EXtremely Early-onset Type 1 Diabetes EXtremely Early-onset Type 1 Diabetes (A Musketeers' Memorandum Study)

Conditions

• Type1 Diabetes Mellitus

Eligibility Criteria

Sex

ALL

Age

N/A - 70 Years

Healthy Volunteers

Not accepted

Interventions

• Beta Cell Loss and Immune Function — DIAGNOSTIC_TEST
  Beta cell loss (measured by serum/urine C-peptide), islet-specific autoantibodies, T1D risk genes and autoreactive CD8 T cells.
• Immune Function with RNAseq — OTHER
  Immune function (measuring autoantibodies, autoreactive CD8 T cells and RNAseq of immune genes).

Study Details

Type 1 diabetes (T1D) results from destruction of insulin-producing beta cells in the pancreas by the body's own immune system (autoimmunity). It is not fully understood what causes this type of diabetes and why there is variation in age of onset and severity between people who develop the disease. The aim of this work is to study very unusual people who develop T1D extremely young, as babies under 2 years of age (EET1D). The investigators think that, for the condition to have developed that early, they must have an unusual or extreme form of autoimmunity. Studying people with EET1D will enable us to look at exactly what goes wrong with the immune system because they have one of the most extreme forms of the disease. Much may be learned about the disease from a small number of rare individuals. The investigators aim to confirm that they have autoimmune type 1 diabetes and then try to understand how they have developed diabetes so young by studying their immune system genes, the function of their immune system, and environmental factors (such as maternal genetics) that may play a role in their development of the disease. People with diabetes diagnosed under 12 months are very rare, live all over the world. and are usually referred to Exeter for genetic testing. Individuals will be contacted via their clinician to ask for more information about their diabetes and their family history. Samples will be collected to study whether they still make any of their own insulin and whether they make specific antibodies against their beta cells in the pancreas. Separately, their immune system will be studied in depth using immune cells isolated from a blood sample. These cells will undergo cutting edge techniques by Dr Tim Tree at King's College London, by Professor Bart Roep at Leiden University Medical Center, Netherlands, and Dr Cate Speake, Benaroya Research Institute, Seattle (USA). Some of these tests have never been used in people of young ages around the world, so an aim of this project will be to develop methods that can be used to study people even if they live far away. Additional funding extended the study for a further 3 years (Phase 2) to include recruitment of infants without diabetes, aged 0-6 years, as controls to enable assessment of how the abnormalities found in autoimmune and non-autoimmune diabetes compare to normal early life development of the immune system. An additional funding award extended the study (Phase 3) until November 2028, to advance the EXE-T1D program into its third phase, building on major discoveries from phases 1 and 2 to identify, validate, and target immune pathways that drive extremely early-onset type 1 diabetes (eeT1D) and are likely relevant to T1D across all ages. eeT1D cases, diagnosed within the first two years of life, represent particularly aggressive onset of beta-cell autoimmunity. They offer a unique lens to uncover mechanisms of immune dysregulation, informed by both polygenic and monogenic causes. The central aim is to move from pathway discovery to demonstration of novel druggable targets with potential to delay or prevent T1D onset across all ages.

Key Dates

Start date

Sep 19, 2017

Status verified

Dec 2025

Primary completion

Oct 31, 2028

Completion

Nov 30, 2028

Study Design

Enrollment

300 participants (estimated)

Arms

• Arm: Study 1: Existing EET1D (Case)
  * Aged 0 to 70 years * Clinical diagnosis of diabetes \<24 months (+ evidence of WHO diabetes criteria) * Negative genetic test for mutations causing non-autoimmune neonatal diabetes if diagnosed \<12 months * Type 1 diabetes genetic risk score \>50th centile of T1D reference group, or monogenic cause of T1D (e.g. STAT3 or FOXP3 mutation).
• Arm: Study 1: T1D (Control)
  * Age 0-70 years (matched to above) * Clinical diagnosis of T1D (diagnosed age 1-20 years) * Insulin treated from diagnosis.
• Arm: Study 2: Newly diagnosed EET1D (Case)
  * Aged 0 to 24 months at recruitment * Clinical diagnosis of diabetes \<24 months (+ evidence of WHO diabetes criteria) * Negative genetic test for mutations causing non-autoimmune neonatal diabetes * Type 1 diabetes genetic risk score \>50th centile of T1D reference group, or monogenic cause of T1D (e.g. STAT3 or FOXP3 mutation)
• Arm: Monogenic / NDM (Control)
  * Diagnosis of diabetes \<24 months * Age 0 to 24 months at recruitment * Diagnosis of Monogenic / NDM (confirmed by Exeter Molecular Genetics Laboratory).
• Arm: Without diabetes (Control)
  * Aged 0-6 years * Attending specified participating hospital sites for elective surgery, including but not limited to: inguinal hernia repair, umbilical/midline hernia repair, orchidopexy, gastrostomy insertion/change, hypospadias repair, cleft palate repair, excision of accessory digit, laryngoscopy, adenoidectomy, tonsillectomy, MRI under general anaesthesia, eye surgery. Should recruitment be slower than anticipated, we would recruit children with congenital non-immune thyroid disease when they attend paediatric clinic for blood draw.

Primary Outcome Measure

Measure beta cell function in EET1D compared to T1D, NDM and non-diabetic controls. [ Time Frame: Within 12 months of last participant's final visit. ]

Central Contacts

• Richard Oram
  +44 (0) 1392 408538
  [email protected]
• Michelle Hudson
  +44 (0) 1392 408181
  [email protected]

Locations (1)

Find similar trials in Seattle, WA

Related Studies

• Genetics Of Autoimmunity In Type I Diabetes
  Recruiting · Medical College of Wisconsin · Milwaukee, Wisconsin