📘 Pre-diabetic stages and T1DM screening

In type 1 diabetes, "prediabetes" doesn't mean the same thing as in type 2. Here we're talking about preclinical stages when the autoimmune process is active, but blood glucose hasn't risen very much yet [1]. You won't have symptoms at this stage because morning blood glucose is only slightly elevated, generally in the range of 100-125 mg/dl (5.6-6.9 mmol/L), and at two hours in the glucose tolerance test 140-199 mg/dl (7.8-11 mmol/L). These blood glucose levels correspond to an HbA1c of 5.7-6.4% (39-47 mmol/mol) [2].

Prediabetes together with two positive autoantibodies already means stage 2 of type 1 diabetes [1]. Unlike prediabetes without associated autoimmunity (actually a precursor to type 2 diabetes), which can sometimes be reversed, here the process is generally progressive toward clinically manifest type 1 diabetes (with high blood glucose, stage 3) [2].

The progression to clinical type 1 diabetes (stage 3) passes through two other well-defined stages [1]. Stage 1 means two or more positive autoantibodies, with normal blood glucose. Stage 2 associates two positive autoantibodies and prediabetes [2].

Stage 3 is clinically manifest diabetes with classic symptoms and blood glucose over 200 mg/dl (11.1 mmol/L). The transition between stages can take months or years, being faster in children [2]. Identification in stages 1-2 allows the beginning of close monitoring and avoidance of ketoacidosis at onset, which affects at least one-third of those not diagnosed early [6].

If you have type 1 diabetes, your children have a risk of developing this condition that is 8-15 times higher than the general population [3]. Testing for autoantibodies can more precisely identify the risk, allowing close monitoring and prevention of ketoacidosis at onset [5].

However, testing can sometimes have psychological disadvantages. The anxiety of knowing that the disease can appear without being able to completely prevent it is not negligible [4]. Discuss with your diabetologist about the risk-benefit ratio (testing is worth it for the vast majority).

For first-degree relatives (children, siblings, parents) of people with type 1 diabetes, screening with autoantibodies is recommended every 3 years, starting from age 2 [4]. If the test is positive for one autoantibody, it is repeated at 6 months for confirmation. With multiple positive autoantibodies, HbA1c monitoring also becomes important [5].

The frequency can sometimes be adjusted based on the presence of HLA risk genes [3]. Those with high genetic risk require more frequent screening. In stage 2 of type 1 diabetes, HbA1c testing may need to be done every six months as it migrates into the upper half of the prediabetes range [5].

Initial screening includes testing for at least two autoantibodies: GAD and IA-2 [4]. If cost is not a barrier, IAA and ZnT8 can be added [5]. If at least two antibodies are positive, fasting blood glucose and HbA1c are additionally verified.

For those with positive autoantibodies, an oral glucose tolerance test (OGTT) is performed to more precisely detect prediabetes (stage 2) [5]. C-peptide evaluates residual beta cell function, but is not involved in screening for stage 1 and 2 of type 1 diabetes [1]. HLA testing can stratify risk but is not essential. It is important that tests be performed in accredited laboratories with experience in autoimmunity [4].

In stages 1 and 2 of type 1 diabetes, most people have no symptoms [1]. Sometimes subtle, easily missed signs may appear, such as unexplained fatigue after meals (when blood glucose temporarily rises above normal), recurrent fungal infections, or temporarily blurred vision [2].

In stage 2, when intermittent hyperglycemia occurs, you may notice short episodes of slightly increased thirst or somewhat more frequent urination, especially after carbohydrate-rich meals [5]. These symptoms disappear spontaneously when the remaining beta cells compensate. Monitoring with a continuous glucose monitoring sensor can detect significant blood glucose fluctuations [4].

Teplizumab (Tzield), recently approved, can delay progression from stage 2 to stage 3 by approximately 2-3 years [7]. This time can be considered valuable for children, especially during periods of accelerated height growth [8]. The treatment consists of intravenous infusions for 14 days and works by modulating the immune response [9]. It is available for people from 8 years old, with the cost of a 14-day course being approximately 194,000 USD (around 180,000 euros).

Other studied interventions include oral or nasal insulin (for inducing tolerance), high-dose vitamin D, omega-3, and various immunotherapies [4]. None of these significantly influence progression. Participation in clinical trials offers free access to experimental therapies. Until definitive solutions are available, careful monitoring remains essential [5].