The stages of type 1 diabetes

Type 1 diabetes 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 characterised 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 type 1 diabetes, when hyperglycaemia is obvious and the typical symptoms appear: intense thirst, frequent urination and unintentional weight loss. At this stage, the marked hyperglycaemia means insulin treatment must be started straight away. Some organisations also describe a fourth stage, which would represent the disease stabilised 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 type 1 diabetes is the testing of your blood to identify pancreatic autoantibodies, which are markers of an autoimmune process directed against the beta cells. The four key autoantibodies that are measured 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 your blood glucose is still normal [1].

This type of screening is useful because it can identify type 1 diabetes 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 hyperglycaemic onset and to be able to access certain treatments or clinical trials 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 type 1 diabetes should be offered first of all to people with a family history of type 1 diabetes, particularly to first-degree relatives (parents, siblings, children) of a patient with type 1 diabetes. 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 features that overlap with type 1 diabetes (younger age at diagnosis, unintentional weight loss, ketoacidosis or rapid need for insulin therapy) should also be tested [6].

It is worth remembering that the majority of people who develop type 1 diabetes (approximately 90%) do not have a relative with type 1 diabetes. For this reason, free population screening programmes 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 should be discussed with your doctor, because it involves not only the test itself, but also a clear plan for subsequent monitoring and access to specialist care in the case of a positive result.

The frequency of testing pancreatic autoantibodies depends on your age. In children under 3 years at 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 dysglycaemia (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 type 1 diabetes) [3].

The age at which screening starts is not fixed, but is established individually, according to the risk profile. In children at 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 started 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 towards clinical type 1 diabetes. If you have two autoantibodies and normal blood glucose levels, the chances of developing clinically manifest type 1 diabetes are approximately 30% at 5 years and 85% at 15 years. If you have three autoantibodies, the chances of progression to type 1 diabetes 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 titre (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 progression tends to be) and genetic predisposition [2]. The transition from stage 1 to stage 2, marked by the appearance of dysglycaemia, is the slowest, after which things accelerate significantly. The risk of moving from stage 2 to stage 3 of type 1 diabetes is 60% at two years and 75% at five years [3].

Yes, there is currently an approved treatment that, given in stage 2, delays the onset of clinically manifest type 1 diabetes (stage 3). Teplizumab (an anti-CD3 monoclonal antibody) is indicated for people aged at least 8 years who are in stage 2 of type 1 diabetes, that is, having two or more pancreatic autoantibodies and dysglycaemia (prediabetes), but without symptoms [8]. The treatment is given intravenously in daily infusions for 14 days and has the role of reducing the autoimmune attack on the 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 roughly doubles the time you would otherwise have taken to progress from stage 2 to stage 3 [9].

In addition to teplizumab, there are numerous ongoing clinical trials that test other approaches for preventing or delaying type 1 diabetes in the preclinical stages. In these trials, various monoclonal antibodies, immune system modulators, biological agents and cell therapies are tested. Enrolment in a clinical trial can be an option if you are in an early stage of the disease and live in a region where these trials are accessible. The decision to start teplizumab or to take part in a trial 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 type 1 diabetes 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 specialist centres for monitoring people who test positive, access to treatments such as teplizumab is unequal, and the cost-effectiveness of generalised screening is not fully demonstrated in all contexts [5]. For this reason, screening remains primarily oriented towards people at high risk, such as first-degree relatives of patients with type 1 diabetes or people with known genetic predisposition.

There are, however, regional population screening programmes operating in various countries (Fr1da and GPPAD in Europe, TrialNet, ASK and CASCADE in the USA, type1screen in Australia). In 2023, Italy introduced at national level a screening for type 1 diabetes and coeliac 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 fall, it is likely that more and more countries will adopt similar programmes, especially given that globally almost 9.5 million people are living with type 1 diabetes 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 afterwards. After confirmation, a complete metabolic evaluation follows in a specialist diabetes centre, which includes measurement of HbA1c, fasting blood glucose and sometimes an oral glucose tolerance test in order to identify a possible stage 2 (dysglycaemia) 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 measurement 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 type 1 diabetes, about the prevention of diabetic ketoacidosis and about the available treatment 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].