Young‐onset type 2 diabetes—Epidemiology, pathophysiology, and management

ABSTRACT

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.

The burden of young‐onset type 2 diabetes is increasing globally, disproportionately affecting non‐White ethnic groups and low‐ and middle‐income countries. Young‐onset type 2 is more heterogeneous regarding the genetic and environmental contributions to its underlying pathophysiology, which poses challenges for glycemic management. This review summarizes recent studies on the epidemiology of young‐onset type 2 diabetes and its complications, discusses the genetic and environmental risk factors, and provides insights on diabetes prevention and management to address the unique medical and psychosocial issues associated with young‐onset type 2 diabetes.

INTRODUCTION

Research on the pathophysiology, complications, and management of young‐onset type 2 diabetes has accelerated in the past decade due to increasing prevalence and incidence observed in many parts of the world, and a growing recognition of the more adverse prognosis compared with later‐onset type 2 diabetes. The COVID‐19 pandemic has highlighted the vulnerability of young individuals with type 2 diabetes, who were less likely to survive than age‐matched peers without diabetes. Large epidemiological studies have shown that type 2 diabetes conferred significantly greater risks of severe manifestations with COVID‐19 in younger individuals than older ones ¹ , ² . Management of type 2 diabetes arising in children and young individuals presents many challenges, as disease etiology and pathophysiology are more heterogeneous in this population. Additional factors including obesity, inadequate uptake of organ‐protective drugs, low adherence to diabetes self‐care, psychosocial barriers, and reproductive concerns add to the complexity in care and contribute to the overall risks. Most of the published literature defined young‐onset type 2 diabetes as diagnosis made before the age of 40 and youth‐onset diabetes as diagnosis made before the age of 20, although these cutoffs are largely arbitrary with minor variations across studies ³ .

In this review, we summarize recent studies on the incidence and prevalence of young‐onset type 2 diabetes and its related complications, including emerging complications. We highlight the differences in the pathophysiology underlying type 2 diabetes between younger and older individuals and explore the roles of genetic factors, environmental influences, and their interaction toward the early development of glycemic dysregulation. We provide perspectives on diabetes management and propose strategies to address the unique medical and psychosocial issues inherent in young‐onset type 2 diabetes.

PREVALENCE OF YOUNG‐ONSET TYPE 2 DIABETES

According to the International Diabetes Federation Atlas, the global prevalence of type 2 diabetes among individuals aged 20–39 years increased by 30%, from 2.9% (63 million people) in 2013 to 3.8% (260 million) in 2021 ⁴ . This rise has been observed in nearly all regions, with the largest relative increase occurring in the Middle East and North Africa region (from 4.0% to 8.0%), while Europe had the smallest increase ⁴ , ⁵ , ⁶ . In the SEARCH for Diabetes in Youth study, which is an observational, cross‐sectional, multicenter study of approximately 3.5 million youths across regions in the United States (US), the prevalence of physician‐diagnosed type 2 diabetes in those aged 10–19 doubled over 16 years, from 0.34 per 1,000 in 2001 to 0.46 per 1,000 in 2009, and further to 0.67 per 1,000 by 2017 ⁷ . In British Columbia, Canada, the prevalence of type 2 diabetes in youth under 20 years of age increased from 0.09 per 1,000 in 2002 to 0.21 per 1,000 in 2013, representing a 2.3‐fold increase over 10 years ⁸ . A hospital‐based study in China showed that the prevalence of type 2 diabetes in individuals younger than 18 years more than doubled, rising from 0.04 per 1,000 in 1995 to 0.10 per 1,000 in 2010 ⁹ . In a study of people enrolled in the National Health Insurance Service program in Korea, the prevalence of type 2 diabetes among young individuals under 29 years of age increased more than 4.4‐fold, rising from 0.26 per 1,000 to 1.14 per 1,000 in boys/men and from 0.20 per 1,000 to 0.86 per 1,000 in girls/women between 2002 and 2016 ¹⁰ .

Young‐onset type 2 diabetes disproportionately affects ethnic minorities, including Native American, First Nations, Indigenous Australian, and Pacific Islander populations ¹¹ . In Manitoba, Canada, the prevalence of youth‐onset type 2 diabetes among First Nations children was 14 times higher than that of all children in the province ¹² . In Australia, Indigenous youth were estimated to be six times more likely to have type 2 diabetes than their non‐Indigenous counterparts ¹³ . In multi‐ethnic countries such as the US and the United Kingdom (UK), ethnic and racial disparities in young‐onset type 2 diabetes are evident. In the SEARCH study, the prevalence of type 2 diabetes in 2017 was highest among Black (1.8 per 1,000) and American Indian (1.6 per 1,000) populations, compared to White (0.2 per 1,000) and Asian or Pacific Islander populations (0.59 per 1,000) ⁷ . The National Paediatric Diabetes Audit for 2012–2013 in England and Wales indicated that among children aged under 19, the highest prevalence of type 2 diabetes was found in Asian (8.0 per 100,000) and mixed ethnic groups, while White children had the lowest prevalence (1.4 per 100,000) ¹⁴ .

INCIDENCE OF YOUNG‐ONSET TYPE 2 DIABETES

The incidence of type 2 diabetes largely reflects the trends in prevalence. Data from the Global Burden of Disease showed that the age‐standardized incidence of type 2 diabetes in individuals aged 15–39 increased by 56%, from 117 per 100,000 in 1990 to 183 per 100,000 in 2019 worldwide ¹⁵ . The highest incidence rates were observed regionally in Oceania, South Asia, and North Africa and the Middle East, while the fastest increases were noted in Western Europe and Southern Latin America, and North Africa and the Middle East ¹⁵ .

In the SEARCH study, the incidence of type 2 diabetes in youth aged 10–19 increased steadily from 9.0 per 100,000 in 2002 to 17.9 per 100,000 in 2018, corresponding to an annual rise of 5.3% ¹⁶ . The largest increases were among Asian/Pacific Islander, Hispanic, and Non‐Hispanic Black youths, while non‐Hispanic Black and American Indian youths had the highest absolute incidence. In the National Health Interview Survey (NHIS) of the noninstitutionalized US civilian population conducted between 2016 and 2022, the incidence of diagnosed type 2 diabetes in adults aged 18–44 was 3.0 per 1,000, disproportionately affecting minority and socioeconomically disadvantaged groups ¹⁷ . A multicountry study of eight administrative datasets from high‐income jurisdictions reported that the incidence of type 2 diabetes among those aged 15–39 increased in four jurisdictions (Denmark, Finland, Japan, and South Korea), but remained stable in Australia and Hungary, and decreased in Scotland and Spain from 2000 to 2020 ¹⁸ .

There is a notable discordance in incidence trends by age. In contrast to the rising trend of young‐onset type 2 diabetes, the incidence of type 2 diabetes in middle‐aged and older adults has plateaued or even declined. A systematic review found that more than 60% of studies reported a stable or decreasing trend in the incidence of diagnosed diabetes among people over 40 between 2006 and 2014 ¹⁹ . A multicountry analysis of 23 data sources from high‐income and middle‐income regions showed that 19 (83%) reported a downward or stable trend in diabetes incidence after 2010 ²⁰ . The NHIS study in the United States reported an annual increase of 3.2% in diabetes incidence in young people aged 20–44, while the incidence remained stable in those aged 45–64 between 2002 and 2012 ²¹ . In Hong Kong, the incidence of type 2 diabetes rose by 4.2% annually in men and by 3.3% in women aged 20–39 years from 2005 to 2015, while it remained stable in both sexes aged 60 and older ²² . In Bavaria, Germany, the incidence of type 2 diabetes was stable in individuals younger than 50 years but declined in those older than 50 years between 2012 and 2021 ²³ .

RISK FACTORS FOR YOUNG‐ONSET TYPE 2 DIABETES

Obesity

Obesity is a significant contributing factor for young‐onset type 2 diabetes. Between 85% and 90% of youths diagnosed with type 2 diabetes have obesity at the time of diagnosis ²⁴ . The rise of young‐onset type 2 diabetes closely mirrors trends in childhood overweight and obesity. Although the prevalence of obesity has plateaued at high levels in high‐income countries in recent years, it continues to rise in many low‐ and middle‐income countries, with the most noticeable increases observed among adolescents and young adults ²⁵ , ²⁶ . The stabilization of obesity prevalence in high‐income countries appears to concur with the stabilization or even decline in young‐onset type 2 diabetes in some of these countries, suggesting a potential link between these trends ¹⁸ . In certain populations, there are encouraging signs that if obesity levels stabilize, diabetes incidence may also plateau. For instance, the slowing increase in type 2 diabetes incidence in Hispanic youth in the 2010s coincided with evidence that childhood obesity rates in this group plateaued during the same period ¹⁶ , ²⁷ .

Observational and interventional studies have demonstrated the effectiveness of weight reduction in improving insulin sensitivity and preventing type 2 diabetes in young individuals with obesity ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ . In a cohort study of the Swedish Childhood Obesity Treatment Register, which followed children and adolescents for over 8 years, a decrease in BMI z‐score of more than 0.25 was associated with a 77% reduction in the risk of young‐onset type 2 diabetes ³⁰ . Other studies have suggested that the risk of young‐onset type 2 diabetes, along with other metabolic risks, among individuals with childhood obesity could be significantly attenuated if the excess body weight is addressed earlier on in life ³¹ , ³³ , ³⁴ , ³⁵ . However, the continuity of obesity from childhood into adolescence (55%) and further into early adulthood (80%) is common ³⁶ .

Dietary factors

Ample evidence has linked the intake of sugar‐sweetened beverages (SSB) to an increased risk of cardiometabolic diseases, partly mediated by weight gain ³⁷ . A global study using the Global Dietary Database, which includes data from 185 countries, found that young people have the highest SSB consumption across all regions ³⁸ , ³⁹ . In 2020, 2.2 million (9.8%) cases of incident type 2 diabetes globally were attributed to SSB intake, with the highest proportional risk attributed to SSB intake (15%) among individuals aged 20–34 ⁴⁰ . Furthermore, the transition to a Westernized diet—characterized by high consumption of refined carbohydrates, added sugars, animal‐source foods, and processed foods, along with a reduced vegetable intake—in low‐ to middle‐income countries undergoing rapid economic development and increased global trade has placed these populations in a vulnerable position amidst the obesity epidemic ³⁷ , ⁴¹ , ⁴² . As individuals with young‐onset type 2 diabetes are more likely to have genetic susceptibility, there could be positive interactions between dietary patterns and genetic composition that amplify the risk of obesity and diabetes ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ . A taxation approach aimed at encouraging the population to adopt healthier dietary patterns has been implemented in some nations, but its long‐term effectiveness is yet to be observed ³⁸ , ⁵⁰ .

Maternal diabetes, obesity, and overnutrition

While the majority of individuals with young‐onset type 2 diabetes have a positive family history of diabetes, the overrepresentation of maternal history cannot be solely explained by shared genetics and environmental factors in later life ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ . The SEARCH study showed that maternal diabetes and maternal obesity independently increased the odds of youth‐onset type 2 diabetes in offspring by 5.7 and 2.8 times, respectively. Youths with type 2 diabetes were diagnosed 1.7 years earlier in those exposed to diabetes in utero than those with a maternal history of diabetes but no in utero exposure ⁵⁵ . In the TODAY cohort of youths with type 2 diabetes, maternal diabetes exerted a larger effect on glycemic deterioration and beta‐cell dysfunction than paternal diabetes ⁵³ . In the hyperglycemia and adverse pregnancy outcome follow‐up study, maternal glycemic indices were positively correlated with offspring's glycemic indices, and negatively correlated with the offspring's beta‐cell function and insulin sensitivity ⁵² . Another study in the UK revealed that offspring of mothers with young‐onset type 2 diabetes had lower beta‐cell function but similar insulin sensitivity compared to the offspring of fathers with young‐onset type 2 diabetes ⁵⁶ .

Maternal overnutrition during pregnancy may affect the metabolic risk profile of offspring. A diet high in glycemic load may increase the risk of macrosomia, large‐for‐gestational‐age, and insulin resistance in offspring, which are linked to the development of type 2 diabetes ⁵⁷ , ⁵⁸ , ⁵⁹ . Two randomized controlled trials found that a low‐glycemic load diet reduces the risk of macrosomia by half in women with gestational diabetes ⁵⁷ .

Maternal undernutrition

Undernutrition and gestational morbidities can lead to restricted fetal growth, as reflected by low birthweight. While undernutrition is more prevalent in low‐ to middle‐income countries, it may also affect women in high‐income areas. Popular vegetarian diets low in protein have been linked to lower birthweights in offspring ⁴² , ⁶⁰ . Previous meta‐analyses have reported an association between low birthweight or small‐for‐gestational‐age and type 2 diabetes, including young‐onset diabetes ⁶¹ , ⁶² . Two Chinese studies found that catch‐up growth in infants who are small‐for‐gestational‐age may lead to insulin resistance in childhood ⁶³ , ⁶⁴ . The Swedish BMI Epidemiology Study Gothenburg, which followed 34,231 men over a median of 34 years, found that both low birthweight and high body weight in young adulthood were independent determinants of early (diagnosis before age 59) and later onset of type 2 diabetes ³⁵ . The risk of early‐onset type 2 diabetes was increased tenfold in men with clinically low birthweight and overweight at age 20, and increased 1.9‐fold among those with low birthweight but normal weight at age 20, compared to men with normal weight both at birth and during young adulthood.

Exposure to intrauterine growth restriction may shape the fetus into a thrifty phenotype that favors fat storage and insulin resistance to survive nutritional deprivation ⁶⁵ . Research from the BrainChild Cohort revealed that early fetal exposure to gestational diabetes can alter the central nervous system during childhood, affecting glucose‐linked hypothalamic signaling and increasing activation of the reward system in response to food cues ⁶⁶ . These changes may predispose the offspring to a long‐term positive energy balance, contributing to obesity, insulin resistance, and type 2 diabetes ⁶⁶ .

Urbanization and environmental exposure

Environmental exposure to endocrine disruptors, including heavy metals, organic substances, and pollutants, may increase the risk of diabetes. The predominant source of measurable human exposure to heavy metals is contaminated drinking water. This problem primarily affects developing countries, where industries generate heavy metal‐contaminated waste but have limited economic capacities to adequately remove these contaminants ⁶⁷ , ⁶⁸ .

Similarly, the emission of persistent organic pollutants such as dioxin, which exhibit a strong dose–response relationship with the risk of type 2 diabetes, has remained at a relatively high level or has continued to increase in developing regions ⁶⁹ , ⁷⁰ . Notably, the association between persistent organic pollutants and diabetes is amplified with decreasing age ⁶⁹ .

GENETIC CONTRIBUTION TO YOUNGER AGE AT TYPE 2 DIABETES PRESENTATION

Heritability takes on a more significant role in the development of type 2 diabetes in younger individuals than in older populations. An early study conducted in the US showed that the age of diabetes presentation tends to decrease as the number of affected family members increases ⁷¹ . In a Chinese cohort without diabetes at baseline, a family history of diabetes diagnosed at an age below 30 conferred a greater risk of conversion to type 2 diabetes (7.0‐fold) compared to a family history of diabetes diagnosed at age 50 or older (2.4‐fold) ⁷² . The prominent familial aggregation of young‐onset type 2 diabetes suggests that there may be a strong genetic basis for glycemic dysregulation, although shared environments and behaviors also contribute. In cohorts of youth and young‐onset type 2 diabetes, undiagnosed monogenic diabetes accounted for only 2% to 3% of all cases and cannot explain the majority of individuals with type 2 diabetes in this demographic ⁷³ , ⁷⁴ .

Genome‐wide association studies in young‐onset type 2 diabetes

The first genome‐wide association study (GWAS) investigating common genetic variants associated with youth‐onset diabetes was conducted by the ProDiGY (Progress in Diabetes Genetics in Youth) Consortium ⁷⁵ . This study compared youths diagnosed with type 2 diabetes under the age of 20 to diabetes‐free adult controls and identified six known loci associated with general type 2 diabetes: TCF7L2, MC4R, CDC123, KCNQ1, IGF2BP2, and SLC16A11, as well as a novel locus at PHF2.

By combining genotyping with whole exome sequencing data, the ProDiGY Consortium identified four common variants and three genes significantly associated with youth‐onset type 2 diabetes. Except for ATXN2L, the other variants and genes have been previously reported in adult‐onset type 2 diabetes ⁷⁴ . These top signals demonstrated larger effect sizes in youth than in older adults with type 2 diabetes. Similarly, the common variants with the strongest associations and genes with nominal associations with adult‐onset type 2 diabetes had greater effect sizes at a greater frequency in youth than in older individuals. Rare variant association enrichment tests revealed an overrepresentation of gene sets related to “obesity,” “beta‐cell function,” and “other type 2 diabetes.” Notably, the genetic liability explained by either common or rare variants is larger in the youth population than in adults with type 2 diabetes. In the ProDiGY youth cohort, 21% possess either maturity‐onset diabetes of the young (MODY) variants, a high rare variant score, a high common variant score, or a high combined rare and common variant score. The rare variant score correlated with younger age at diagnosis, whereas the common variant score was linked to high C‐peptide levels. Overall, these findings indicate substantial genetic heterogeneity in youth‐onset type 2 diabetes.

Several candidate genes have been identified for young‐onset type 2 diabetes diagnosed before the age of 40. These include PPAR‐alpha (peroxisome proliferator‐activated receptor), implicated in fatty acid metabolism and reported in Caucasians; DACH1 (Dachshund homolog 1) and PAX4 (Paired box 4), implicated in pancreatic development and identified in Chinese and East Asian populations; and ALMS1 (Alström syndrome 1), which is associated with severe insulin resistance in Chinese ⁷⁶ , ⁷⁷ , ⁷⁸ , ⁷⁹ , ⁸⁰ . Genome‐wide scans for young‐onset type 2 diabetes are limited, including one study involving Pima Indian sibling pairs, one whole genome sequencing study in a family with young‐onset type 2 diabetes, and a trans‐ethnic GWAS for age at diagnosis that included South Indians and Europeans ⁸¹ , ⁸² , ⁸³ .

Studies leveraging established genetic risk loci for adult‐onset type 2 diabetes have reported an enrichment of beta‐cell function‐related type 2 diabetes genetic risk scores among individuals diagnosed at a younger age in Chinese and Asian Indian populations ⁸⁴ , ⁸⁵ . Furthermore, the beta‐cell function‐related polygenic score was associated with younger age at diagnosis in Asian Indians but not in white Europeans ⁸⁵ . Researchers have utilized clustering methods to categorize genetic variants associated with type 2 diabetes into distinct pathways and mechanisms using multi‐ancestry cohorts ⁸⁶ , ⁸⁷ , ⁸⁸ . In Europeans, the partitioned polygenic scores for obesity were associated with younger age at diagnosis of type 2 diabetes ⁸⁹ . In contrast, among British Pakistani and British Bangladeshi individuals, the partitioned polygenic scores for insulin deficiency and unfavorable fat distribution had the strongest association with younger age at diagnosis. In the Chinese population, nearly all partitioned and total polygenic scores were correlated with an earlier diagnosis age ⁹⁰ , ⁹¹ , although beta‐cell and lipodystrophy partitioned polygenic scores were more prevalent in normal‐weight than overweight individuals ⁹¹ . Using common variants located in 34 genes related to monogenic diabetes to compute a polygenic risk score, this score was associated with young age of diagnosis and cardiovascular‐kidney complications in Chinese with type 2 diabetes ⁹² . Collectively, these findings provide evidence for ethnic and racial differences in genetic contributions underlying pathophysiological mechanisms in young‐onset type 2 diabetes.

PATHOPHYSIOLOGY OF TYPE 2 DIABETES IN YOUTH AND YOUNG ADULTS

The development of type 2 diabetes results from inadequate insulin secretion in the context of insulin resistance, obesity‐related inflammation, and glucolipotoxicity ⁹³ . Young individuals with type 2 diabetes experience a more rapid decline in β‐cell function compared to those diagnosed later in life. Studies have found that youth‐onset type 2 diabetes is associated with an annual decline in beta‐cell function of 20–35% ⁹⁴ , ⁹⁵ , ⁹⁶ , ⁹⁷ , while individuals diagnosed in adulthood experience a loss of beta‐cell function at an annual rate of 7–11% ⁹⁸ , ⁹⁹ .

The US‐based Restoring Insulin Secretion (RISE) study assessed the effects of 1 year of insulin or metformin treatment on β‐cell function using hyperglycemic clamps in obese youth and adults with impaired glucose tolerance or newly diagnosed type 2 diabetes ¹⁰⁰ , ¹⁰¹ , ¹⁰² , ¹⁰³ . Although youth exhibited a greater β‐cell response to glucose stimulation at baseline, their β‐cell function, adjusted for insulin sensitivity, declined throughout the treatment period and 3 months post withdrawal, while it remained stable in adults.

Among Asian Indians and Chinese, individuals with type 2 diabetes diagnosed before the age of 40 showed more pronounced β‐cell dysfunction shortly after diagnosis compared to those with later‐onset diabetes (Figure 1) ⁸⁵ , ¹⁰⁴ . A cross‐sectional analysis of a register‐based cohort in Hong Kong demonstrated a steeper decline in the Homeostatic Model Assessment of β‐cell function (HOMA2‐β) with increasing diabetes duration in young‐onset than later‐onset type 2 diabetes ¹⁰⁴ . The suboptimal glycemic trajectories observed in youth‐ and young‐onset type 2 diabetes reflect the rapid deterioration of β‐cell function in this population ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ .

Figure 1.

A conceptual framework explaining (a) how reduced endowment of β‐cell mass or function at birth due to genetic factors and intrauterine exposure may influence age at diabetes diagnosis given the same rate of β‐cell function decline and metabolic stress; (b) how increasing metabolic stress can accelerate the decline in β‐cell function to influence age at diabetes diagnosis given the same β‐cell mass or function at birth; (c) how the management of hyperglycemia through medication and behavioral change may slow down the decline in β‐cell function. Adapted from reference ¹⁹³ .

Besides β‐cell dysfunction, youth with type 2 diabetes in the RISE study had greater insulin resistance than adults, partly attributed to the hormonal dynamics associated with puberty and a higher prevalence of obesity ¹⁰⁰ , ¹⁰¹ , ¹⁰⁹ . Likewise, among adults with type 2 diabetes, those diagnosed at a younger age are more likely to have overweight or obesity ¹⁰⁴ , ¹¹⁰ . In addition to overall adiposity, fat distribution plays a critical role in determining the effectiveness of both endogenous and exogenous insulin ¹¹¹ , ¹¹² , with increased proportions of visceral, hepatic, and intramuscular fat linked to reduced insulin sensitivity in both youth and adults ¹¹³ . Metabolic dysfunction‐associated steatotic liver disease, which reflects hepatic insulin resistance, is an independent risk factor for young‐onset type 2 diabetes ¹¹⁴ , ¹¹⁵ , ¹¹⁶ . Importantly, the relationship between hepatosteatosis and the development of type 2 diabetes appears to be stronger in younger than older individuals ¹¹⁷ , ¹¹⁸ . Young individuals with type 2 diabetes can harbor up to three times the amount of hepatic fat and exhibit approximately 50% lower peripheral insulin sensitivity compared to BMI‐matched peers without diabetes ¹¹² , ¹¹⁹ .

Ethnicity, insulin sensitivity, and insulin secretion

Ethnic disparities in body composition, insulin sensitivity, and β‐cell function contribute to the disproportionate burden of young‐onset type 2 diabetes among non‐White populations ¹²⁰ , ¹²¹ , ¹²² . South Asians are particularly susceptible to type 2 diabetes due to impaired insulin sensitivity, which is followed by compensatory insulin secretion and earlier β‐cell exhaustion ¹²³ , ¹²⁴ , ¹²⁵ , ¹²⁶ . Compared to White populations, South Asians exhibit greater central adiposity, increased visceral, hepatic, and intramuscular fat deposition, and lower muscle mass at any given BMI, all of which exacerbate insulin resistance and accelerate β‐cell exhaustion ¹²⁷ , ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹ , ¹³² , ¹³³ , ¹³⁴ . While East Asians share similar fat distribution patterns, they tend to maintain relatively preserved insulin sensitivity ¹³⁵ , ¹³⁶ , ¹³⁷ . However, their insulin secretory capacity is more severely impaired, especially during the early phase of insulin response ¹³⁷ , ¹³⁸ , ¹³⁹ , ¹⁴⁰ . Consequently, even a modest decline in insulin sensitivity can trigger diabetes onset, as their β‐cells struggle to meet increasing metabolic demands. Researchers from Europe have endeavored to reclassify diabetes into five clusters based on several factors, including age of diagnosis, BMI, glutamic acid decarboxylase auto‐antibodies, and homeostatic model assessment for insulin resistance (HOMA‐IR) and HOMA2‐β ¹⁴¹ . Notably, Indian and Chinese individuals with type 2 diabetes were overrepresented for the severe insulin deficiency diabetes cluster compared to their White counterparts ¹⁴² , ¹⁴³ .

A US‐based study involving multi‐ethnic participants with varying glycemic tolerance statuses found the lowest insulin secretion capacity in South Asians and Chinese Americans ¹²⁵ . While Black populations generally have greater lean mass and lower visceral and hepatic adiposity than White Europeans ¹³¹ , ¹⁴⁴ , they tend to have lower insulin sensitivity ¹³⁷ , ¹⁴⁵ , ¹⁴⁶ , ¹⁴⁷ , ¹⁴⁸ , potentially related to differences in the expression of genes involved in mitochondrial energy and metabolic pathways ¹⁴⁹ . Among African children and adolescents, an exaggerated insulin secretory response, exceeding what is necessary to compensate for insulin resistance, may lead to earlier β‐cell exhaustion and a heightened risk of type 2 diabetes in youth ¹⁴⁵ , ¹⁴⁷ , ¹⁵⁰ , ¹⁵¹ , ¹⁵² .

Due to these ethnic disparities, type 2 diabetes develops at a younger age and lower BMI thresholds in Asians, Africans, and other ethnic minority groups compared to Caucasians ¹⁵³ , ¹⁵⁴ . In the UK, the BMI threshold for an equivalent prevalence of type 2 diabetes was 22.0 kg/m² in South Asians, 26.0 kg/m² in Black populations, 24.0 kg/m² in Chinese women, and 26.0 kg/m² in Chinese men, compared to 30 kg/m² in White Europeans ¹⁵⁵ . These disparities underscore the need for ethnicity‐specific screening and prevention strategies to address the rising burden of young‐onset type 2 diabetes in high‐risk populations.

TRADITIONAL AND EMERGING COMPLICATIONS IN YOUNG‐ONSET TYPE 2 DIABETES

A high burden of microvascular complications in youth and young adults with type 2 diabetes has been first reported in Indigenous populations ¹⁵⁶ . Similar observations of a more adverse complication trajectory in young‐onset type 2 diabetes are evident in other ethnic and racial groups. In the TODAY study of 500 youth aged 10–17 with type 2 diabetes and obesity, microvascular complications were detected in 80% of participants after a follow‐up period of 15 years ¹⁵⁷ , ¹⁵⁸ , ¹⁵⁹ . Generally, the excess risks of cardiovascular disease, chronic kidney disease, and premature mortality associated with type 2 diabetes are larger in younger individuals than in older adults ¹⁶⁰ , ¹⁶¹ , ¹⁶² . A population‐based study in Sweden comparing individuals with type 2 diabetes to age‐matched individuals in the general population showed that the risks of coronary heart disease, cardiovascular‐related mortality, and all‐cause mortality were the highest in the youngest age group, with a range of 2.1‐ to 4.3‐fold greater risk ¹⁶⁰ . These risks diminished with increasing age at diagnosis. Correspondingly, the estimated years of life lost due to type 2 diabetes were 4–5 years for men and 5–6 years for women diagnosed at age 60, increasing to 6–8 years for men and 7–9 years for women diagnosed at age 40 ¹⁶⁰ , ¹⁶³ .

At the same attained age, young‐onset type 2 diabetes is associated with increased risks of most diabetes‐related complications and premature mortality compared to later‐onset type 2 diabetes, partly driven by longer disease duration ¹⁶⁴ , ¹⁶⁵ , ¹⁶⁶ . In a population‐based cross‐sectional study involving 222,773 Chinese with type 2 diabetes, age at diabetes diagnosis below 40 was associated with a 1.9‐fold increase in age‐ and sex‐adjusted odds of developing cardiovascular disease ¹⁶⁵ . Across a 7‐year follow‐up of 9,509 Chinese with type 2 diabetes in the Hong Kong Diabetes Register, young‐onset diabetes increased the risks of cardiovascular disease and chronic kidney disease by 48% and 35%, respectively, when age was equated ¹⁶⁶ .

Glycemic burden due to delayed diagnosis and suboptimal treatment

Available evidence also indicates that an earlier age at diabetes development heralds a more rapid progression to end‐organ damage due to worse glycemic regulation, compounded by a blunted response to glucose‐lowering therapies, suboptimal drug adherence, and clinical inertia ¹⁰⁵ , ¹¹⁰ , ¹⁶⁷ . In a retrospective study of 0.4 million Chinese with type 2 diabetes, a younger age at presentation amplified the effect of diabetes duration on the risk of progression to chronic kidney disease ¹⁶⁸ . It is noteworthy that the diagnosis of type 2 diabetes among youth and young adults is more likely to be delayed due to the absence of prominent symptoms and a low level of awareness of type 2 diabetes in this age demographic. This is supported by studies showing that glycemic indices at diagnosis of type 2 diabetes are higher in younger than older individuals ¹¹⁵ . Guidelines on screening for intermediate hyperglycemia or type 2 diabetes in younger age groups are currently lacking. Consequently, individuals with young‐onset type 2 diabetes may have experienced a unrecognized period of untreated hyperglycemia before diagnosis, which contributes to their overall glycemic burden and risks of downstream complications.

Metabolic morbidities, including obesity, hypertension, dyslipidaemia, and metabolic‐dysfunction‐associated steatotic liver disease, frequently coexist with young‐onset type 2 diabetes, mirroring observations in older adults ¹¹⁰ , ¹⁵⁷ . In the multinational, multi‐ethnic Joint Asia Diabetes Evaluation cohort of 41,029 Asians with type 2 diabetes, central obesity, hypertension, and mixed dyslipidaemia were detected in 61% to 88% of those with young‐onset disease, in whom the use of corresponding pharmacotherapy was lower than that in their older adult counterparts ¹¹⁰ . In cohorts of youth and young adults, metabolic indices were more adverse in those with type 2 diabetes compared to those with type 1 diabetes ¹⁶⁹ , ¹⁷⁰ . Most studies examining the risks of diabetes‐related complications in youth and young adults showed a higher incidence of chronic kidney disease, diabetic retinopathy, and cardiovascular disease in type 2 diabetes than in type 1 diabetes ¹⁷¹ , ¹⁷² . Some or all of the excess risks were attenuated when the differences in metabolic indices between the groups were accounted for, underscoring the importance of metabolic risk factors, independent of hyperglycemia, in driving complications in this population.

Mental health conditions and young‐onset type 2 diabetes

Mental health conditions, such as depression and anxiety, affect close to 20% of young individuals with type 2 diabetes ¹⁷³ and account for 40% of hospitalizations in this age group ¹⁷⁴ . In a population‐based cohort study, individuals with young‐onset type 2 diabetes were 3.4‐ to 4.2‐fold more likely to have mood disorders and anxiety or stress‐related disorders ¹⁷⁵ . Young individuals with diabetes often have more negative emotions, as they are less prepared to receive a diagnosis of a chronic disease and experience more difficulties coping with diabetes self‐management in the face of other life priorities. Conversely, those with preexisting mental health conditions are also more likely to exhibit cardiometabolic anomalies due to shared risk factors and the metabolic side effects of psychotropic drugs. Many mental health conditions, including schizophrenia and bipolar disorders, typically present in late teens to early adulthood, exposing affected individuals to increased cardiometabolic risks from a young age and predisposing them to earlier onset of type 2 diabetes. Recent familial co‐aggregation analyses of individuals with young‐onset type 2 diabetes and mental health conditions indicated that shared genetic liability may also explain the co‐occurrence of these two conditions ¹⁷⁵ . Furthermore, the presence of mental health conditions in individuals with young‐onset type 2 diabetes can complicate diabetes management and accelerate the progression to vascular complications ¹⁷⁶ , ¹⁷⁷ . Cardiovascular disease remains the leading cause of mortality among individuals with mental health conditions, exceeding deaths from external causes such as suicide ¹⁷⁸ .

SCREENING, PREVENTION, AND MANAGEMENT

Although effective therapeutics and technologies are now available to improve the standard of care for type 2 diabetes, most clinical trials have excluded individuals younger than 50 years old ¹⁷⁹ , ¹⁸⁰ . This knowledge gap hinders the development of practice guidelines tailored to these younger patients. In many areas, declines in the incidence of diabetes‐related complications have been observed in older age groups but not in younger people, in whom glycemic measures have not changed over time ¹⁶³ , ¹⁸⁰ , ¹⁸¹ , ¹⁸² , ¹⁸³ . Individuals with young‐onset type 2 diabetes face additional concerns, including sexual dysfunction, preconception care, and the safety of glucose‐lowering drugs and organ‐protective drugs for women ¹⁸⁴ , ¹⁸⁵ . Phenotypic heterogeneity and aggressive clinical courses in this disease population necessitate regular assessment and timely intervention. However, unless these young patients can establish trust in their healthcare team for advice and support, their competing priorities—such as jobs, families, and social life—may result in nonadherence and missed appointments ¹⁸⁶ . These unmet needs call for the development of care models specifically tailored to young‐onset type 2 diabetes ¹⁸⁷ .

Multicomponent person‐centered program for young‐onset type 2 diabetes

In an ongoing randomized controlled trial (Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes, abbreviated as PRISM), we randomized 884 Chinese with young‐onset type 2 diabetes (Figure 2) ¹⁸⁸ . Half of the participants were assigned to a 3‐year multicomponent program delivered by a specialized team of doctors and nurses in a diabetes centre, while the other half received usual care. All participants had measurements of biogenetic markers, including C‐peptide, glutamic acid decarboxylase antibodies (GADA), whole exome sequencing of 34 monogenic diabetes, and GWAS to derive diabetes‐related polygenic risk scores for risk profiling and classification. Only the intervention group received a personalized report detailing their clinical risk profiles and biogenetic markers, along with an explanation by doctors on how these factors may contribute to their diabetes and its progression. These participants also underwent a structured assessment of their psychological and behavioral health. This information aimed to assist the care team in reviewing the diagnosis (e.g., monogenic diabetes, slowly evolving immune‐mediated  diabetes of adults), individualizing treatment, and intensifying control of multiple risk factors, supplemented by intensive education and support from nurses and research assistants. After 3 years, all diabetes‐related clinical outcomes will be compared between the precision care and usual care groups.

Figure 2.

Treatment algorithm for participants randomized to the precision care group of the Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes—Randomized Controlled Trial (PRISM‐RCT). Adapted from reference ¹⁸⁸ .

Pending outcome analysis, we have reported the baseline profiles of the participants ¹⁸⁸ . Among them, 75% had a positive family history of diabetes, 50–70% exhibited general and/or central obesity, 30–70% had multiple cardiovascular, kidney, and metabolic risk factors, and 26–38% experienced emotional distress and suboptimal quality of life. Additionally, 2% carried pathogenic or likely pathogenic variants of monogenic diabetes genes, and 5% were positive for GADA. Other notable morbidities included low or high birthweight (33%), mental health conditions (10%), and previous suicidal attempts (4%). Among the women, 17% had polycystic ovary syndrome, 45% required insulin treatment during pregnancy, and 17.3% experienced adverse pregnancy outcomes. The PRISM study highlights the complexity of young‐onset type 2 diabetes, and the need for a dedicated team of specialists, family doctors, and paramedical staff. The use of biomarkers is important for enhancing the precision of diagnoses to facilitate timely interventions, such as early initiation of insulin or dipeptidyl peptidase‐4 inhibitors for individuals with positive GADA, and sulfonylureas for those with transcription factor MODY ¹⁸⁹ , ¹⁹⁰ , ¹⁹¹ , ¹⁹² . It is important to consider the personal, social, and psychological dimensions of these individuals, as they are closely intertwined with their biomedical condition.

Precision prediction and prevention of young‐onset type 2 diabetes

Type 2 diabetes can be delayed by early diagnosis of prediabetes, particularly impaired glucose tolerance (IGT), through intensive lifestyle interventions and use of medications such as metformin. In individuals with obesity and type 2 diabetes, a weight loss of at least 15 kg could induce remission for 2 years and restore beta‐cell function ¹⁶² . In a modeling study, intensive control of multiple risk factors in young individuals with type 2 diabetes has been shown to reduce their lifetime risk of recurrent hospitalizations ¹⁷⁴ . Wearable devices and digital tools, with decision support derived from big data analytics, provide timely feedback to motivate behavioral change.

The prevalence of diabetes and prediabetes among individuals under the age of 40 is low, affecting fewer than 5–10% of this population. Consequently, the challenge lies in developing a cost‐effective strategy to identify at‐risk individuals for early intervention. The ongoing Precision Prevention Program on Young‐Onset Diabetes (PPPYOD) supported by a major charity, targets 9,000 people aged 18–45 with at least one risk factor for diabetes in Hong Kong. This implementation program is coordinated by academia and nongovernmental organizations, and is supported by a network of nurses, doctors, allied healthcare workers, and partners including housing estates, schools, work unions, and corporate entities. Our approach is structured in two tiers: initially, capillary blood glucose, saliva for DNA testing, and a simple questionnaire will be obtained from the participants. This enables us to identify individuals in the highest 30% risk category for developing diabetes over the next decade. Subsequently, those identified as high risk will be assigned a doctor–nurse team, and they will undergo annual oral glucose tolerance tests to facilitate early detection of IGT or diabetes. The interventions will encompass the use of digital tools such as weighing scales and continuous glucose monitoring, alongside regular webinars, workshops, text messages for psychological‐behavioral support, and medications aimed at preventing or delaying the onset of diabetes (NCT06693934).

Young‐onset type 2 diabetes differs from later‐onset type 2 diabetes in underlying etiology, pathophysiology, glycemic trajectory, and risks of developing diabetes‐related complications. The contribution of genetic risk factors to type 2 diabetes is more pronounced in individuals diagnosed at younger ages, where the composition of inherited genetic risk factors is also more heterogeneous. Exposure to an unfavorable intrauterine environment, including nutritional deprivation, maternal hyperglycemia, and maternal obesity, may alter fetal metabolic programming through epigenetic modifications. Additionally, extremes of birthweight, compensatory growth, childhood and adolescent obesity, and major illnesses including mental health conditions that manifest during childhood or adolescence are significant risk factors for young‐onset type 2 diabetes. Non‐White ethnic and racial groups are more susceptible as they tend to have lower β‐cell function and/or greater insulin resistance than their White counterparts. Countries undergoing rapid industrialization and nutritional transition experience the largest rise in the prevalence and incidence of young‐onset type 2 diabetes, which parallels the trends in childhood and adolescent obesity. Young‐onset type 2 diabetes is associated with more rapid progression to vascular complications, partly due to inadequate glycemic and other risk factor management.

Current guidelines for diabetes management do not differentiate based on the age of disease onset, and recommendations for young‐onset diabetes have been extrapolated from evidence obtained in older individuals. Additional concerns, including biological heterogeneity, psychosocial and behavioral factors, and social determinants of health, add to challenges in care. In Hong Kong, the PRISM and PPPYOD programs engage stakeholders in both private and public sectors to predict and prevent young‐onset type 2 diabetes and its complications using a personalized risk‐based approach focusing on health literacy and psychological‐behavioral well‐being. By sharing these best practices, we will be one step closer to transforming the devastating trajectories and outcomes of these people with or at risk of young‐onset type 2 diabetes.

DISCLOSURE

The current work received no funding support. A.O.Y.L. has served as a member of the advisory panel for Amgen, AstraZeneca, Boehringer Ingelheim, and Sanofi and has received research support from Amgen, Asia Diabetes Foundation, Bayer, Biogen, Boehringer Ingelheim, Lee's Pharmaceutical, MSD, Novo Nordisk, Roche, Sanofi, Sugardown Ltd, and Takeda, outside the submitted work. J.C.N.C holds patents for using genetic markers to predict diabetes and its complications for personalized care and is a co‐founder of a start‐up biotech company partially supported by the Technology Start‐up Support Scheme for Universities (TSSSU) of the Hong Kong Government Innovation and Technology Commission to support precision care.

Approval of the research protocol: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.