The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled over 8,000 infants identified to have an increased genetic risk for type 1 diabetes (T1D) and were followed prospectively for 15 years for the development of T1D and islet cell antibodies. There were 400 children projected to develop T1D over the course of the study, and follow-up of these children stopped upon development of T1D. The JDRF Follow-up of Children Diagnosed with Diabetes (JDRF-TEDDY Follow-Up) study sought to understand whether these children were diagnosed at an earlier stage of T1D compared to children not enrolled in prospective studies, and to identify if they maintained the ability to produce C-peptide longer than children diagnosed through standard clinical care in the community. The JDRF-TEDDY Follow-Up study analyzed the preservation of C-peptide over time in children diagnosed with T1D through prospective studies and compared them to a group of age matched controls identified from the community. Furthermore, the JDRF-TEDDY Follow-Up study collected samples to investigate immunological changes occurring after diagnosis and how these changes may relate to earlier T1D diagnoses.

The purpose of the JDRF-TEDDY Follow-Up study was to better understand how early T1D diagnoses may impact disease course and outcomes in children through three primary aims:

• Aim 1: To evaluate participants diagnosed with diabetes through the prospective TEDDY study and control children with T1D of similar age for factors including C-peptide production at diagnosis, diabetic ketoacidosis (DKA), symptoms at diagnosis, and HbA1c at diagnosis, and to correlate these factors with decline and duration of decline of C-peptide loss.
• Aim 2: To assess the impact of ‘early’ diagnosis on glucose control, quality of life, and psychological functioning.
• Aim 3: To collect and store samples for correlative studies to assess changes that occur before and after diagnosis of T1D in TEDDY children with respect to T-cell and B-cell activity and gene expression as indicators of active autoimmunity.

The primary outcome measure was C-peptide levels over time from diagnosis of diabetes.

The secondary outcome measures included presence of DKA at onset, C-peptide, islet cell antibodies, hemoglobin A1c and insulin dose, glycemic control and glycemic variability, health-related quality of life and psychological functioning from children and their parents, T-cell activity and gene expression prior to antibody development, post antibody development, post diagnosis of T1D, and changes in human biome from stool samples as feasible.

Inclusion criteria for Case subjects:

• Participated in regular follow-up through the TEDDY study (i.e., seen within a year prior to diagnosis, and enrolled within 3 months of diagnosis)
• Diabetes diagnosed:
  • With symptoms of diabetes (e.g., polyuria, polydipsia) and confirmatory blood sugar greater than or equal to 200 mg/dL (11.1 mmol/L)
  • Fasting glucose greater than or equal to 126 mg/dL (7 mmol/L) and/or random blood sugar greater than or equal to 200 mg/dL (11.1 mmol/L) at least twice
  • Abnormalities of oral glucose tolerance testing (OGTT) with fasting glucose greater than or equal to 126 mg/dL (7 mmol/L) and/or 2-hour post blood sugar greater than or equal to 200 mg/dL (11.1 mmol/L) at least twice
  • Unequivocal hyperglycemia with acute metabolic decompensation (diabetic ketoacidosis)
• Informed consent and assent of subjects where appropriate
• Children greater than or equal to age 3

Inclusion criteria for Control subjects:

• Did not participate in any other prospective studies such as TrialNet, DAISY, TRIGR, etc.
• Diabetes diagnosed:
  • With symptoms of diabetes (e.g., polyuria, polydipsia) and confirmatory blood sugar greater than or equal to 200 mg/dL (11.1 mmol/L)
  • Fasting glucose greater than or equal to 126 mg/dL (7 mmol/L) and/or random blood sugar greater than or equal to 200 mg/dL (11.1 mmol/L) at least twice
  • Abnormalities of oral glucose tolerance testing (OGTT) with fasting glucose greater than or equal to 126 mg/dL (7 mmol/L) and/or 2-hour post blood sugar greater than or equal to 200 mg/dL (11.1 mmol/L) at least twice
  • Unequivocal hyperglycemia with acute metabolic decompensation (diabetic ketoacidosis)
• Autoimmunity documented with positive GAD65, IA-2, ZnT8 and/or insulin autoantibodies within the first 3 months of diabetes onset
• Matched to case subjects by age of diagnosis within one year and clinical center location
• Followed and recruited in the clinic with informed consent and assent of subjects where appropriate
• Children greater than or equal to age 3
• Enrolled within 3 months of diagnosis

Exclusion criteria:

• Not diagnosed with diabetes
• Do not provide informed consent
• Children less than 3 years of age
• The parent or primary caretaker refused to have the child’s samples stored

The primary outcome of the study was the preservation of stimulated C-peptide over time in TEDDY subjects versus the community diagnosed children. Higher C-peptide levels persisted for at least 12 months following diabetes onset in TEDDY participants compared to community diagnosed children. Symptom-free diagnosis, reduction of DKA, and the potential for immune intervention with increased baseline C-peptide may portend additional long-term benefits of early diagnosis.