieve and maintain blood glucose levels as close to normal as possible and to achieve normal physical and psychological growth and development. Insulin is available in two forms: animal insulins and human insulins. The latter may be of animal origin and human insulins produced by biotechnological techniques, including insulin analogs. Despite this advance, non-insulin therapy has not yet become a reality and it was not possible to change the progression of the autoimmune β-cell destruction process [66].

Blood Glucose Monitoring

The most important aspect in the collection of capillary blood for glucose measurement is to clean the fingers because the accuracy of the blood glucose results and the safety of both the caregiver and patient are very important. Soap and water should be used for cleaning, rubbing and drying the skin using a plastic bottle. The recommended way is to wash the hand with soap and water, dry it with a towel, moisten the tip with a washer containing only pure glycerin and then gently prick the finger that is cleaned thoroughly and dried. This way, the chances of skin irritation and cuts will be minimized. To avoid transmitting infections from the caregiver and other family members to the patient and from the patient to other people, the patient should use her own and pediatric needles for sampling [67]. Monitoring of blood glucose levels is necessary to regulate and adjust the use of insulin because changes in insulin doses and glucose can occur daily or at different times. Frequent sample collection can reduce discomfort, facilitate better adherence to regulation and ultimately lead to better metabolic control. Children and families should receive training using blood glucose meters when they receive the patient's diagnosis and then retraining should be provided when changing to a new device or using a different model. Although the fingerticks taken with conventional lancets to obtain blood are painful, the needles used by today's devices are thinner and shorter, which causes less pain [68].

Future Research Directions

Prospective studies of T1DM in adolescents are also needed to develop a comprehensive expansion of inclusion criteria for secondary prevention trials, as different intervention-based therapeutic trials will be needed for different age groups within this age range. New therapeutic targets need to be identified, as well as the means to monitor the impact of therapeutic interventions. Finally, the acceptance, cost and logistical issues for T1DM prevention in adolescent populations should be defined and pilot studies to inform intervention trial designs should be undertaken. To summarize, the knowledge on type 1 diabetes mellitus (T1DM) in teenagers lags behind the progress made by T1DM and type 2 diabetes mellitus (T2DM) in adults and children. There is a pressing need for additional prospective studies that focus on the natural history and heterogeneity of the T1DM disorder in this vulnerable group. This includes the need to validate and refine clinical risk scores and/or genetic biomarkers that may predict T1DM later in life. Identifying those at highest risk should also facilitate the development of innovative prevention trials [69].

Emerging Risk Factors

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of pancreatic β-cells and absolute insulin deficiency. Although the etiology of T1DM remains unknown, several genetic and immunologic determinants have been identified. In this case, the incidence of T1DM significantly increases by the dietary exposure of cow's milk during infant years. Nowadays, another dietary factor, named omega-3 fatty acids, has been widely investigated and appeared to play a protective role in T1DM. Similarly, other environmental factors (vitamin D and trace metals Zn and Se) and toxins, such as virus infections, including enteroviruses, cytomegalovirus, mumps virus, rubella virus and rotavirus and H. pylori, are associated with T1DM. Another trigger is parasitic infections, which have been found to play a protective role in rodent models of diabetes. With diminishing exposures to particular parasites, children and adolescents may become more susceptible to other parasitic infections and autoimmune diseases such as T1DM. This review aims to summarize the current status of the raised risk factors, including their possible association with T1DM and disease development after exposure; and also to depict the potential protective mechanisms or future alternative treatments of the raised risk factors. We believe that the recapitulation of this information will provide convenience to both private and public stakeholders engaged in health practice or environmental regulation [70]. There is a global increase in the incidence of type 1 diabetes mellitus (T1DM) and the age at diagnosis is decreasing progressively. These epidemiological changes highlight the contribution of environmental factors in the development of T1DM. A number of emerging environmental risk factors that act before the appearance of seroconversion, including history of cow's milk formula exposure, vitamin D deficiency, trace metals such as Zn and Se, omega-3 fatty acid, microbiota, H. pylori, virus infections, toxins, pesticides, etc., are associated with T1DM disease development. It is unclear how some of the risk factors are associated with T1DM development. The purpose of this review is to summarize and discuss potential emerging environmental risk factors believed to be associated with the development of T1DM in young patients. This review is important for stakeholders involved in public health practices and future research [70].

Innovative Treatment Approaches

Promising research tools, as well as potential new therapeutic options, are a result of advances in both the transplantation of insulin-producing pancreatic islets and the setting of pluripotent and adult stem cells into these. A number of factors stimulate the pancreatic and liver cells to reprogram their alcohol derivatives back into the cells of the desired functionality. Research on cell replacement and regeneration still switches from animal models to human pancreatic research, but using switch-source cells for diabetes cell therapy has the facility to generate enough cells. Over the years, many clinical programs have been launched to measure the power and compatibility of this approach, as well as to minimize long-term dysfunction of the treated people. Although many of these treatments are now considered well-established and have potential for community usage, stem-cell recovery and CRISPR present multiple unusual approaches to treating a disease that sometimes requires complex and expensive final management [71]. Innovative treatment approaches. The standard treatment option for patients with type 1 diabetes mellitus is the administration of insulin on a daily basis. The goal of the treatment is to minimize the fluctuations of the glucose levels. Insulin therapy is focused on controlling the day-to-day glucose fluctuations for prevention of diabetes-related complications. Four different types of insulin can be used: long-acting, intermediate-acting, short-acting and rapid-acting insulin [51].

Although there is still much to be done, which will decrease endemic T1DM rates in childhood that are increasing in the world, fields for investigation such as the Microbiome, interactions between the Human Genomics and Genes, the Exposome and other Epigenomics, gene-environment and stochastic chance, the Journal provides a bridge between the most current scientific research in various areas of genetics and genomics. Moreover, the findings from the literature related to T1DM that has been currently reviewed cannot be generalized, a possible relation or link with age ranges, BMI status, some of the factors introduced in meta-analyses, while pointing out the need of additional research related to factors, namely maternal, fetal, newborn, children and adolescents will be addressed to researchers. The inclusion of all age range-specific risk factors besides addressing pregnancy, the newborn and childhood, including specific new risk factors that have not been previously known, evaluating them according to the race and country, it is thought to be beneficial for future work. It is aimed that new studies will be asked to distinctly define these new potential prevention causes and prove them by logical methods.

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