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Page 118 Chan et al. J Transl Genet Genom 2024;8:13-34 https://dx.doi.org/10.20517/jtgg.2023.36

Figure 1. A quantitative analysis of 100 pancreases obtained from individuals in the United Kingdom in the mid-1930, including newly-
born infants and adults up to the age of 64 years, all of whom apparently had normal nutrition and died from different causes including
pneumonia, cerebral hemorrhage, perforated gastric ulcer burns, showing the proportional weight of islets and their increase in size
over time, reaching a plateau in early adulthood. The small islet mass and its plateau in early adulthood might contribute to the marked
increase in diabetes prevalence given the average adult body weight of 60-70 kg today compared to 50 kg nearly 100 years ago
(reproduced with permission) [26] .

[32]
was familial clustering of type 1 diabetes with 50% concordance amongst monozygotic twins . Human
leukocyte antigen (HLA) haplotypes were associated with increased (e.g., HLA DQ2/DQ8) and decreased
(e.g., HLA DQ6/x) risk of islet autoimmunity [33,34] . Genetic risk score incorporating HLA haplotypes and
non-HLA genetic variants predicted the onset of type 1 diabetes in European populations [35-37] .

In a proof-of-concept RCT conducted in the 1980s, researchers reported that 1-year treatment with
cyclosporine, an immuno-modulating therapy, was more effective than placebo in causing remission in
patients with type 1 diabetes (10-35 years old) . In 2022, teplizumab, a modified mono-antibody against C3
[38]
component on cytotoxic T cells, with a considerably safer profile, was approved by the regulatory agency for
delaying the onset of type 1 diabetes [39,40] . In the latest publication, teplizumab was also found to improve
[41]
beta-cell function in children newly diagnosed with type 1 diabetes . These therapeutic advancements have
opened up avenues for using biogenetic markers, such as polygenetic risk scores, to identify high-risk
individuals for early prevention and intervention [33,42] . From a treatment perspective, severe insulin
deficiency and dysregulation of glucagon secretion put patients with type 1 diabetes at high risk of
hyperglycemia and severe hypoglycemia. Advanced insulin formulation and delivery systems ,
[43]
supplemented by continuous glucose monitoring devices , had improved the safety and effectiveness of
[44]
intensive insulin therapy, making early diagnosis of type 1 diabetes imperative to improve their
prognosis [45,46] .

Atypical forms of type 1 diabetes
There are rare forms of type 1 diabetes due to islet destruction. One example is fulminant type 1 diabetes,
which occurs within a few days after a viral illness presenting with diabetic ketoacidosis, often accompanied
by increased biomarkers of exocrine dysfunction. These patients usually require life-long insulin
treatment . These rare examples inspire new insights into alternative pathogenesis for acute diabetic
[47]