Examining the Stages of T1D Progression

The following Frontline Insights manuscript has been edited for clarity and length.

Natalie Bellini, DNP, FNP-BC, BC-ADM, CDCES: Let’s walk through the stages of type 1 diabetes (T1D) and the role of antibody testing. There are five antibodies associated with T1D that can be measured to identify autoimmune activity against beta cells. The presence of two or more of these antibodies indicates a 100% lifetime risk of developing T1D. However, the challenge lies in the fact that individuals in this stage often feel completely asymptomatic.

The first stage of T1D, now recognized with its own ICD-10 code, is referred to as stage 1 type 1 diabetes. At this stage, two or more antibodies are present, signaling an active autoimmune process targeting beta cells. Despite this, blood glucose levels remain within the normal range. Even under glucose challenges, such as a high-carbohydrate meal or a glucose tolerance test, the data remains euglycemic. These individuals have no symptoms and do not require insulin or other treatments at this point.

As the autoimmune process progresses, we move to stage 2 type 1 diabetes. At this stage, more beta cells have been destroyed, leading to dysglycemia. Glucose levels start to rise, resulting in a slightly elevated A1C—higher than normal but below the diagnostic threshold of 6.5%. Similarly, fasting glucose levels are elevated but not above the diagnostic level of 126 mg/dL. The hallmark of stage 2 is postprandial hyperglycemia, as the remaining beta cells cannot produce sufficient insulin to manage carbohydrate intake. Again, these individuals are asymptomatic and do not require treatment at this stage.

Finally, stage 3 type 1 diabetes is the stage most familiar to clinicians. By this point, significant beta-cell destruction has occurred, resulting in overt hyperglycemia and the classic symptoms of T1D: polyuria, polydipsia, polyphagia, fatigue, dry mouth, and unexplained weight loss despite increased appetite. Additional signs may include slow wound healing and, in advanced cases, diabetic ketoacidosis (DKA). DKA results from the breakdown of fat for energy due to insufficient insulin, leading to an accumulation of acidic ketones in the blood.

Javier Morales, MD: Thank you for outlining the stages so clearly. I suspect many of us weren’t aware of the distinct progression from stage 1 through stage 3. I have a question: What if only one antibody is present? How do we approach such patients?

Bellini: In individuals with only one antibody present, the risk of developing a second antibody—and thus progressing to stage 1—ranges from 20% to 30%. These patients require careful monitoring, especially if they have a family history of autoimmune conditions. For instance, a patient with a first-degree relative with T1D, along with extended family members affected by autoimmune diseases like Hashimoto’s thyroiditis or celiac disease, warrants closer follow-up.

Recent guidelines published by Breakthrough T1D, formerly JDRF, and endorsed by the ADA, ISPAD, and the European Association for the Study of Diabetes (EASD), provide consensus on monitoring antibody-positive individuals. For patients with even one antibody, referral to endocrinology is crucial. Endocrinologists can assess whether additional testing for other autoimmune markers, such as thyroid or celiac antibodies, is needed to rule out concurrent autoimmune conditions. Even if the patient does not currently have diabetes, ongoing surveillance is often appropriate.

Morales: Frequent follow-up seems to be essential in managing these cases.

Abha Choudhary, MD: Exactly. Additionally, antibodies can sometimes become undetectable over time. In fact, up to 50% of patients with only one antibody may later test negative. However, as Dr. Bellini noted, it’s critical to evaluate all such patients thoroughly. Even if antibody testing turns negative, they may require ongoing follow-up to ensure their health remains stable.