A new, all‐encompassing aetiology of type 1 diabetes

Abstract

The aetiology of type 1 diabetes (T1D) is considered multifactorial with the contribution of the MHC on chromosome 6 being most important. Multiple factors also contribute to the aetiology of colorectal neoplasia, but the final event causing the change from normal mucosa to polyp and from polyp to cancer is due to a single somatic mutation event. Repeated formation of colorectal neoplasia within an at‐risk population results in a predictable, tapering, exponential neoplasia distribution. Critical mutations driving colorectal neoplasia formation occur in mutation‐prone DNA. These observations led to three hypotheses related to T1D. First, a single somatic mutation within the MHC of antigen presenting cells results in a change in phenotype from normal to T1D. Second, the distribution of additional autoimmune diseases (AAIDs) among persons with T1D adheres to a predictable, tapering, exponential distribution. And third, critical mutations driving development of T1D occur in mutation‐prone DNA. To address the hypotheses in an orderly fashion, a new analytical method called genome‐wide aetiology analysis (GWEA) consisting of nine steps is presented. All data required for GWEA of T1D are obtained from peer‐reviewed publications or publicly available genome and proteome databases. Critical GWEA steps include AAID distribution among persons with T1D, analysis of at‐risk HLA loci for mutation‐prone DNA, determination of the role of non‐MHC genes on GWAS, and verification of human data by cell culture or animal experiments. GWEA results show that distribution of AAID among persons with T1D adheres to a predictable, tapering, exponential distribution. A single, critical, somatic mutation within the epitope‐binding groove of at‐risk HLA loci alters HLA‐insulin‐peptide‐T‐cell‐receptor (TCR) complex binding affinity and creates a new pathway that leads to loss of self‐tolerance. The at‐risk HLA loci, in particular binding pockets P1, P4 and P9, are encoded by mutation‐prone DNA: GC‐rich DNA sequence and somatic hypermutation hotspots. All other genes on GWAS can but do not have to amplify the new autoimmune pathway by facilitating DNA mutations, changing peptide binding affinity, reducing signal inhibition or augmenting signal intensity. Animal experiments agree with human studies. In conclusion, T1D is caused by a somatic mutation within the epitope‐binding groove of an at‐risk HLA gene that affects HLA‐insulin‐peptide‐TCR complex binding affinity and initiates an autoimmune pathway. The nature of the peptide that binds to a mutated epitope‐binding groove of an at‐risk HLA gene determines the type of autoimmune disease that develops, that is, one at‐risk HLA locus, multiple autoimmune diseases. Thus, T1D and AAIDs, and therefore common autoimmune diseases, share a similar somatic mutation‐based aetiology.

Association between diabetes mellitus and primary biliary cholangitis: a two-sample Mendelian randomization study

“…This connection also gives rise to the potential occurrence of multiple autoimmune diseases stemming from a single at-risk HLA locus. Consequently, T1DM and common autoimmune diseases exhibit a comparable etiology centred around somatic mutations ( 32 ). In animal experiments, researchers utilized a traditional method of recombining breeding to exhibit that the NOD background’s existence of the altered Pkhd1del36-67 prompts the emergence of autoimmune biliary disease, showcasing resemblances to human PBC ( 33 ).…”

Enhancing equity in access to automated insulin delivery systems in an ethnically and socioeconomically diverse group of children with type 1 diabetes

“…Type 1 diabetes (T1D) is a lifelong condition, marked by an autoimmune mediated deficiency in insulin production. 1 This presents an ongoing challenge for children and young people (CYP) with T1D to adjust their exogenous insulin administration to maintain a glycated hemoglobin (HbA1c) level below 48 mmol/mol. 2 For CYP who have access to advanced technologies, continuous glucose monitoring (CGM) has enabled the evaluation of glycemic control beyond HbA1c by using time in range (TIR, 3.9–10.0 mmol/L) with the target being 70%.…”

“…Type 1 diabetes (T1D) is a lifelong condition, marked by an autoimmune mediated deficiency in insulin production. 1 This presents an ongoing challenge for children and young people (CYP) with T1D to adjust their exogenous insulin administration to maintain a glycated hemoglobin (HbA1c) level below 48 mmol/mol. 2 For CYP who have access…”