The prevalence and incidence of young-onset type 2 diabetes is increasing globally, especially in low- and middle-income countries, and predominantly affects non-White ethnic and racial populations. Young-onset type 2 is heterogeneous in terms of the genetic and environmental contributions to its underlying pathophysiology, which poses challenges for glycemic management. Young at-risk individuals remain underrepresented in clinical trials, including diabetes prevention studies, and there is still an insufficient evidence base to inform practice for this age group. Improvements in diabetes care delivery have not reached young people who will progress to have disabling complications at an age when they are most productive. This review summarizes recent studies on the epidemiology of young-onset type 2 diabetes and its complications. We discuss the genetic and environmental risk factors that act in concert to promote glycemic dysregulation and early onset of type 2 diabetes. We provide perspectives on diabetes prevention and management, and propose strategies to address the unique medical and psychosocial issues associated with young-onset type 2 diabetes. The Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes Randomized Controlled Trial (PRISM-RCT) is the first large-scale clinical trial designed to evaluate the effect of a structured care model that integrates biogenetic markers with communication and information technology on attaining strict metabolic targets and improving clinical outcomes in individuals with young-onset type 2 diabetes. The results of this study will inform the scientific community about the impact of multifactorial intervention and precision care in young patients, for whom the legacy effect is particularly significant.

Continuous glucose monitoring (CGM) technology has grown rapidly to track real-time blood glucose levels and trends with improved sensor accuracy. The ease of use and wide availability of CGM will facilitate safe and effective decision making for diabetes management. Here, we developed an attention-based deep learning model, CGMformer, pretrained on a well-controlled and diverse corpus of CGM data to represent individual's intrinsic metabolic state and enable clinical applications. During pretraining, CGMformer encodes glucose dynamics including glucose level, fluctuation, hyperglycemia, and hypoglycemia into latent space with self-supervised learning. It shows generalizability in imputing glucose value across five external datasets with different populations and metabolic states (MAE = 3.7 mg/dL). We then fine-tuned CGMformer towards a diverse panel of downstream tasks in the screening of diabetes and its complications using task-specific data, which demonstrated a consistently boosted predictive accuracy over direct fine-tuning on a single task (AUROC = 0.914 for type 2 diabetes (T2D) screening and 0.741 for complication screening). By learning an intrinsic representation of an individual's glucose dynamics, CGMformer classifies non-diabetic individuals into six clusters with elevated T2D risks, and identifies a specific cluster with lean body-shape but high risk of glucose metabolism disorders, which is overlooked by traditional glucose measurements. Furthermore, CGMformer achieves high accuracy in predicting an individual's postprandial glucose response with dietary modelling (Pearson correlation coefficient = 0.763) and helps personalized dietary recommendations. Overall, CGMformer pretrains a transformer neural network architecture to learn an intrinsic representation by borrowing information from a large amount of daily glucose profiles, and demonstrates predictive capabilities fine-tuned towards a broad range of downstream applications, holding promise for the early warning of T2D and recommendations for lifestyle modification in diabetes management.

Early dipeptidyl peptidase-4 inhibitors and metformin (DPP4i-Met) combination has been shown to extend the time to treatment failure and provide better glycaemic control for newly diagnosed type 2 diabetes (T2D) patients; however, the long-term clinical and economic outcomes of early DPP4i-Met combination remain unknown. We seek to assess the comparative long-term clinical and cost-effectiveness of DPP4i-Met versus Met for treatment-naïve T2D patients with inadequately controlled HbA1c (i.e., ≥8.5%).

The IQVIA CORE Diabetes Model was used to simulate the quality-adjusted life years (QALYs) and healthcare costs over a lifetime from Taiwan's National Health Insurance Administration's perspective, with both QALYs and costs discounted at 3% annually. Model inputs were taken from the analyses of Taiwanese or Asian populations. Primary outcomes included the number needed to treat (NNT) to prevent one case of a clinical event and the incremental cost-effectiveness ratios (ICERs). Costs are presented in 2023 US dollars.

Over 40 years of projection, Met-DPP4i-treated patients had fewer complications than those using Met alone (e.g., lowering the incidence of stroke by 2.21% [2.68, 1.74]). The NNT using DPP4i-Met versus Met alone to prevent one case of stroke, microalbuminuria, neuropathy and background retinopathy was 45, 135, 65 and 182, respectively. Such long-term benefits in reducing costly complications offset the higher treatment cost of DDP4i-Met versus Met ($5796 vs. $5484/person). As a result, using DPP4i-Met versus Met yielded 0.086 QALYs gained and savings of $489 for overall treatment-naïve T2D patients and 0.064 QALYs gained and savings of $714 for young-onset T2D patients.

Early DPP4i-Met provides long-term clinical and economic benefits compared to Met alone for newly diagnosed T2D patients, including those with young-onset T2D.

Type 2 diabetes mellitus (T2DM) is increasingly affecting people aged 15-34, posing a serious public health challenge due to its faster progression and higher complication risks. This study examines the global, regional, and national burden of early-onset T2DM from 1990 to 2021, emphasizing trends and disparities across different sociodemographic contexts.

Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, we analyzed incidence, prevalence, mortality, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) in people aged 15-34. Stratifications included age, sex, and the Socio-Demographic Index (SDI). Joinpoint regression significant temporal shifts, and decomposition analysis attributed changes in T2DM burden to factors such as prevalence, population growth, aging, and case fatality rates. Inequality was assessed with the Slope Index of Inequality and Concentration Index.

From 1990 to 2021, early-onset T2DM incidence and prevalence rose significantly worldwide, especially in high-SDI regions. Although global mortality and DALYs appeared relatively stable, low-SDI regions showed worrisome increases. Rising T2DM prevalence was the principal driver of mortality and DALYs, notably in low- and middle-SDI regions. Inequality analyses indicated widening disparities, with higher incidence and prevalence in high-SDI countries and more severe outcomes in low-SDI countries.

The global burden of early-onset T2DM among youths is escalating, with significant disparities across different sociodemographic levels. The findings underscore the urgent need for targeted public health interventions. Future research should focus on the underlying factors driving these trends and explore strategies for effective prevention and management of early-onset T2DM.

The prevalence of early-onset type 2 diabetes (EOD) is rapidly increasing. This study intends to screen for early cardiovascular abnormalities in patients newly diagnosed with EOD and evaluate the cardiovascular risk across cluster phenotypes.

A total of 400 patients ≤ 40 years old with newly diagnosed type 2 diabetes were enrolled from the START cohort (the Study of The newly diAgnosed eaRly onset diabeTes). Cluster classification was performed using the K-means method based on age, BMI, HbA1c, HOMA2-β, HOMA2-IR, and GAD antibodies. Echocardiography and carotid ultrasound were performed within 3 months of diabetes diagnosis. Carotid ultrasound abnormalities included intimal thickening and plaque formation, while echocardiography assessed changes in cardiac structure and systolic/diastolic function. Cluster-specific partitioned polygenic scores (pPS) were used to validate our findings from a genetic perspective.

Carotid artery abnormalities were detected in 26.3% of patients, and echocardiography abnormalities were observed in 20.0%. Patients with severe insulin resistant diabetes (SIRD) had the highest incidence of carotid artery abnormality (40.0%). After adjusting for relevant risk factors, fasting C-peptide levels were significantly associated with a 1.247-fold increase in the risk of carotid artery abnormalities. Left atrial enlargement was more prevalent in the SIRD (16.7%) and mild obesity-related diabetes (MOD) (18.5%) classifications. A high proportion of patients with SIRD had abnormal left ventricular geometry (36.1%). Increases in BMI, fasting C-peptide level and HOMA2IR were accompanied by a further increase in left atrial enlargement risk by 1.136-, 1.781- and 1.687-fold respectively. The pPS for lipodystrophy was higher in the EOD group with plaque formation, and showed a significant linear correlation with the ratio of the left atrial anteroposterior diameter to body surface area (LAAP/BSA) (R = 0.344, p < 0.001).

Heart and carotid artery abnormalities are common in patients with early-onset T2DM at the time of diagnosis. Patients with obesity and insulin resistance are at higher risk for cardiovascular abnormalities. Cluster classification based on clinical characteristics enables more accurate identification of patients at increased risk of cardiovascular complications at an early stage.

This study investigated the relationship between fibrinogen-to-albumin ratio (FAR) and glucose metabolic state in patients with coronary heart disease (CHD). A total of 52,062 patients were enrolled in this study. Patients were classified according to FAR tertiles (T1: FAR < 0.0073; T2: 0.0073 ≤ FAR ≤ 0.0886; T3: FAR ≥ 0.0887). Patients were also classified into the normal glucose regulation (NGR) and elevated blood glucose (EBG) groups. The relationship between FAR and EBG was analyzed using logistic regression, and the association was evaluated according to sex and age. Among the participants, 32,471 (62.4%) had EBG, which was positively associated with FAR (odds ratio [OR], 1.19; 95% confidence interval [CI] 1.15-1.23). The OR of the FAR for EBG in males was higher than that in females (1.25; 95% CI 1.18-1.33 vs 1.15; 95% CI 1.10-1.20). Moreover, the OR of FAR for EBG was greater in patients aged 60 or younger (OR: 1.25; 95% CI 1.18-1.33) than in the elderly patients (over 60 years of age) (OR: 1.15; 95% CI 1.10-1.20). The results indicated a significant relationship between FAR and EBG and this association was higher in males and middle-aged patients.

This study aimed to understand the influencing factors of diabetes among the cardiovascular high-risk population aged 35-75 in Hainan Province, in order to provide a reference basis for the development of scientific prevention strategies and intervention measures. From January 2016 to February 2023, a random sample of 71,819 residents aged 35-75 in Hainan Province was screened, identifying 12,936 cardiovascular high-risk individuals. All 2,908 diabetic patients were chosen as cases, with a 1:1 age- and gender-matched control group selected from the high-risk pool. Data were organized in Excel and analyzed using SPSS 27.0 for t-tests, chi-square tests, and multi-factorial logistic regression to evaluate lifestyle, dietary habits, blood glucose, and medical history as influencing factors among the high-risk cardiovascular population. BMI (OR = 1.071, 95%CI: 1.053-1.090) and elevated systolic blood pressure (OR = 1.005, 95%CI: 1.002-1.009), a frequency of seafood consumption more than three times per month (OR = 8.098, 95%CI: 7.100-9.237), and an increased ratio of triglycerides to high-density lipoprotein (OR = 1.296, 95%CI: 1.208-1.390) were risk factors for diabetes; whereas high school and below educational level (OR = 0.798, 95%CI: 0.678-0.938), high school above educational level (OR = 0.660, 95%CI: 0.491-0.886), exercise frequency of four or more times per week (OR = 0.621, 95%CI: 0.538-0.716), consumption of fresh vegetables 1-3 times per week (OR = 0.425, 95%CI: 0.283-0.640), and consumption of fresh fruits four or more times per week (OR = 0.743, 95%CI: 0.639-0.865) were protective factors against diabetes. Increased BMI, blood pressure, triglyceride-to-HDL ratio, and frequent seafood consumption were diabetes risks for Hainan's high-risk cardiovascular population. Enhanced screening, follow-up, and promotion of healthy lifestyles, including diet and weight control, were needed to lower disease risks.

This study aimed to evaluate the association between type 2 diabetes mellitus (T2DM) onset age and risk of cardiovascular disease (CVD) and mortality.

Two retrospective cohort studies were conducted using the electronic health records from the United Kingdom (UK) and Hong Kong (HK) on adults without CVD. During 2008-2013, 128,918 and 185,646 patients with new-onset T2DM were assigned to the T2DM group, and 5,052,770 and 3,159,396 patients without T2DM were included as controls in the UK and HK cohort, respectively. Patients were stratified into six age groups. Multivariable Cox regression, adjusted for baseline characteristics and fine stratification weights, was used to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs) for each outcome.

New-onset T2DM was associated with increased CVD and mortality risk, but the risks decreased with age. Compared to those without T2DM in the same age groups, the HR (95 % CI) for CVD in the UK cohort was 3.22 (2.80, 3.71), 1.21 (1.15, 1.26), and 0.99 (0.93, 1.05) for T2DM individuals at ages 18-39, 60-69, and ≥ 80, respectively. Similarly, the HR (95 % CI) for mortality among new-onset T2DM patients was 2.41 (2.06, 2.83) for age 18-39, 1.40 (1.34, 1.46) for age 60-69, and 1.12 (1.08, 1.16) for age ≥ 80. Results from the HK cohort showed a similar pattern.

Young onset of T2DM is associated with a significant impact on cardiovascular health later in life. This highlights the importance of the prevention of DM in young adults.

Preventing cardiovascular disease (CVD) in adults with hypertension is essential, but it remains uncertain whether optimizing modifiable factors can eliminate the excess CVD risk associated with new-onset hypertension.

In this prospective cohort study, 29,597 adults with new-onset hypertension and no prior CVD (from 2006-2016 surveys) were each matched by age and sex to a normotensive control. Eight modifiable factors were assessed using the American Heart Association's Life's Essential 8 algorithm. We followed participants for incident CVD until December 2020, estimating 10-year and lifetime (age 25-95) CVD risks using the Fine-Gray competing risks model.

Over a median follow-up of 9.81 years, adults with new-onset hypertension had higher 10-year (8.97% vs. 6.31%) and lifetime CVD risks (45.55% vs. 34.98%) compared to normotensive controls. After adjusting for age, sex, and other unmodifiable factors, each additional favorable factor was associated with a stepwise reduction in CVD risk (P-trend < 0.05). Hypertensive participants with four or more favorable factors had a 17% lower 10-year CVD risk (HR 0.83; 95% CI 0.72-0.97) and a similar lifetime CVD risk (HR 0.90; 95% CI 0.78-1.05) compared to normotensive controls. Notably, the protective effect was weaker among those with early-onset (before age 45) hypertension than those with later-onset (age ≥ 60) hypertension (P-interaction < 0.05).

In adults with new-onset hypertension, maintaining four or more modifiable factors at favorable levels was associated with a CVD risk comparable to that of normotensive individuals. However, young hypertensive adults may require more aggressive interventions to mitigate CVD risk.

Rising prevalence of Type 2 Diabetes (T2D) among young Asians has emerged as a public health crisis that threatens the long-term health, economic stability, and productivity of nations across Asia (1). Early-onset T2D poses unique challenges, including higher rates of undiagnosed cases, more aggressive disease progression, an increased risk of chronic complications and higher mortality (2). Hyperglycemia during the reproductive age especially among the female population can potentially have transgenerational impact through epigenetic changes.

A comprehensive search was conducted on PubMed with a combination of relevant keywords. A preliminary draft prepared after review of literature was electronically circulated among a panel of 64 experts from various parts of the region and representatives of the participating organizations - Diabetes India (www.diabetesindia.org.in) and the Diabetes Asia Study Group (DASG, www.da-sg.org).

This Ahmedabad Declaration outlines the scale of the problem, its root causes, and a comprehensive action plan for Asian populations. The objectives of this declaration include raising awareness, addressing systemic barriers, and advocating for evidence-based policies and interventions, limited to people with T2D. Through collaborative efforts, we aim to mitigate the growing burden of diabetes in young Asians and secure a healthier future.

Monogenic diabetes is caused by rare mutations in genes usually implicated in beta cell biology. Common variants of monogenic diabetes genes (MDG) may jointly influence the risk of young-onset type 2 diabetes (YOD, diagnosed before the age of 40 years) and cardiovascular and kidney events.

Using whole-exome sequencing data, we constructed a weighted polygenic risk score (wPRS) consisting of 135 common variants (minor allele frequency >0.01) of 34 MDG based on r2>0.2 for linkage disequilibrium in a discovery case-control cohort of 453 adults with YOD (median [IQR] age 39.7 [34.9-46.9] years) and 405 without YOD (median [IQR] age 56.7 [50.3-61.0] years), followed by validation in an independent cross-sectional cohort with array-based genotyping for YOD and a prospective cohort of individuals with type 2 diabetes for cardiovascular and kidney events.

In the discovery cohort, the OR of the 135 common variants for YOD ranged from 1.00 to 2.61. In the validation cohort (920 YOD and 4910 non-YOD), top-10%-wPRS was associated with an OR of 1.42 (95% CI 1.03, 1.95, p=0.033) for YOD compared with bottom-10%-wPRS. In 2313 individuals with type 2 diabetes (median [IQR]: age 53.4 [45.4-61.7] years; disease duration 4.0 [1.0-9.0] years) observed for a median (IQR) of 17.5 (14.4-21.8) years, standardised wPRS was associated with increased HR for incident cardiovascular events (1.16 [95% CI 1.06, 1.27], p=0.001), kidney events (1.09 [95% CI 1.02, 1.16], p=0.013) and cardiovascular-kidney events (1.10 [95% CI 1.03, 1.16], p=0.003). Using the 'bottom-20%-wPRS plus baseline disease duration <5 years' group as referent, the 'top-20%-wPRS plus baseline disease duration 5 to <10 years' group had unadjusted and adjusted HR of 1.60 (95% CI 1.17, 2.19, p=0.003) and 1.62 (95% CI 1.16, 2.26, p=0.005), respectively, for cardiovascular-kidney events compared with 1.38 (95% CI 0.97, 1.98, p=0.075) and 1.06 (95% CI 0.72, 1.57, p=0.752) in the 'bottom-20%-wPRS plus baseline disease duration ≥10 years' group.

Common variants of MDG increased risk for YOD and cardiovascular-kidney events.

To investigate the association of diabetes duration with cardiovascular disease (CVD) risk and to examine the relationship between lipid levels and CVD risk over the duration.

Using the Korean National Health Insurance Service Cohort database, we identified 2 359 243 subjects with type 2 diabetes aged ≥ 20 years in 2015 to 2016. Baseline lipid levels and diabetes duration were evaluated and followed up until December 2020 (mean follow-up, 3.9 years). Subjects were categorized according to diabetes duration (new-onset, < 5 years, 5-9 years, or ≥ 10 years). We analyzed the new-onset diabetes group with low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL as the reference group. The hazard ratios (HRs) and 95% CIs of myocardial infarction (MI) and ischemic stroke (IS) were estimated using a Cox proportional hazards model adjusted for potential confounders.

During follow-up, 45 883 cases of MI and 53 538 cases of IS were identified. The risk of MI or IS began to increase at LDL-C ≥ 160 mg/dL in the new-onset diabetes group, and at LDL-C ≥ 130 mg/dL in the group with diabetes duration < 5 years. Among subjects with diabetes duration of 5 to 9 years, LDL-C levels of 100-129 mg/dL, 130-159 mg/dL, and ≥ 160 mg/dL were significantly associated with the risk of MI (HR [95% CI] 1.13 [1.04-1.22], 1.28 [1.17-1.39], and 1.58 [1.42-1.76], respectively). MI risk in the diabetes duration ≥ 10 years group was increased by 16%, even in the LDL-C 70-99 mg/dL population (HR [95% CI] 1.16 [1.08-1.25]).

This population-based longitudinal study revealed that the LDL-C cutoff level for increasing the risk of CVD varied with diabetes duration and that the target LDL-C level should depend on the duration.

To investigate the relationship between age at diagnosis of type 2 diabetes and the risk of macrovascular disease, heart failure, and microvascular disease.

In August 2022, PubMed/EMBASE were searched for articles reporting (i) coronary artery disease, cerebrovascular disease, peripheral vascular disease, amputation; (ii) heart failure; and (iii) retinopathy, neuropathy, nephropathy (albuminuria, chronic kidney disease [CKD], end-stage renal disease) by age at diagnosis of type 2 diabetes. Random effects, non-linear dose-response meta-analysis was undertaken for each outcome to assess the association with age at diagnosis (40 years = reference), using both crude and maximally adjusted odds ratios separately, with and without adjustment for current age (age at sampling).

We identified 42 articles (230,003 to 3,465,590 participants; 1035 to 391,140 events). Age at diagnosis was positively associated with the risk of macrovascular diseases, heart failure, and CKD, independent of current age, and negatively associated with retinopathy. For other microvascular outcomes, when adjusting for current age, a "reverse U" relationship was observed (peak risk = 55-60 years).

Retinopathy was negatively associated with age at diagnosis, highlighting the importance of retinopathy screening in early-onset type 2 diabetes. The implications of other associations were unclear due to the heterogeneity in methodologies and findings.

The time course of chronic kidney disease in young-onset type 2 diabetes mellitus remains unclear. We compared the trajectories of proteinuria and estimated glomerular filtration rate (eGFR) decline between young-onset (aged ≤40 years) and late-onset (aged >40 years) type 2 diabetes mellitus in a Japanese multicenter cohort.

Participants without diabetic kidney disease were divided into two groups according to age at diagnosis: young- and late-onset. The primary endpoint was eGFR <60 mL/min/1.73 m2, proteinuria or both. Multivariable Cox proportional hazards were calculated to estimate incidence.

Among 626 participants with type 2 diabetes mellitus, 78 (12.4%) had young-onset and 548 (87.6%) had late-onset diabetes. The incidence of eGFR <60 mL/min/1.73 m2 was lower (16.7% vs 33.5%, P = 0.003), but that of proteinuria was higher (46.2% vs 28.9%, P = 0.002) in the young-onset type 2 diabetes mellitus group. The Kaplan-Meyer curve showed that young-onset type 2 diabetes mellitus was associated with a decreased hazard ratio (HR) for eGFR <60 mL/min/1.73 m2 and an increased HR for proteinuria compared with late-onset type 2 diabetes mellitus. In the multivariate Cox analysis, young-onset type 2 diabetes mellitus increased the HR (95% confidence interval) of proteinuria (1.53, 95% confidence interval 1.03-2.26), but did not change the eGFR <60 mL/min/1.73 m2 HR.

Young-onset type 2 diabetes mellitus has a lower HR of eGFR <60 mL/min/1.73 m2 and an increased HR of proteinuria compared with late-onset type 2 diabetes mellitus, indicating that young-onset type 2 diabetes mellitus has a different time course for the development of proteinuria and subsequent eGFR decline.

It is unclear whether type 2 diabetes diagnosed in young adulthood is associated with increased severity than that occurring later in life beyond longer lifetime exposure to hyperglycemia. This study aimed at assessing the independent association of age at type 2 diabetes diagnosis with all-cause mortality.

This prospective cohort study enrolled 15,773 Caucasian patients with type 2 diabetes in 19 Italian centers in 2006-2008. Cardiometabolic risk profile and presence of complications and comorbidities were assessed at baseline and participants were stratified by quartiles of age at diabetes diagnosis. All-cause mortality was verified on 31 October 2015.

Valid information on vital status was retrieved for 15,656 participants (99.3%). Patients in the lowest quartile had the longest diabetes duration, the worst glycemic control and the highest prevalence of insulin treatment, obesity, atherogenic dyslipidemia, and smoking habits. All complications were inversely associated with age at diabetes diagnosis after adjustment for age and sex, but not after further adjustment for diabetes duration. Percentages of death, Kaplan-Meier estimates, and unadjusted hazard ratios and mortality rates increased from the lowest to the highest quartile. In contrast, when adjusting for age and sex, participants falling in the lowest quartile, showed the highest mortality risk [hazard ratio 1.321 (95% confidence interval 1.196-1.460), P < 0.0001]. However, differences among quartiles disappeared after adjustment for diabetes duration, complications/comorbidities, or other cardiovascular risk factors.

Type 2 diabetes onset in young adulthood is associated with increased mortality that is mainly driven by longer diabetes duration favoring the development of complications.

ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

To examine the impact of current age, age at diagnosis, and duration of diabetes on the incidence rate of complications among people with type 2 diabetes.

Baseline data from 19,327 individuals with type 2 diabetes in the UK Biobank were analysed. Poisson regression was used to model incidence rates by current age, age at diagnosis, and duration of diabetes for the following outcomes: myocardial infarction (MI), heart failure (HF), stroke, end-stage kidney diseases (ESKD), chronic kidney diseases (CKD), liver diseases, depression, and anxiety.

The mean age at baseline was 60.2 years, and median follow-up was 13.9 years. Diabetes duration was significantly longer among those with younger-onset type 2 diabetes (diagnosed at <40 years) compared to later-onset type 2 diabetes (diagnosed at ≥40 years), 16.2 and 5.3 years, respectively. Incidence rates of MI, HF, stroke, and CKD had strong positive associations with age and duration of diabetes, whereas incidence rates of ESKD liver diseases, and anxiety mainly depended on duration of diabetes. The incidence rates of depression showed minor variation by age and duration of diabetes and were highest among those diagnosed at earlier ages. No clear evidence of an effect of age of onset of diabetes on risk of complications was apparent after accounting for current age and duration of diabetes.

Our study indicates age at diagnosis of diabetes does not significantly impact the incidence of complications, independently of the duration of diabetes. Instead, complications are primarily influenced by current age and diabetes duration.

The key aim of diabetes management is to prevent complications, which are a major cause of morbidity and mortality. At an individual level, people with diabetes are less likely than they were several decades ago to experience classical macrovascular and microvascular complications as a result of improvements in modifiable cardiovascular risk factors and preventive healthcare. However, a significant burden of diabetes complications persists at a population level because of the increasing incidence of diabetes, as well as longer lifetime exposure to diabetes because of younger diagnosis and increased life expectancy. Trials have shown that the most effective strategy for preventing complications of diabetes is a multifactorial approach focussing simultaneously on the management of diet, exercise, glucose levels, blood pressure and lipids. In addition to the cornerstone strategies of addressing diet, exercise and lifestyle measures, the introduction of newer glucose-lowering agents, including sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 agonists, have brought about a paradigm shift in preventing the onset and progression of complications of type 2 diabetes, particularly cardiovascular and renal disease. The improvement in rates of classical complications of diabetes over time has been accompanied by a growing awareness of non-traditional complications, including non-alcoholic fatty liver disease. These emerging complications may not respond to a glycaemic-centred approach alone and highlight the importance of foundational strategies centred on lifestyle measures and supported by pharmaceutical therapy to achieve weight loss and reduce metabolic risk in patients living with diabetes.

We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines.

In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications.

In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes.

Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events.

NCT04049149.

Over the past 20 years, the incidence and prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents have increased, particularly in racial and ethnic minorities. Despite the rise in T2DM in children and adolescents, the pathophysiology and progression of disease in this population are not clearly understood. Youth-onset T2DM has a more adverse clinical course than is seen in those who develop T2DM in adulthood or those with T1DM. Furthermore, the available therapeutic options are more limited for children and adolescents with T2DM compared to adult patients, mostly due to the challenges of implementing clinical trials. A better understanding of the mechanisms underlying the de-velopment and aggressive disease phenotype of T2DM in youth is important to finding effective prevention and management strategies. This review highlights the key evidence about T2DM in children and adolescents and its current burden and challenges both in clinical care and research activities.

Precision diagnosis is the keystone of clinical medicine. In East Asians, classical type 1 diabetes is uncommon in patients with youngonset diabetes diagnosed before age of 40, in whom a family history, obesity, and beta-cell and kidney dysfunction are key features. Young-onset diabetes affects one in five Asian adults with diabetes in clinic settings; however, it is often misclassified, resulting in delayed or non-targeted treatment. Complex aetiologies, long disease duration, aggressive clinical course, and a lack of evidence-based guidelines have contributed to variable care standards and premature death in these young patients. The high burden of comorbidities, notably mental illness, highlights the numerous knowledge gaps related to this silent killer. The majority of adult patients with youngonset diabetes are managed as part of a heterogeneous population of patients with various ages of diagnosis. A multidisciplinary care team led by physicians with special interest in young-onset diabetes will help improve the precision of diagnosis and address their physical, mental, and behavioral health. To this end, payors, planners, and providers need to align and re-design the practice environment to gather data systematically during routine practice to elucidate the multicausality of young-onset diabetes, treat to multiple targets, and improve outcomes in these vulnerable individuals.

The incidence rates of type 2 diabetes among adults in Asia have been stable, but the rates in youth and young adults have increased. In territory-wide surveillance in Hong Kong, Special Administrative Region of People's Republic of China, all-cause mortality rates among people with diabetes have exhibited a declining trend in the past 15 years, with a narrowing in the mortality gap between people with and without diabetes. At the same time, the improvement in survival resulted in a changing age structure and disease profile of people with diabetes, towards an increasing proportion of older people with long diabetes duration and multi-morbidities. Reductions in event rates were not observed in the youngest age group who also had the least gains in risk factor control and uptake in organ protective drugs over time. A young age at diabetes diagnosis, associated with exposure to high glycemic burden from an early age, predicted higher risks of complications and premature mortality compared with later-onset of diabetes. People presenting with type 2 diabetes below 40 years of age were 5-fold more likely to die and their life expectancy was shortened by 8 years than age-matched counterparts without diabetes. Analysis of population-based data in Hong Kong Chinese identified hypertension followed by chronic kidney disease as the leading contributor to mortality in young people, indicating that efforts to optimize non-glycemic risk factors and organ protection are as important in young individuals as it is in the older population.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide, the global burden of which is rising. It is still unclear the extent to which prediabetes contributes to the risk of CVD in various age brackets among adults. To develop a focused screening plan and treatment for Chinese adults with prediabetes, it is crucial to identify variations in the connection between prediabetes and the risk of CVD based on age.

To examine the clinical features of prediabetes and identify risk factors for CVD in different age groups in China.

The cross-sectional study involved a total of 46239 participants from June 2007 through May 2008. A thorough evaluation was conducted. Individuals with prediabetes were categorized into two groups based on age. Chinese atherosclerotic CVD risk prediction model was employed to evaluate the risk of developing CVD over 10 years. Random forest was established in both age groups. SHapley Additive exPlanation method prioritized the importance of features from the perspective of assessment contribution.

In total, 6948 people were diagnosed with prediabetes in this study. In pre-diabetes, prevalences of CVD were 5 (0.29%) in the younger group and 148 (2.85%) in the older group. Overall, 11.11% of the younger group and 29.59% of the older group were intermediate/high-risk of CVD for prediabetes without CVD based on the Prediction for ASCVD Risk in China equation in ten years. In the younger age group, the 10-year risk of CVD was found to be more closely linked to family history of CVD rather than lifestyle, whereas in the older age group, resident status was more closely linked.

The susceptibility to CVD is age-specific in newly diagnosed prediabetes. It is necessary to develop targeted approaches for the prevention and management of CVD in adults across various age brackets.

This study investigated the effects of early-onset type 2 diabetes (EOD) vs late-onset type 2 diabetes (LOD) on nonfatal cardiovascular diseases (CVD) in China.

We conducted a cross-sectional survey of 46 239 participants from 14 provinces in China from 2007 to 2008, selecting 4949 participants with type 2 diabetes for analysis. Participants were categorized as EOD (<40 years) or LOD (≥40 years) based on age at diabetes diagnosis. Sociodemographic and nonfatal CVD information was collected through an interviewer-assisted questionnaire and clinical examination. Logistic regression analysis was used to investigate the nonfatal CVD risk.

Out of 4949 participants with type 2 diabetes, 390 (7.88%) had nonfatal CVD. Participants with EOD had a higher age-standardized prevalence of nonfatal CVD than those with LOD (11.4% vs 4.4%). Compared to LOD patients, EOD patients tended to be males and had a higher family history of diabetes, unhealthy lifestyle behaviors, and lower blood pressure levels. After adjustment for age and sex, EOD patients had a higher risk of nonfatal CVD than LOD patients (odds ratio [OR] 2.3, 95% CI 1.5-3.5). After further adjustment for diabetes duration, use of drugs, and other risk factors, the OR of nonfatal CVD was reduced but significant (OR 1.8, 95% CI 1.1-2.9). Sensitivity analysis revealed that EOD patients with metabolic syndrome had an increased nonfatal CVD risk compared to LOD patients (OR 2.0, 95% CI 1.2-3.5).

EOD patients are at increased risk of nonfatal CVD. Individualized intervention and management measures for EOD patients are necessary.

Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with Type 2 diabetes (T2D).

We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies.

Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort.

Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

High cardiovascular mortality has been reported in young patients with diabetes. However, the underlying pathology in different age groups of patients with diabetes has not been studied.

The aim of this study was to investigate the plaque characteristics and underlying pathology of acute coronary syndrome in different age groups of patients with or without diabetes in a large cohort. Patients who presented with acute coronary syndrome and underwent preintervention optical coherence tomography imaging were included. Culprit plaque was classified as plaque rupture, plaque erosion, or calcified plaque and stratified into 5 age groups. Plaque characteristics including features of vulnerability were examined by optical coherence tomography. Among 1394 patients, 482 (34.6%) had diabetes. Patients with diabetes, compared with patients without diabetes, had a higher prevalence of lipid-rich plaque (71.2% versus 64.8%, P=0.016), macrophage (72.0% versus 62.6%, P<0.001), and cholesterol crystal (27.6% versus 19.7%, P<0.001). Both diabetes and nondiabetes groups showed a decreasing trend in plaque erosion with age (patients with diabetes, P=0.020; patients without diabetes, P<0.001). Patients without diabetes showed an increasing trend with age in plaque rupture (P=0.004) and lipid-rich plaque (P=0.018), whereas patients with diabetes had a high prevalence of these vulnerable features at an early age that remained high across age groups.

Patients without diabetes showed an increasing trend with age in plaque rupture and lipid-rich plaque, whereas patients with diabetes had a high prevalence of these vulnerable features at an early age. These results suggest that atherosclerotic vascular changes with increased vulnerability start at a younger age in patients with diabetes.

URL: https://www.clinicaltrials.gov; Unique identifiers: NCT04523194, NCT03479723. URL: https://www.umin.ac.jp/ctr/. Unique identifier: UMIN000041692.

To examine the associations between age at type 2 diabetes diagnosis and the relative and absolute risk of all-cause and cause-specific mortality in England.

In this cohort study using primary care data from the Clinical Practice Research Datalink, we identified 108,061 individuals with newly diagnosed type 2 diabetes (16-50 years of age), matched to 829,946 individuals without type 2 diabetes. We estimated all-cause and cause-specific mortality (cancer, cardiorenal, other [noncancer or cardiorenal]) by age at diagnosis, using competing-risk survival analyses adjusted for key confounders.

Comparing individuals with versus without type 2 diabetes, the relative risk of death decreased with an older age at diagnosis: the hazard ratio for all-cause mortality was 4.32 (95% CI 3.35-5.58) in individuals diagnosed at ages 16-27 years compared with 1.53 (95% CI 1.46-1.60) at ages 48-50 years. Smaller relative risks by increasing age at diagnosis were also observed for cancer, cardiorenal, and noncancer or cardiorenal death. Irrespective of age at diagnosis, the 10-year absolute risk of all-cause and cause-specific mortality were higher in individuals with type 2 diabetes; yet, the absolute differences were small.

Although the relative risk of death in individuals with versus without type 2 was higher at younger ages, the 10-year absolute risk of all investigated causes of death was small and similar in the two groups. Further multidecade studies could help estimate the long-term risk of complications and death in individuals with early-onset type 2 diabetes.

Type 2 diabetes diagnosed in childhood or early adulthood is termed early-onset type 2 diabetes. Cases of early-onset type 2 diabetes are increasing rapidly globally, alongside rising obesity. Compared with a diagnosis later in life, an earlier-onset diagnosis carries an unexplained excess risk of microvascular complications, adverse cardiovascular outcomes, and earlier death. Women with early-onset type 2 diabetes also have a higher risk of adverse pregnancy outcomes. The high burden of complications renders individuals with early-onset type 2 diabetes at future risk of multimorbidity and interventions to reverse these concerning trends should be a priority. Within the early-onset cohort, disease pathophysiology and interventions have been better studied in paediatric-onset (<19 years) type 2 diabetes compared to adults; however, young adults aged 19-39 years (a larger number proportionally) are not well characterised and are also invisible in the current evidence base supporting management, which is derived from trials in later-onset type 2 diabetes. Young adults with type 2 diabetes face challenges in self-management that older individuals are less likely to experience (being in education or of working age, higher diabetes distress, and possible obesity-related stigma and diabetes-related stigma). There is a major research gap as to the optimal strategies to deploy in managing type 2 diabetes in adolescents and young adults, given that current models of care appear to not work as well in this age group. In the face of manifold risk factors (obesity, female sex, social deprivation, non-White European ethnicity, and genetic risk factors) prevention strategies with tailored lifestyle interventions, where needed, are likely to have greater success, but more evidence is needed. In this Review, we draw on evidence from both adolescents and young adults to provide a contemporary update on the current insights and emerging trends in early-onset type 2 diabetes.

We examined ethnic differences in the association between age at diagnosis of diabetes and the risk of cardiovascular complications.

We conducted a population-based cohort study in Ontario, Canada among individuals with diabetes and matched individuals without diabetes (2002-18). We fit Cox proportional hazards models to determine the associations of age at diagnosis and ethnicity (Chinese, South Asian, general population) with cardiovascular complications. We tested for an interaction between age at diagnosis and ethnicity.

There were 453,433 individuals with diabetes (49.7% women) and 453,433 matches. There was a significant interaction between age at diagnosis and ethnicity (P < 0.0001). Young-onset diabetes (age at diagnosis < 40) was associated with higher cardiovascular risk [hazard ratios: Chinese 4.25 (3.05-5.91), South Asian: 3.82 (3.19-4.57), General: 3.46 (3.26-3.66)] than usual-onset diabetes [age at diagnosis ≥ 40 years; Chinese: 2.22 (2.04-2.66), South Asian: 2.43 (2.22-2.66), General: 1.83 (1.81-1.86)] versus ethnicity-matched individuals. Among those with young-onset diabetes, Chinese ethnicity was associated with lower overall cardiovascular [0.44 (0.32-0.61)] but similar stroke risks versus the general population; while South Asian ethnicity was associated with lower overall cardiovascular [0.75 (0.64-0.89)] but similar coronary artery disease risks versus the general population. In usual-onset diabetes, Chinese ethnicity was associated with lower cardiovascular risk [0.44 (0.42-0.46)], while South Asian ethnicity was associated with lower cardiovascular [0.90 (0.86-0.95)] and higher coronary artery disease [1.08 (1.01-1.15)] risks versus the general population.

There are important ethnic differences in the association between age at diagnosis and risk of cardiovascular complications.

Background Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with type 2 diabetes (T2D). Methods We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies. Results Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort. Conclusions Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

We investigated the risk of developing chronic kidney disease (CKD) in patients with young-onset Type 2 diabetes (YOD, diagnosed age < 40 years). We enrolled 84,384 patients aged 20-64 who started anti-diabetic medication between 2010 and 2011 from the Korea National Health Insurance Sharing Service; patients with Type 1 diabetes or a history of CKD were excluded. Multivariate logistic regression analyses were performed to adjust for YOD-distinct variables and compare the incidence of CKD between YOD and late-onset diabetes (LOD, diagnosed age ≥ 40 years). During the median observation period of 5.16 years (interquartile range: 4.58-5.77 years), 1480 out of 77,039 LOD patients and 34 out of 7345 YOD patients developed CKD. Patients with YOD had distinct baseline characteristics compared with the patients with LOD. The odds ratio of developing CKD in patients with YOD over LOD was 1.70 (95% CI 1.15-2.51) after adjusting clinically distinct variables. The increased CKD odds in YOD compared with LOD was greater in the non-smoking group (OR 2.03, 95% CI 1.26-3.26) than in the smoking group (OR 1.49, 95% CI 0.74-2.98, p = 0.0393 for interaction). Among YOD patients, hypertension (34.76% vs. 64.71%, p = 0.0003), dyslipidemia (46.87% vs. 73.53%, p = 0.0019), and sulfonylurea use (35.54% vs. 52.94%, p = 0.0345) were associated with CKD development. YOD patients have a greater risk of developing CKD than LOD patients after adjusting clinically distinct variables.

To ascertain the risk of progression to diabetes among Chinese women with PCOS.

Women with PCOS (n = 3978) were identified from the Hong Kong Diabetes Surveillance Database based on the ICD-9 code for PCOS diagnosis and women without PCOS served as controls (n = 39780), matched 1:10 by age.

The mean follow-up was 6.28 ± 4.20 and 6.95 ± 4.33 years in women with PCOS and controls, respectively. The crude incidence rate of diabetes was 14.25/1000 person-years in women with PCOS compared with 3.45 in controls. The crude hazard ratio of diabetes in women with PCOS was 4.23 (95 % CI: 3.73-4.80, p < 0.001). Further stratified by age group, the risk of developing diabetes decreased with increasing age but it remained significantly higher in women with PCOS across all age groups. It also suggested that the incidence rate of diabetes in women with PCOS aged 20-29 is highly comparable to that in healthy women aged ≥ 40. More than half of the incident diabetes captured during the follow-up in women with PCOS cohort were young-onset diabetes.

Women diagnosed with PCOS at a younger age have the highest relative risk of developing diabetes, suggesting frequent glycemic status screening is required to detect diabetes at an early stage.

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined. While methylation is known to alter gene expression, the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n = 39) that was subsequently replicated in a larger validation cohort (n = 296). Gene body-related regions made up more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, lipid metabolism, and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.