NCT03369821 EXtremely Early-onset Type 1 Diabetes EXtremely Early-onset Type 1 Diabetes (A Musketeers' Memorandum Study)

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What to Expect as a Participant

This is an observational study. You will not receive an experimental treatment; researchers will collect data based on your existing condition or standard treatment.

This trial targets 300 participants in total. It began in 2017-09-19 with a primary completion date of 2028-10-31.

Brief Summary

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.

Eligibility Criteria

Inclusion Criteria: Study 1: EET1D * 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. T1D Controls * Age 0-70 years (matched to above) * Clinical diagnosis of T1D (diagnosed age 1-20 years) * Insulin treated from diagnosis. Monogenic / NDM controls * Diagnosis of diabetes \<12 months * Diagnosis of monogenic / NDM (confirmed by Exeter Molecular Genetics Laboratory). Study 2: EET1D * 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. Monogenic/NDM controls * Diagnosis of diabetes \<24 months * Age 0 to 18 months at recruitment * Diagnosis of monogenic/NDM (confirmed by Exeter Molecular Genetics Laboratory). Non-diabetic controls * 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. Exclusion Criteria: Study 1: * Aged \>70 years * No diagnosis of diabetes * MODY (e.g. caused by HNF1A/HNF4A/HNF1B/GCK mutations), type 2 diabetes or diabetes related to pancreatic insufficiency or syndromic diabetes * Intercurrent illness at time of sampling for PBMCs (see below). Study 2: * Aged \>24 months * Clinical diagnosis of diabetes \>24 months * Intercurrent illness at time of sampling for PBMCs or RNA (see below). Non-diabetic controls: * Aged \>6 years * Diagnosis of diabetes or other autoimmune condition * Known immunological disorder * On immunosuppressive medication * Ongoing infections/sepsis * Major congenital abnormality or significant systemic illness that may affect the immune system, e.g. metabolic disease, 22q deletion syndrome * Recent (within two weeks) febrile illness * Renal failure. For PBMC and RNA sampling: Exclusion for factors that may alter T cell function and RNAseq Review the following exclusion criteria carefully at time of appointment as some details may have changed since initial contact: * Recreational drug use (excluding cannabis use more than 1 week prior to blood sampling) - drug abuse may alter T cell function * Alcohol related illness (excessive alcohol consumption may alter T cell function) * Renal failure: Creatinine \>200 (as may alter T cell function) * Any other medical condition which, in the opinion of the investigator, would affect the safety of the subject's participation. Factors that if temporary would lead to rearrangement of study visit but if long duration, may lead to exclusion subject to the CI's discretion: * Pregnant or lactating (as this may limit blood sampling and affect T cell function) * Any infectious illness within the last 2 weeks if it was a febrile illness, or within 2-3 days if it was non-febrile (as this may activate T cells non-specifically) * Taking steroids or other immunosuppressive medications (as these may alter T cell function) * Received any immunoglobulin treatments or blood products in the last 3 months (as these may alter T cell function).

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