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Chan et al. J Transl Genet Genom 2024;8:13-34 https://dx.doi.org/10.20517/jtgg.2023.36 Page 117
with diabetic ketoacidosis. In our discussion on monogenic diabetes, including Maturity-Onset Diabetes of
the Young (MODY), we highlighted the pitfalls of sole reliance on bioinformatics and few reported cases to
classify the pathogenic nature of variants, which can lead to missed opportunities for early diagnosis and
intervention, especially in populations where common genetic variants may contribute to trajectories of
YOD different from that reported in European populations. With the availability of genome sequencing and
preconception counseling services, we used clinical examples, albeit rare, to highlight how the detection of
mutations with autosomal recessive inheritance in patients with YOD may alert the possibility of syndromic
diabetes in homozygous carriers, which calls for genetic and preconception counseling.
We then discussed the clinical application of polygenetic risk scores, now widely accepted by the scientific
community to have potential utilities for improving the precision of prediction, prevention, diagnosis, and
therapies in complex diseases such as diabetes, and their relevance to YOD. We concluded by summarizing
the design of the PRISM-RCT aimed at closing these knowledge gaps but at the same time advocating the
need to create an environment conducive to reducing genomic medicine to practice, taking into
consideration the unmet psychosocial-behavioral needs in YOD.
Against this background, the motivation underlying this perspective is to encourage more physicians who
stand between patients (and their families) and technologies, to gather data systematically to improve our
understanding of the nature of this complex syndrome and implement person-centered solutions with
ongoing evaluation to inform practice and policies. To non-physicians involved in creating these genomic/
genetic data, we emphasize to them the myriad of factors that need to be considered when interpreting these
data and translating them into a technology or service aimed at beneficiating the patients and those at risk.
DIABETES AND PANCREATIC ISLETS
Blood glucose is maintained within a narrow range of 4-8 mmol/L most of the time, irrespective of energy
intake or expenditure, due to efficient glucose sensing and insulin release by the pancreatic beta-cells [19-21] .
Stress hormones, including catecholamines, glucagon, growth hormone, and cortisol, can increase blood
glucose, while insulin is the only hormone that lowers blood glucose [19,20] . Other mechanisms of type 2
diabetes include non-suppression of glucagon and hepatic glucose production, excessive lipolysis, insulin
resistance in peripheral tissues, dysregulation of appetite control, and abnormal incretin physiology .
[22]
Recent meta-analyses of multi-ethnic genome-wide association studies (GWAS) discovered hundreds of
loci implicated in pancreas, adipose, and muscle tissue biology in type 2 diabetes [23-25] .
In an autopsy series of 100 deceased subjects, the weight of pancreatic islets increased from approximately
0.2 grams at birth to a plateau of 1.0 gram at the age of 21 with marked inter-individual variations
[Figure 1] . Other autopsy series revealed close correlations between body mass index (BMI) and
[26]
pancreatic islet mass, with diabetes cases having lower beta-cell mass and larger alpha-cell mass than cases
without diabetes . Oxidized proteins, fat infiltration, amyloid deposits, and atherosclerosis were common
[27]
[28]
features in diabetes pancreas . Insufficient islet mass may lead to diabetes and early insulin requirement,
so-called type 3c diabetes, due to chronic pancreatitis, pancreatic ductal adenocarcinoma,
[29]
hemochromatosis, cystic fibrosis, and previous pancreatic surgery .
Islet autoimmunity and type 1 diabetes
Autoimmune destruction of islets can lead to progressive and severe insulin deficiency with rising blood
glucose. This is accompanied by lipolysis as an alternative fuel with weight loss and ketone formation,
culminating in diabetic ketoacidosis and coma . In 2021, 8 million people had type 1 diabetes. Amongst
[30]
them, 1.5 million were children and adolescents, with the majority diagnosed after the age of 18 . There
[31]