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Page 116 Chan et al. J Transl Genet Genom 2024;8:13-34 https://dx.doi.org/10.20517/jtgg.2023.36

lifecourse and psychosocial-behavioral factors in patients with YOD. Apart from detailed clinical evaluation, we
propose using plasma C peptide, homeostasis model of assessment (HOMA) indexes, autoantibodies, and
polygenic risk scores to stratify risk, classify diabetes subtypes, and personalize treatment in YOD. To achieve
these goals, we advocate changing the practice environment and team structure to enable physicians to use the
insights they learn from patients and their family members to implement precision medicine and improve the
outlook of these high-risk individuals.

Keywords: Young-onset type 2 diabetes, YOD, genomic medicine, precision medicine, autoimmunity, type 1
diabetes, monogenic diabetes, MODY, LADA, PRISM, randomized controlled trial

INTRODUCTION
In 2021, diabetes affected 537 million people, with 80% coming from low- and middle-income countries .
[1]
[2]
Age, obesity, and family history of diabetes are major risk factors for diabetes . Thus, people who develop
diabetes at a young age, especially if lean, require comprehensive investigations to explain their early
metabolic decompensation. In part due to childhood obesity, there is a growing prevalence of young-onset
[3]
type 2 diabetes (YOD), defined as diabetes diagnosis before the age of 40 , which affects one in five adults
[4]
with type 2 diabetes in Asia .
Patients with YOD may be exposed to decades of glycemic burden with rapid deterioration of glycemic
control and shortened lifespan by 10 years or more . Compared to their peers with late-onset diabetes,
[5]
[6]
patients with YOD had a 2-6 times higher risk of cardiovascular-renal events, recurrent hospitalizations,
and premature death, with mental illness and kidney dysfunction being prominent clinical features .
[7-9]
[10]
[11]
While there are ongoing large-scale epidemiological, genetic , and interventional studies in people with
youth-onset diabetes (less than 18 years old), there are research gaps in YOD diagnosed during adulthood to
[12]
guide diagnosis and management . In high-income jurisdictions with well-developed healthcare systems,
such as Hong Kong, despite overall falling trends of diabetes and related death [13,14] , the incidence of YOD
continued to rise . Individuals with YOD have experienced mortality rates that are 5-8 times higher than
[15]
[16]
those with late-onset diabetes .
MOTIVATION, FRAMEWORK AND OBJECTIVES
During the last three decades, the Chinese University of Hong Kong Diabetes Care and Research Team has
combined practice and research to gather data and use data to inform practice and policies [3,17] . In the
ongoing Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes Randomized Controlled
Trial (PRISM-RCT) in Chinese Patients with Young-Onset Diabetes, we performed comprehensive clinical
assessment and used biogenetic information to increase the precision of diagnosis and management of these
high-risk patients (https://clinicaltrials.gov/ct2/show/NCT04049149) .
[18]

In part motivated by learnings from the PRISM-RCT, in this invited perspective not intended to be a review
article, we shared our three decades of insights learned from diagnosing, classifying, and managing patients
with YOD while pursuing active research in the field of genetics/genomics of diabetes focusing on
translation. We first highlighted the minute amount of islets endowment at birth and the many lifecourse
factors that may damage their structure and function, ultimately leading to diabetes. We briefly discussed
Latent Autoimmune Diabetes in Adults (LADA) and monogenic diabetes as well-recognized subtypes of
YOD. In our discussion on autoimmune type 1 diabetes, we highlighted the caveat that atypical diabetes due
to acute destruction of islets related to viral infections and immunomodulating therapies may also present