Multifaceted nature of young-onset diabetes - can genomic medicine improve the precision of diagnosis and management?

Abstract

Young-onset type 2 diabetes (YOD), defined as diabetes diagnosis before age 40, has an aggressive clinical course with premature mortality, in part due to long disease duration and lack of evidence to guide diagnosis and management. Autoimmune type 1 diabetes, maturity-onset diabetes of the young (MODY), and latent autoimmune diabetes in adults (LADA) are subtypes of diabetes in young people, which, however, cannot fully explain their complex clinical course. Similarly, family members carrying the same rare genetic variant of monogenic diabetes can have different presentations and outcomes. Ancestral heterogeneity, ecological transition, inter-ethnic differences in genomic architecture, and variations in living environment, lifestyles, access to care, and timeliness of diagnosis and treatment can influence the age of diagnosis and exposure to these cardiometabolic-renal risk factors. Despite the wealth of literature on genetic associations with diabetes, the familial cosegregation of rare variants and their relevance to YOD remains uncertain. This perspective was motivated by decades of clinical observations and learnings from an ongoing randomized controlled trial that uses biogenetic markers to classify patients with YOD for improving outcomes. Apart from highlighting the need to use family-based studies to improve the precision of diagnosis, we discussed atypical causes for diabetic ketoacidosis and the importance of 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.

Personalised genomic medicine is shaping the future of healthcare

“…The art of genome sequencing and analysis offers valuable insights into early and precise diagnosis, personalised treatment and management of various diseases, highlighting the expanding influence of genomics across diverse areas of clinical practice. In this special issue, we gathered an application of genomics in prenatal molecular diagnosis of a rare disease, X-linked Bartter Syndrome, as well as reviews on how genomics benefits clinical practice in various common disease cohorts, such as inherited cardiovascular conditions (ICCs), adult myeloid leukaemia (AML), and young-onset diabetes (YOD) [7][8][9][10] . Xu et al presented an application of genomics in the prenatal diagnosis of Bartter syndrome (BS), which is important for the early onset of polyhydramnios related to BS [7] .…”

“…Their experience provides insights for international counterparts when implementing similar services in local healthcare centres to address the healthcare burden of ICCs. Leung et al reviewed that the genomic revolution in AML has ushered in a new era of personalised medicine, shifting the treatment paradigm from a generalised approach, which has reached an impasse, to one that targets individual genetic alterations [9] . The integration of genomics, the detection of measurable residual disease, drug sensitivity testing, and single-cell transcriptomics hold tremendous potential for optimising AML management through personalised approach based on genomic and transcriptomic information.…”

Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial (PRISM-RCT) in Chinese patients with young-onset diabetes: design, methods and baseline characteristics

“…Collectively, these factors influence the age of onset of diabetes. 2 The long disease duration puts these young patients at high risk of poor quality of life, multiple morbidities, recurrent hospitalizations and premature mortality, which can be modified by control of risk factors, medications and self-management with ongoing support. [3][4][5][6] In contrast to declining trends of complications and death in older adults with T2D, population-level studies reported stagnation or even resurgence in incidence rates of cardiovascular disease and lower extremity amputation in patients with T2D in the youngest age group.…”

“… 7 Despite this disproportionate burden in young patients with T2D, there is a lack of evidence-based practice guidelines in these patients who were under-represented in most clinical trials. 2 8 9 …”