📘 Stages of evolution of type 1 diabetes

Type 1 diabetes mellitus does not appear suddenly, but goes through several stages before symptoms become visible. The at-risk person stage long precedes the appearance of clinical signs and is characterized by genetic predisposition, exposure to certain environmental factors and possibly the presence of a single pancreatic autoantibody. Stage 1 is defined by the presence of two or more pancreatic autoantibodies, but blood glucose remains normal and there are no symptoms. Stage 2 implies the same presence of two or more autoantibodies, but is associated with blood glucose values raised above normal, in the prediabetes range, and symptoms are absent [1].

Stage 3 corresponds to the moment of the classic diagnosis of T1D, when hyperglycemia is obvious and the typical symptoms appear: intense thirst, frequent urination and unintentional weight loss. At this stage, the marked hyperglycemia mandates the obligatory initiation of insulin treatment. Some organizations also describe a fourth stage, which would represent the disease stabilized after a possible period of remission [2]. The pace of progression from one stage to another varies significantly, being faster in children and slower in adults, because the destruction of pancreatic beta cells does not occur at the same pace in all people [3].

Autoimmune screening for T1D is the testing of blood to identify pancreatic autoantibodies, which are markers of an autoimmune process directed against beta cells. The four key autoantibodies that are determined are anti-insulin autoantibodies (IA), anti-glutamate decarboxylase autoantibodies (GAD), anti-tyrosine phosphatase autoantibodies (IA-2) and autoantibodies against zinc transporter 8 (ZnT8). The presence of these autoantibodies indicates that the immune system is already attacking the beta cells, even if blood glucose is still normal [1].

This type of screening is useful because it can identify T1D years before symptoms appear, in what is called the presymptomatic stage. Early detection offers you several advantages: time to learn about the disease, to receive education about symptoms, to avoid diabetic ketoacidosis at hyperglycemic onset and to be able to access certain treatments or clinical studies that try to delay clinical onset [4]. A positive test for one autoantibody should be confirmed by a second test within at most three months, because a significant proportion can become negative on subsequent testing [4].

Autoimmune screening for T1D should be offered first of all to people with a family history of T1D, particularly to first-degree relatives (parents, siblings, children) of a patient with T1D. Screening is also indicated for people identified as being at high genetic risk, either through genetic risk scores or through the presence of HLA variants known for this predisposition [5]. Adults diagnosed with other forms of diabetes, but with phenotypic characteristics that overlap with T1D (younger age at diagnosis, unintentional weight loss, ketoacidosis or rapid need for insulin therapy) should also be tested [6].

It must be remembered that the majority of people who develop T1D (approximately 90%) do not have a relative with T1D. For this reason, free population screening programs exist in several regions of the world (Fr1da and GPPAD in Europe, TrialNet and ASK in the USA, type1screen in Australia), with a particular focus on children and adolescents [3]. The intention to do this screening must be discussed with your doctor, because it requires not only the test itself, but also a clear plan for subsequent monitoring and access to specialized care in the case of a positive result.

The frequency of testing pancreatic autoantibodies depends on your age. In children under 3 years with high risk, screening is repeated every 6 months for 3 years, then annually for another 3 years. In children and adolescents aged between 3 and 18 years, testing is done annually, and if after 3 years there is no progression to multiple autoantibodies or dysglycemia (prediabetes) it can be considered to either relax to a 3-year interval, or even stop screening. In adults, testing is done as a rule once every 3 years, or annually if additional risk factors are present (associated autoimmune disease, high genetic risk score, first-degree relative with T1D) [3].

The age at which screening starts is not fixed, but is established individually, according to the risk profile. In children with high genetic risk, testing can begin in the first years of life, because seroconversion (the appearance of the first autoantibodies) often occurs in childhood. In adults with a family history or suggestive features, testing can be initiated at any age [6]. If an initial test is positive for a single autoantibody, it must be confirmed within at most 3 months by a second test, because a significant percentage can become negative on subsequent testing [3].

The confirmed presence of two or more pancreatic autoantibodies represents the strongest known risk factor for progression toward clinical T1D. If you have two autoantibodies and normal blood glucose levels, the chances of developing clinically manifest T1D are approximately 30% at 5 years and 85% at 15 years. If you have three autoantibodies, the chances of progression to T1D stage 3 become approximately 45% at 5 years and 90% at 15 years [7]. This reflects the progressive nature of the autoimmune process, which once triggered and consolidated tends to continue without stopping (it is self-sustaining).

The risk is not however identical for all people and depends on several practical factors: the number of autoantibodies (more autoantibodies = higher risk), their titer (higher values indicate a more active autoimmune process), the type of autoantibodies (IA-2 are associated with more rapid progression), age at seroconversion (the earlier they appear, the more rapid the evolution tends to be) and genetic predisposition [2]. The transition from stage 1 to stage 2, marked by the appearance of dysglycemia, is the slowest, after which things accelerate significantly. The risk of moving from stage 2 to stage 3 of T1D is 60% at two years and 75% at five years [3].

Yes, there is currently an approved treatment that, administered in stage 2, delays the onset of clinically manifest T1D (stage 3). Teplizumab (an anti-CD3 monoclonal antibody) is indicated for people aged at least 8 years who are in stage 2 of T1D, that is, having two or more pancreatic autoantibodies and dysglycemia (prediabetes), but without symptoms [8]. The treatment is administered intravenously in daily infusions for 14 days and has the role of reducing the autoimmune attack on beta cells. The proven effects include delaying by sometimes several years the moment when you will need daily insulin therapy and prolonging the period of residual beta cell function. This delay is generally a doubling of the time in which you were destined to make the progression from stage 2 to stage 3 [9].

In addition to teplizumab, there are numerous ongoing clinical studies that test other approaches for preventing or delaying T1D in the preclinical stages. In these studies, various monoclonal antibodies, immune system modulators, biological agents and cellular therapies are tested. Enrollment in a clinical study can be an option if you are in an early stage of the disease and live in a region where these clinical studies are accessible. The decision to start teplizumab or to participate in a study is taken together with your doctor, after the potential benefits and risks (transient lymphopenia or some skin reactions) are explained to you [3].

Currently, universal screening of the entire population for T1D is not recommended as a standard strategy. This is due to several practical considerations: not all countries have certified laboratories for autoantibody testing, there are not enough specialized centers for monitoring positive people, access to treatments such as teplizumab is unequal, and the cost-effectiveness of generalized screening is not fully demonstrated in all contexts [5]. For this reason, screening remains primarily oriented toward people at high risk, such as first-degree relatives of patients with T1D or people with known genetic predisposition.

There are, however, regional population screening programs operating in various countries (Fr1da and GPPAD in Europe, TrialNet, ASK and CASCADE in the USA, type1screen in Australia). In 2023, Italy introduced at the national level a screening for T1D and celiac disease for all children aged between 1 and 17 years, becoming the first major example of universal screening in children [10]. As preventive treatments become more accessible and testing costs decrease, it is likely that more and more countries will adopt similar programs, especially given that globally almost 9.5 million people are living with T1D in 2025, with a projected increase to 14.7 million by 2040 [11].

If your initial screening is positive for autoantibodies, the first step is confirmation of the result by a second test within at most 3 months, preferably in a certified laboratory. This confirmation is important because a significant percentage of people with a single positive autoantibody (especially children) become negative subsequently. After confirmation, a complete metabolic evaluation follows in a specialized diabetes center, which includes determination of HbA1c, fasting blood glucose and sometimes an oral glucose tolerance test in order to identify a possible stage 2 (dysglycemia) or stage 3 (clinically manifest diabetes) [4].

The frequency of subsequent tests depends on your age and on the number of confirmed autoantibodies. In people with multiple autoantibodies, monitoring includes the periodic determination of the four pancreatic autoantibodies, blood glucose and HbA1c, at intervals of 6 months in children under 3 years, annually in children and adolescents aged between 3 and 18 years and every 3 years in adults (or annually if additional risk factors are present) [3]. In parallel, you receive detailed education about the symptoms of T1D, about the prevention of diabetic ketoacidosis and about the available therapeutic options, such as teplizumab for stage 2. This approach can mean that, when the disease becomes clinically manifest, the diagnosis is made early and you avoid severe acute complications at onset [4].