The growing burden of metabolic and cardiovascular disease (CVD) often directs clinical focus and research direction towards populations classically considered to be high risk, such as middle age to older adults and those with obesity. While understandable, it is important to also recognize that dysglycemia can impact younger adults [1] with early onset diabetes reflecting a particular aggressive phenotype [2]. Furthermore, growing diabetes prevalence is not fully explained by obesity where more than 50% of newly diagnosed patients with type 2 diabetes mellitus have a body mass index (BMI) below 30 kg/m² [3]. Here, we highlight our recent findings demonstrating the striking presence of dysglycemia in apparently healthy young adults without obesity. These data suggest that glycemic disturbances are common in this population and represent one of the earliest manifestations of cardiometabolic disease that occurs independently of overt obesity.

We accumulated data from several cohorts recruited within our laboratory between 2016 and 2024 (some of which has been published [4,5]). Inclusion criteria were identical across studies including young (18 to 35 years), apparently healthy adults without obesity (BMI <30 kg/m²) with no previous diagnosis of diabetes or other endocrine or CVDs. All participants completed the same 2-hour 75 g oral glucose tolerance test (OGTT) and comprehensive phenotyping, and identical laboratory analysis was performed. In total, 406 apparently healthy adults (228 females and 178 males) were included. Prediabetes was common, being present in 32% of individuals when using the American Diabetes Association (ADA) criteria for impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (Table 1). The incidence of dysglycemia was even higher (37% of individuals) with the inclusion of those with normal glucose tolerance (NGT) but with a 1 hour post-OGTT glucose >8.6 mmol/L (normal glucose tolerance with intermediate hyperglycemia [NGT-IH]), an emerging marker that is highly predictive for the development of overt dysglycemia [6,7]. Strikingly, the prevalence of dysglycemia in our cohort broadly align with larger scale studies that have examined young adults without diabetes but included individuals with obesity who accounted for >30% of those studied [1,8]. The incidence of dysglycemia was not explained by family history of diabetes, dietary macronutrient composition or energy intake, which were similar across groups. Furthermore, while the IGT group had a higher proportion of overweight (48% of IGT had a BMI >25 kg/m²), there were no differences in the prevalence of overweight between the NGT, IFG, and NGT-IH groups (approximately 30% had a BMI >25 kg/m²) (Table 1). Therefore, most individuals with dysglycemia in this cohort were lean, demonstrating that the absence of obesity does not confer absolute protection against its development.

Further interrogation of the cardiometabolic phenotypes provides additional insight into the metabolic status and trajectory of this cohort. As expected, the IGT group presented as the most severe phenotype, exhibiting the highest fasting and postprandial insulin, consistent deteriorations in indices of insulin sensitivity, higher total and visceral fat mass and higher fasting plasma non-esterified fatty acid concentrations (Table 1). Most notably however, was that while the NGT-IH group showed an intermediary phenotype based on hyperinsulinemia and indices of insulin sensitivity, there were no differences in adiposity between the NGT-IH and NGT groups (Table 1). Given that hyperinsulinemia can compensate for initial declines in insulin sensitivity to maintain glycemia, it is likely that a decline in beta-cell function contributes to the initial loss of glycemic control in NGT-IH [9]. As these initial metabolic dysfunctions arise without excess adiposity, it seems unlikely that classic lipotoxicity and related inflammatory pathways play a major role in this early loss of glycemic control. While genetic susceptibility could be linked to initial declines in β-cell function, further work is clearly required to understand the mechanisms underlying the pathogenesis of NGT-IH that occurs independently of adiposity.

Conversely, other than the elevation in fasting glucose, the IFG group shared many similarities to the NGT group, with no differences in fasting and post-OGTT insulin, and insulin sensitivity indices were only marginally impacted (Table 1). This aligns with previous work showing insulin action, measured by the euglycemic-hyperinsulinemic clamp, to be largely unaffected in those with isolated IFG [10]. IFG therefore presents a distinct phenotype with a natural history that differs from either NGT-IH and IGT. Collectively, these data highlight that regardless of their pathogenesis, dysglycemia can occur frequently in young adults without obesity. These insights challenge the obesity-centric focus on insulin resistance and prediabetes, where hyperinsulinemia and an initial loss of glycemic control are seemingly prevalent in young normal weight adults.

Given the well described link between dysglycemia and the long-term risk of CVD, we also examined CVD risk factors across these groups. Collectively there were only minor differences between groups and little evidence of elevated cardiovascular risk as blood pressure and blood lipids were within normal ranges (Table 1). Additionally, future risk of CVD based on the Framingham 30-year risk score remained low across all groups (i.e., <6%). These results suggest that dysglycemia could be one of the earliest signs of deterioration in metabolic health in young individuals without obesity and that cardiovascular risk lags behind the deterioration in glycemic control in this demographic.

We believe these results warrant further attention. Young adults without obesity are often considered healthy and are not typically targeted for clinical screening. When combined with the silent nature of hyperinsulinemia and early stage dysglycemia, these phenotypes will likely remain undiagnosed for years, during which prolonged cumulative exposure to hyperglycemia and hyperinsulinemia could drive CVD and related complications. Given the scale of the obesity epidemic, our data likely understate the true scale of dysglycemia in young adults as we only studied those without obesity. While these findings provide valuable insight, it is important to note that they are based on a volunteer cohort, therefore larger scale population-based and longitudinal studies are needed to establish the community-level prevalence and cardiometabolic health trajectory of dysglycemia in young adults without obesity. It is also noteworthy to highlight the utility in examining young adult populations when investigating the initial drivers of dysglycemia. Investigations in individuals with obesity are confounded by concurrent adiposity, insulin resistance and hyperinsulinemia, which makes it difficult to isolate the drivers of dysglycemia from the consequences of obesity. We have shown that examining young individuals without obesity may help to shed light on the earliest mechanisms driving the pathogenesis of dysglycemia and CVD.