GRAPHICAL ABSTRACT

Highlights

• This study compared young-onset T2DM (YOD) and later-onset T2DM (LOD) in Koreans.

• YOD patients exhibited higher HbA1c, obesity, and liver fat than LOD patients.

• YOD patients had lower β-cell function and insulin sensitivity at diagnosis.

• After 1 year of treatment, β-cell function improved in YOD but remained lower than in LOD.

• YOD patients retain unfavorable metabolic features despite treatment.

INTRODUCTION

Young-onset type 2 diabetes mellitus (YOD) refers to type 2 diabetes mellitus diagnosed in individuals younger than 40 years of age, and it is becoming increasingly prevalent worldwide [1]. The global prevalence of diabetes mellitus among people aged 20 to 39 years was estimated to be approximately 63 million in 2013 and increased to 260 million in 2021 [2].

Individuals with YOD often experience more aggressive disease progression, a higher likelihood of complications, and distinct psychosocial impacts in comparison with those diagnosed with type 2 diabetes mellitus at older ages [3-6]. The primary driver of YOD is insulin resistance, which is often exacerbated by obesity and physical inactivity, along with an accelerated loss of β-cell function, leading to a rapid progression to insulin dependence [7-9].

The incidence and prevalence of YOD vary significantly across regions and ethnic groups due to genetic, environmental, and lifestyle factors [10,11]. In East Asia, its prevalence is increasing due to rapid urbanization, dietary changes, and sedentary lifestyles, coupled with a genetic predisposition to diabetes mellitus at a lower body mass index (BMI) [12,13]. Notably, a prospective cohort study in South Korea highlighted the crucial role of β-cell function deterioration and an insufficient compensatory response to declining insulin sensitivity in the development of diabetes mellitus [14-16]. These findings suggest that YOD in East Asia may have a distinct phenotype that differs from that in other ethnicities.

Therefore, in this study, we aimed to elucidate β-cell function, insulin sensitivity, and metabolic phenotypes of YOD in the early stages of the disease in a prospective diabetes cohort. The metabolic characteristics were directly compared with those of a later-onset type 2 diabetes mellitus (LOD) population, which further elucidated the distinct nature of YOD.

METHODS

Data source and study participants

The Anam Diabetes Observational Study (ADIOS) is a single-center, prospective, observational cohort of adults with prediabetes or newly diagnosed type 2 diabetes mellitus [17]. Since May 1, 2017, adults (aged ≥19 years) with suspected or recently diagnosed diabetes mellitus or prediabetes were enrolled in the Korea University Anam Hospital. Individuals receiving antidiabetic medications before enrollment were excluded.

After providing written informed consent, participants completed questionnaires and underwent anthropometric and blood pressure measurements, bioelectrical impedance analysis (BIA), and blood tests, including a 75 g oral glucose tolerance test (OGTT). The questionnaire collected information on age, sex, medical history, family history, and concurrent drug use. Anthropometric measurements included height, weight, and waist circumference (WC) measurement. Blood tests included glycosylated hemoglobin (HbA1c), creatinine, complete blood count, liver function tests, lipid profiles, and OGTT. During the OGTT, serum glucose and insulin levels were measured at 0 (fasting), 30, and 120 minutes after 75 g glucose loading. This protocol was performed at baseline and annually thereafter for 5 years. The participants underwent OGTT before initiating antidiabetic medications at baseline.

Antidiabetic medications were classified as follows: metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, thiazolidinediones, α-glucosidase inhibitors, meglitinides, and insulin. The ADIOS is an observational, non-intervention cohort; therefore, there are no regulations on diabetes management strategies or drug choices that are entirely at the discretion of investigators.

Patients newly diagnosed with type 2 diabetes mellitus between March 2017 and December 2023 were selected from the ADIOS cohort (n=228). The diagnosis of type 2 diabetes mellitus was based on fasting blood glucose ≥126 mg/dL, HbA1c ≥6.5%, or 2-hour blood glucose ≥200 mg/dL on 75 g OGTT. To ensure a diagnosis of type 2 diabetes mellitus, those with fasting C-peptide <0.6 ng/mL, stimulated C-peptide <1.8 ng/mL, or glutamic acid decarboxylase antibodies were excluded. Next, 11 people who did not undergo blood tests were also excluded. Finally, 217 participants, consisting of 39 with YOD (aged <40 years) and 178 with LOD (aged ≥40 years), were included in the analysis.

This study was approved by the Institutional Review Board of Korea University Anam Hospital (IRB number 2017AN0050). All the participants provided written informed consent.

Measurement of β-cell function and insulin sensitivity

β-Cell function was estimated by disposition index (DI), which reflects β-cell function relative to insulin sensitivity. DI was calculated as insulinogenic index (IGI)×Matsuda insulin sensitivity index (ISI) [14]. IGI, representing an early insulin response, was computed as (insulin _{30 min}–insulin _{0 min} [μIU/mL])/(glucose _{30 min}–glucose _{0 min} [mg/dL]) [18]. Matsuda ISI was calculated as 10,000/(fasting glucose [mg/dL]×fasting insulin [μIU/mL]×mean glucose [mg/dL]×mean insulin [μIU/mL])^1/2 [19]. Another index reflecting β-cell function adjusted for insulin sensitivity, oral disposition index (DI_O), was calculated as IGI×(1/fasting insulin [μIU/mL]) [20].

We also estimated the homeostasis model assessment of β-cell function using the updated model (HOMA2-B) [21] with the publicly available HOMA2 Calculator (http://www.dtu.ox.ac.uk/homacalculator/index.php; accessed September 20, 2024). Insulin sensitivity was determined using ISI and homeostasis model assessment of insulin resistance (HOMA2-IR).

Plasma glucose was measured by the glucose oxidase method using a Beckman Coulter chemistry analyzer AU5800 (Beckman Coulter, Brea, CA, USA), and plasma insulin was measured by radioimmunoassay.

Assessment of body composition and hepatic steatosis

Body weights and heights were measured using an automatic system (GL-150, G-Tech International, Seoul, Korea). BMI was calculated as weight (kg) divided by height squared (m²). WC was measured in the horizontal plane midway between the lowest ribs and the iliac crest by trained nurses. Skeletal muscle mass, body fat mass, percent body fat, and visceral fat area were estimated using BIA (Inbody720, Biospace, Seoul, Korea).

The fatty liver index (FLI) was calculated to estimate hepatic steatosis. The FLI was calculated as follows [22,23]:

(e^{0.953×loge(triglycerides)+0.139×BMI+0.718×loge(gamma-glutamyl transpeptidase)+0.053×WC−15.745})/(1+e^{0.953×loge(triglycerides)+0.139×BMI+0.718×loge(gamma-glutamyl transpeptidase)+0.053×WC−15.745})×100.

Statistical analysis

Data for continuous variables are presented as mean±standard deviation or median and interquartile range. Categorical variables are presented as numbers and percentages (%).

The characteristics of individuals with YOD (aged <40 years) and LOD (aged ≥40 years) were compared at baseline and 1 year later. Continuous variables were compared using Student’s t-test or the Mann-Whitney U test depending on the distribution of the data. Specifically, when the continuous variables exhibited significant deviations from normality or displayed markedly skewed distributions, the non-parametric Mann-Whitney U test was employed. Statistical significance was also assessed after adjusting for sex using a generalized linear model. Categorical variables were primarily compared using Pearson’s chi-square test. However, when more than 25% of the cells had expected counts less than 5, Fisher’s exact test was employed to ensure the validity of the results. Additionally, the indices of β-cell function and insulin sensitivity were compared based on obesity status, assessed using BMI categories (<25 and ≥25 kg/m²) [24,25]. Subgroup analyses were performed based on the use of antidiabetic medications.

To investigate the association between metabolic parameters and the age at diagnosis of type 2 diabetes mellitus, scatter plots of metabolic parameters according to the age of onset of type 2 diabetes mellitus were plotted. Simple linear regression analysis was performed to quantify the relationship between these variables.

All statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at a two-sided P value <0.05.

RESULTS

Characteristics of study participants at the onset of diabetes mellitus

Table 1, Supplementary Fig. 1 compare the characteristics of patients in the YOD and LOD groups at the time of diagnosis. Mean age was 29.8 years for YOD and 57.7 years for LOD. This cohort showed male preponderance of new-onset type 2 diabetes mellitus; 76.9% of YOD and 60.1% of LOD patients were male. YOD patients had higher body weight (88.8 kg vs. 73.2 kg) and BMI (29.8 kg/m² vs. 27.2 kg/m²) than LOD patients. BIA indicated higher body fat mass and skeletal muscle mass in YOD than in LOD; however, no statistically significant differences were observed between groups in terms of percent body fat (P=0.488).

The YOD group generally had an unhealthy lifestyle, characterized by a higher proportion of current smokers (30.8%), alcohol drinkers (43.6%), and individuals who did not engage in regular exercise (76.9%) compared to the LOD group. Overall, comorbidities of metabolic or cardiovascular diseases were less prevalent in YOD than in LOD patients: hypertension (10.3% vs. 40.0%), dyslipidemia (18.0% vs. 52.8%), and coronary artery disease (0% vs. 11.8%). However, mean FLI scores were significantly higher in YOD vs. LOD (65.4 vs. 49.2, P=0.005), and 60.7% of YOD patients had severely increased FLI scores (FLI ≥60).

Glycemic parameters, β-cell function, and insulin sensitivity

Mean HbA1c level at the time of the disease onset was significantly higher (9.3% vs. 7.7%, P<0.001), along with higher fasting glucose and insulin levels, in YOD compared to LOD (Table 1, Supplementary Fig. 1C).

Insulin secretory function assessed by IGI and HOMA2-B did not differ between the groups. However, insulin sensitivity assessed by ISI (2.79 vs. 3.26, P=0.008) and HOMA2-IR (2.72 vs. 1.83, P<0.001) was significantly lower in YOD than in LOD (Fig. 1). This resulted in significantly lower β-cell function, as assessed by DI (0.41 vs. 0.72, P=0.003) and DI_O (0.01 vs. 0.02, P<0.001) in YOD than in LOD. Similar results were observed after adjusting for sex (Supplementary Table 1).

Fig. 2 shows the correlation between the metabolic parameters and age as a continuous variable. This clearly shows that an increase in age at diagnosis is associated with lower HbA1c levels, lower BMI, and higher β-cell function, indicating multiple detrimental metabolic phenotypes in YOD.

To elucidate whether β-cell function and insulin sensitivity were determined by obesity status, the indices were compared by BMI categories (<25 and ≥25 kg/m²) (Supplementary Fig. 2). Insulin sensitivity was lower in obese people; however, β-cell function did not differ according to the obesity status in either YOD or LOD. Overall, individuals with YOD had lower β-cell function than those with LOD.

Changes in glycemia and metabolic parameters after 1-year treatment

Fig. 3, Supplementary Table 2 show the 1-year changes in glycemic and metabolic parameters. After treatment in a routine clinical practice, HbA1c levels were significantly decreased in both YOD and LOD patients. Mean decreases in HbA1c were 2.4% and 1.5% in YOD and LOD patients, reaching 6.7% and 6.3%, respectively. Insulin sensitivity indices were aggravated with an increase in BMI in YOD, whereas they improved in LOD, resulting in a widening of the gap in HOMA2-IR and ISI between the groups (P<0.001 in both). This pattern was similar to that of the FLI measurements. DI improved in YOD patients during 1 year (from 0.33 to 0.64); however, it was still significantly lower than that of LOD (P=0.017).

Glucose-lowering agents resulting in body weight reduction, such as SGLT2 inhibitors and GLP-1R agonists, were more frequently used in YOD compared to LOD (Supplementary Table 3). Given that antidiabetic medications might affect metabolic parameters, additional analyses were conducted based on their use. First, as exogenous insulin and insulin secretagogues could affect insulin levels, we conducted analyses among patients not receiving sulfonylurea or insulin (Supplementary Fig. 3). Results similar to the main analyses were observed.

Next, we performed analyses among patients receiving SGLT2 inhibitors or GLP-1R agonists and those not receiving these drugs (Supplementary Fig. 4). YOD patients receiving SGLT2 inhibitors or GLP-1R agonists exhibited improvement in ISI with a decrease in BMI, whereas those not receiving these medications showed a worsening of ISI with an increase in BMI. DI dramatically increased in YOD patients using SGLT2 inhibitors or GLP-1R agonists, resulting in no statistical difference between YOD and LOD patients at 1 year. DI of YOD patients not receiving these medications also increased after 1 year but remained lower than that of LOD patients.

DISCUSSION

In this cohort study, we found that Koreans with YOD presented with higher glucose levels, attenuated β-cell function to compensate for increased insulin resistance, and multiple metabolic derangements, including obesity and higher liver fat, compared to those with LOD. These characteristics were prominent at diagnosis and lasted for 1 year, even after a profound reduction in HbA1c. These findings indicate that YOD presents a distinct phenotype at a very early stage of type 2 diabetes mellitus and requires intensive management to prevent further deterioration of β-cell function and metabolic derangement. To the best of our knowledge, this is the first study to assess early changes in β-cell function and insulin sensitivity in Koreans with YOD.

Type 2 diabetes mellitus has long been considered to affect middle-aged or elderly individuals. However, with the increasing obesity epidemic, the incidence of youth-onset or young-adult-onset type 2 diabetes mellitus has substantially increased over the past decades [26]. A notable increase in the incidence and prevalence of YOD has been reported in Asian countries [27], partly because of the genetic predisposition and vulnerability to the development of type 2 diabetes mellitus for the same BMI compared to Western populations [28,29]. In South Korea, from 2006 to 2015, the incidence rate of diabetes mellitus has slowly decreased in people older than 40 years; however, that in younger people under 40 years of age has increased by approximately 30% [30]. This feature appears to be closely linked to increasing prevalence of obesity in young adults. In 2009, the mean BMI of patients with type 2 diabetes mellitus aged 20 to 39 years was 25.6 kg/m², which substantially increased to 28.1 kg/m² in 2017 [31]. The mean WC also increased from 85.0 to 91.0 cm during the same period.

Our study (2017–2023) indicated similar but more aggravated findings: mean BMI was 29.8 kg/m² and mean WC was 95.7 cm in YOD people. Among YOD people, 82.1% and 38.5% had obesity (BMI ≥25 kg/m²) and severe obesity (BMI ≥30 kg/m²), respectively. Obesity status was closely associated with insulin resistance, represented by low ISI and high HOMA2-IR values, suggesting that it is a dominant feature in Koreans with YOD. In contrast, insulin secretory function, as measured by IGI and HOMA2-B, was not significantly different between YOD and LOD individuals. Therefore, significantly lower DI and DIo values in YOD, which were about half of those in LOD, suggested decompensated insulin secretion over insulin resistance in YOD patients. Considering that few studies have directly compared OGTT-derived measures of insulin secretion and sensitivity between patients with YOD and LOD, our study provides valuable insights into the pathophysiology of YOD.

Repeated measurements of the OGTT and metabolic parameters in the cohort participants suggested some implications for the disease course of YOD. Intensive management of glycemia with the use of multiple antidiabetic drugs was well engaged for 1 year, which resulted in mean HbA1c under 7.0% in both YOD and LOD. However, the BMI and insulin sensitivity indices did not improve in YOD, whereas those in LOD improved. DI improved in the YOD group with narrowing of the gap between the groups; however, the difference remained significant. Because these findings are only for 1-year changes in the study subjects, we do not guarantee that these patterns would persist for a longer time. Previous studies have indicated a unique characteristic of people with YOD, which is a rapidly progressive β-cell function decline. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed a profound 12% to 25% annual decline in DIo in youths aged 10 to 17 years [32]. Compared to previous studies, our study investigated a very early stage, approximately 1 year from the time of YOD diagnosis; thus, it is difficult to say whether this is a characteristic of Asian YOD. Further studies are required to elucidate the long-term clinical course of patients with YOD.

These worrisome features of YOD were attenuated in individuals receiving SGLT2 inhibitors and GLP-1R agonists. These medications are known to promote weight loss [33-38]. While YOD patients receiving these medications demonstrated a decrease in BMI along with an improvement in ISI, those not receiving them experienced an increase in BMI and a deterioration of ISI. However, even among patients receiving these medications, YOD patients exhibited a numerically higher BMI and lower ISI than LOD patients at 1 year. This highlights the concerning features of YOD and suggests that additional strategies beyond the use of these medications may be necessary. SGLT2 inhibitors and GLP-1R agonists have also been reported to support the preservation of β-cell function [39-41]. Indeed, YOD patients receiving these medications showed a significant increase in DI. Further studies are warranted to determine whether these medications have long-term beneficial effects on β-cell function and insulin sensitivity in YOD patients.

We also investigated body fat components using multiple measures. BIA showed that both body fat mass and skeletal muscle mass were higher in YOD than in LOD, resulting in a similar percentage of body fat between the groups. Notably, higher central fat and liver fat calculated by the FLI were a dominant feature of YOD people. Among YOD patients, 60.7% had severe fatty liver disease, which was significantly higher than the 37.5% in LOD patients. Management for 1 year decreased FLI scores in LOD patients, whereas it did not change the overall FLI score in YOD patients. Considering that central and visceral obesity are the primary drivers of insulin resistance [42,43], they may be hallmarks of YOD phenotypes.

Early onset of microvascular and cardiovascular complications is considered an important feature of YOD. In the SEARCH for Diabetes in Youth (SEARCH) study, youth-onset type 2 diabetes mellitus patients had 2- to 3-fold higher odds of diabetic kidney disease, retinopathy, and peripheral neuropathy than youth-onset type 1 diabetes mellitus patients [44]. Cardiovascular risks in YOD patients also increased compared to those in LOD patients after adjusting for age and sex [45]. A prospective cohort study of Chinese patients found that young people with type 2 diabetes mellitus had a 15-fold higher risk of cardiovascular disease, and 5.4-fold higher risk of end-stage kidney disease than those with type 1 diabetes mellitus [46]. Our study only measured 1-year changes after disease onset, and we did not compare the complication risks among the study individuals. We found that comorbid cardiovascular or metabolic conditions such as hypertension, dyslipidemia, coronary artery disease, and ischemic stroke were less prevalent in the YOD group than in the LOD group. The mean urinary albumin to creatinine ratio and the proportion of patients with elevated albuminuria, which are also indicators of cardiovascular disease, did not differ between the groups. These findings indicate that aging is a major factor contributing to the development of microvascular and cardiovascular diseases. Nonetheless, it is assumed that YOD individuals will experience a higher risk of complications at the same age as LOD individuals.

This study has several limitations. First, the study was based on a single-center diabetes cohort with a small number of participants. In particular, the number of individuals with YOD was smaller than that with LOD. Therefore, our study has some limitations in generalizing the findings to all patients with YOD. Moreover, our study population exhibits a greater male predominance compared to the general Korean YOD population [47]. However, similar results were observed after adjusting for sex. Second, this was an observational cohort; thus, treatment and routine care were individualized by clinicians. Third, the OGTT was conducted with only three measurements (at 0, 30, and 120 minutes); therefore, detailed results obtained through frequent sampling were not provided.

In conclusion, we found a distinct phenotype of YOD at the first presentation of the disease, including central and visceral obesity, aggravated insulin resistance, and β-cell dysfunction, which did not adequately compensate for insulin resistance. The age at onset of type 2 diabetes mellitus largely determines these characteristics. YOD phenotypes were seldom corrected with the 1-year treatment.

SUPPLEMENTARY MATERIALS

NOTES

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: J.Y.K., N.H.K.

Acquisition, analysis, or interpretation of data: all authors.

Drafting the work or revising: all authors.

Final approval of the manuscript: N.H.K.

FUNDING

This study was sponsored by Yuhan Corporation, and the Korean Endocrine Society Bid Data Research Fund 2022 (Ji Yoon Kim). The funders played no role in the design and conduct of the study, analysis, interpretation of the data, or review or approval of the manuscript.

ACKNOWLEDGMENTS

The authors thank the participants and volunteers in the Anam Diabetes Observational Study (ADIOS) cohort.

Fig. 1.

Oral glucose tolerance test-derived measures according to onset age of type 2 diabetes mellitus. Mean±standard deviation is presented. YOD, young-onset type 2 diabetes mellitus; LOD, later-onset type 2 diabetes mellitus; IGI, insulinogenic index; ISI, insulin sensitivity index; DI, disposition index; HOMA2-B, homeostasis model assessment of β-cell function; HOMA2-IR, homeostasis model assessment of insulin resistance; DIO, oral disposition index.

Fig. 2.

Metabolic parameters according to onset age of type 2 diabetes mellitus. YOD, young-onset type 2 diabetes mellitus; LOD, later-onset type 2 diabetes mellitus; HbA1c, glycosylated hemoglobin; BMI, body mass index; HOMA2-IR, homeostasis model assessment of insulin resistance; ISI, insulin sensitivity index; DI, disposition index; DI_O, oral disposition index.

Fig. 3.

One-year changes in metabolic parameters according to onset age of type 2 diabetes mellitus. Mean±standard errors are presented. The analyses were conducted among individuals who underwent oral glucose tolerance test at both time points. YOD, young-onset type 2 diabetes mellitus; LOD, later-onset type 2 diabetes mellitus; HbA1c, glycosylated hemoglobin; BMI, body mass index; FLI, fatty liver index; ISI, insulin sensitivity index; HOMA2-IR, homeostasis model assessment of insulin resistance; DI, disposition index. ^aP<0.05.

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Kim JY, Lee J, Kim SG, Kim NH. Beta-Cell Function, Insulin Sensitivity, and Metabolic Characteristics in Young-Onset Type 2 Diabetes Mellitus: Findings from Anam Diabetes Observational Study. Diabetes Metab J. 2025 May 21. doi: 10.4093/dmj.2024.0601. Epub ahead of print.

Received: Oct 01, 2024; Accepted: Feb 18, 2025

DOI: https://doi.org/10.4093/dmj.2024.0601.

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