June 06, 2026
Until recently, type 1 diabetes (T1D) was typically diagnosed only after the onset of symptomatic hyperglycemia. It is now recognized as a staged autoimmune disease characterized by a prolonged asymptomatic phase. It begins with stage 1 islet autoimmunity and advances to stage 2 dysglycemia. Ultimately, it progresses to stage 3, which is characterized by the onset of symptomatic disease.
Advances in autoantibody screening and immunotherapy are beginning to change the clinical approach to T1D, particularly in specialized centers.
Today, pediatric endocrinologists at Mayo Clinic Children's Pediatric Type 1 Diabetes Immunotherapy Clinic not only diagnose type 1 diabetes at the autoantibody stage, but they also use a newer immune-modulating therapy to slow disease progression in patients with early-stage T1D.
"This reflects an important shift in how we approach type 1 diabetes," says Ana L. Creo, M.D., a pediatric endocrinologist at Mayo Clinic Children's in Rochester, Minnesota. She specializes in pediatric diabetes and leads the multidisciplinary team in providing disease-modifying treatment for children with early-stage type 1 diabetes.
Instead of simply treating the disease with insulin, physicians can now treat the underlying autoimmune process in select patients with early-stage disease. Doing so can delay disease progression and the need for intensive diabetes management.
Screening children at risk of pediatric type 1 diabetes
The lifetime risk of developing T1D is approximately 15 times higher in family members of individuals with T1D compared with the general population.
Consensus guidelines from screening programs such as TrialNET (trialnet.org) recommend autoantibody screening for children age 2 and age 6 who have a first-degree relative, such as a parent or sibling, with T1D. Screening at these ages will identify the majority of children who will develop T1D by the time they are 18 years old. Repeat screenings at defined intervals through adolescence is recommended, with earlier testing if clinical suspicion arises.
When ordering screening tests, clinicians should request all four validated autoantibodies:
- Glutamic acid decarboxylase autoantibodies.
- Insulin autoantibodies (IAA).
- Insulinoma-associated antigen-2 autoantibodies.
- Zinc transporter 8 autoantibodies.
Note that IAA must be drawn prior to significant insulin exposure, as exogenous insulin invalidates the result.
Interpreting the test results
Staging and management decisions following autoantibody testing depend on the number of positive autoantibodies and metabolic status.
Stage 1: Two or more positive autoantibodies with no dysglycemia
Children who test positive for two or more autoantibodies have an 80% to 90% lifetime risk of progressing to clinical type 1 diabetes, also known as stage 3 T1D, with risk varying by age and antibody profile. These patients should begin periodic metabolic monitoring by their primary healthcare professional to detect early progression.
Stage 2: Two or more positive autoantibodies, asymptomatic with dysglycemia
Asymptomatic dysglycemia is defined as:
- Fasting plasma glucose (FPG) of 100 to 125 mg/dL.
- Two-hour glucose of 140 to 199 mg/dL during oral glucose tolerance testing (OGTT).
- Hemoglobin A1C (HbA1c) of 5.7% to 6.4%.
Any of these results indicate the disease may be advancing and warrants timely referral for subspecialty evaluation. Closer metabolic monitoring is recommended while awaiting specialty evaluation.
Stage 3: Two or more positive autoantibodies, symptomatic with hyperglycemia
Stage 3 refers to clinical, symptomatic type 1 diabetes defined as:
- FPG of 126 mg/dL or greater.
- Two-hour glucose of 200 mg/dL or greater during OGTT.
- HbA1c of 6.5% or greater.
Single positive autoantibody
Although the risk of progression is lower with a single positive autoantibody, primary healthcare professionals need to follow up and monitor as needed, especially if the antibody is strongly positive.
"While the presence of two or more positive autoantibodies has historically been the benchmark, emerging evidence suggests that even a single strong positive result may warrant evaluation depending upon the child's age and which antibody is positive," Dr. Creo says.
Repeat autoantibody testing within 6 to 12 months is advised to assess persistence or progression to multiple autoantibodies.
No autoantibodies
Children with risk factors who test negative for autoantibodies at age 2 and again at age 6 may continue screening periodically until age 18. Earlier repeat testing may be considered if symptoms or clinical suspicion arise.
At the Pediatric Type 1 Diabetes Immunotherapy Clinic at Mayo Clinic Children's, most patients can be seen within weeks of referral. Expedited appointments are available for children demonstrating dysglycemia or other signs of rapid progression.
Monitoring after a positive autoantibody result
Following identification of islet autoimmunity, ongoing monitoring is essential to detect progression from stage 1 to stage 2 disease.
Stage 1
Children with stage 1 T1D should have periodic assessments to detect dysglycemia, which may include FPG, OGTT, HbA1c or a combination of measures. Often, OGTT is the first test to be out of range as a child progresses to stage 2 T1D.
For convenience, Mayo Clinic Children's works with primary healthcare professionals to determine the optimal way to individualize follow-up care for each child with stage 1 T1D.
When a child exhibits dysglycemia consistent with stage 2 disease, the care team meets with the family to discuss options for initiating immunotherapy.
Stage 2
Children identified during stage 2 T1D require expedited referral for consideration of disease-modifying therapy as well as monitoring for progression to stage 3 T1D and consideration of insulin initiation. Recommended monitoring modalities during this stage may include OGTT and HbA1c.
Early-stage T1D monitoring supports multiple clinically meaningful objectives, including:
- Prevent diabetic ketoacidosis and the risk of requiring emergency care.
- Initiate therapeutic intervention to delay the onset of stage 3 T1D and prolong beta cell function.
- Educate patients and families about T1D treatment and management before symptoms appear.
- Reduce the risk of misclassifying as type 2 diabetes and delaying the start of insulin therapy.
- Refer patients for clinical trials if appropriate.
"Teplizumab represents a new disease-modifying approach to treat the disease process."
A novel treatment approach for early-stage type 1 diabetes
For children with stage 2 T1D, pediatric endocrinologists at Mayo Clinic Children's may recommend treatment with teplizumab for eligible patients. This novel anti-CD3 monoclonal antibody therapy, which slows immune-mediated beta cell destruction, is approved by the Food and Drug Administration for children age 1 and older. "Teplizumab represents a new disease-modifying approach to treat the disease process," Dr. Creo says.
Teplizumab is administered in the clinic as a 14-day infusion, with research demonstrating that it delays the onset of stage 3 disease by a median of two years. Compared with other immunotherapies, it is generally safe and well tolerated. The most commonly reported adverse effects include transient lymphopenia, rash and headache.
Delaying progression to insulin-dependent diabetes provides meaningful clinical benefits for pediatric patients and their families. "That's more years of not needing intensive insulin therapy and pump management," Dr. Creo says.
For more information
Type 1 diabetes screening program. TrialNET.
Refer a patient to Mayo Clinic.