Evolving Characteristics of Type 2 Diabetes Mellitus in East Asia
Article information
Abstract
In East Asians, type 2 diabetes mellitus (T2DM) is primarily characterized by significant defects in insulin secretion and comparatively low insulin resistance. Recently, the prevalence of T2DM has rapidly increased in East Asian countries, including Korea, occurring concurrently with rising obesity rates. This trend has led to an increase in the average body mass index among East Asian T2DM patients, highlighting the influence of insulin resistance in the development of T2DM within this group. Currently, the incidence of T2DM in Korea is declining, which may indicate potential adaptive changes in insulin secretory capacity. This review focuses on the changing epidemiology of T2DM in East Asia, with a particular emphasis on the characteristics of peak functional β-cell mass.
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a complex disorder that arises from an imbalance between insulin resistance and pancreatic β-cell dysfunction. When individuals develop insulin resistance, β-cells initially respond by increasing insulin production. However, if β-cells cannot sustain the heightened insulin demand, blood glucose levels rise, leading to T2DM [1,2]. The relative contributions of insulin resistance and β-cell dysfunction to the development of T2DM vary among individuals and regions. East Asian patients with T2DM, who represent a significant portion of the global diabetes burden, exhibit distinct characteristics [3,4]. Previous research, including our own, has shown that East Asian patients with T2DM typically present with a lower body mass index (BMI), reduced insulin secretion, and earlier onset of the disease [4-7]. Recently, the prevalence of T2DM in East Asia has surged. For example, the prevalence of diabetes in Korea increased from 1.5% in 1971 to 16.7% in 2022 [8,9], and in China, it rose from 1% in 1980 to 12.4% in 2018 [10,11]. This increase in diabetes prevalence in East Asia has occurred concurrently with a rise in obesity rates [12]. In Korea, the prevalence of obesity increased by 10.7% over the last 24 years [13,14], accompanied by a 16.6% increase in the prevalence of obesity in patients with T2DM [9,15]. Consequently, insulin sensitivity in Korean patients with T2DM has gradually decreased [16]. Despite the steady increase in the prevalence of obesity in Korea, the steep rise in T2DM incidence appears to have slowed recently [8,9]. This shift in the epidemiological landscape prompts a reevaluation of whether the characteristics of T2DM in East Asians are changing. In this paper, we explore the current evidence and perspectives on the evolving characteristics of T2DM in East Asia.
COMPENSATORY INSULIN SECRETION DEFECT IN EAST ASIAN PATIENTS WITH T2DM
Cumulative evidence suggests that East Asian patients with T2DM exhibit compensatory defects in insulin secretion. The Botnia study, which conducted oral glucose tolerance tests (OGTT) on 5,396 individuals across various glucose spectra, revealed increased insulin secretory function during the prediabetes stage in Caucasians [17]. In contrast, our research has shown that insulin secretion in response to oral glucose challenges is impaired in the Korean prediabetes population, indicating a compensatory defect in β-cell function [18,19]. Similarly, cross-sectional OGTT studies in Japan and China have demonstrated that the prediabetic population does not exhibit a compensatory increase in insulin secretion [20,21]. These findings are supported by a prospective cohort study in Korea, which showed a progressive decline in the disposition index during the transition from normal glucose tolerance to diabetes [22]. The frequently sampled intravenous glucose tolerance test (FSIGT) is a useful and accurate method for evaluating early insulin secretory responses. When performed in the Korean population, FSIGT indicated that the acute insulin response decreased even at the prediabetic stage [23]. The Japanese population also showed a decreased acute insulin response compared to Caucasians [24,25]. A comprehensive meta-analysis of FSIGT studies demonstrated that East Asians have a lower acute insulin response than Caucasians or Africans, regardless of their glucose spectra [26]. Direct quantitative comparisons of β-cell mass between East Asians and Westerners are lacking. However, indirect histological evidence supports a compensatory defect in insulin secretory capacity in East Asians. The Japanese population exhibits limited changes in β-cell mass and Ki67+ replicative β-cells in response to obesity, regardless of the presence of diabetes [27,28], which contrasts with findings in Western populations [29,30]. These findings indicate that compensatory defects in insulin secretion are common in East Asian populations.
SUGGESTED MECHANISM OF DEFECTIVE INSULIN SECRETION IN EAST ASIANS WITH T2DM
Despite clear evidence of insulin secretory defects, the mechanisms underlying the limited insulin secretory capacity in East Asia remain unclear. The systemic threshold for β-cell compensatory capacity is influenced by the insulin secretion demand placed on β-cells, which in turn depends on the number and function of these cells, collectively referred to as functional β-cell mass. This leads to the question of what determines the peak functional β-cell mass in individuals. Previous studies indicate that β-cell mass is established early, as non-obese patients with T2DM exhibit lower β-cell mass regardless of the duration of diabetes or glycemic levels [4]. In human adults, β-cell regeneration primarily occurs in scattered islets, potentially originating from pancreatic duct cells [31]. However, although these scattered islets are commonly observed in adults, they contribute minimally to the overall β-cell mass [32]. The relative area of these scattered islets adjacent to the pancreatic duct accounts for only 0.1% in healthy controls and 0.2% in patients with T2DM, supporting the idea that peak functional β-cell mass is determined early in life. Therefore, environmental factors encountered early in life, along with genetic predispositions, may play a role in the reduced functional β-cell mass observed in East Asians [33].
Several genetic studies have identified East Asian-specific diabetes-related single nucleotide polymorphisms (SNPs) that may contribute to insulin secretory defects in this population [22,34,35]. A genome-wide association study (GWAS) involving 4,106 participants from the Korean Genome and Epidemiology Study found that genetic variants in glucokinase (GCK; rs4607517 G>A) were associated with a decreased disposition index and progression to diabetes [22]. Previously, GCK was shown to be a key regulator of glucose-induced β-cell replication in vivo [36]. Whole-exome sequencing of 917 Korean participants, including 619 with T2DM and 298 controls, suggested that genetic variants of paired box 4 (PAX4; rs2233580 C>T) are associated with the development of T2DM. PAX4 is a transcription factor that plays a crucial role in cell development [37]. Currently, the correlation between the SNP in PAX4 (rs2233580 C>T) and the development of T2DM is under investigation. An integrative meta-analysis of eight GWAS across East Asian countries, involving 6,952 patients with T2DM and 11,865 controls from Korea, Japan, China, Taiwan, Singapore, and the Philippines, identified several East Asian-specific genetic variants [38]. These include SNPs that potentially affect β-cells, such as GLI-similar family zinc finger 3 (GLIS3; rs7041847 G>A), FITM2-R3HDML-HNF4A (rs6017317 T>G), KCNK16 (rs1535500 G>T), and GCC1-PAX4 (rs6467136 A>G). However, the relationship between these genetic variants, compensatory insulin secretion defects, and the onset of T2DM remains unclear. Additionally, the epigenetic variance of β-cells with respect to ethnicity has been poorly characterized. Recently, the epigenetic landscape of human islets has been described at single-cell resolution [39]. Understanding how the epigenetic landscape of East Asian islets differs from that of other ethnicities, and how chromatin accessibility is associated with genetic variance in East Asians, are important topics for future research.
Environmental factors may contribute to the low functional β-cell mass in East Asians. During the developmental period, insulin-positive cells emerge as small clusters at 5 to 7 weeks postconceptional, with numbers increasing significantly by 11 weeks postconception [40]. Post-birth, β-cells are dispersed in small clusters and exhibit a high replication rate during the postnatal period. After 10 weeks, β-cells organize into islets and increase in size. Although the replication rate of β-cells gradually declines, the expansion of pancreatic volume allows for an increase in total β-cell mass until approximately 20 years of age [41]. Therefore, environmental exposure during this period can substantially impact the level of functional β-cell mass. The fetal period is crucial, as intrauterine environmental factors can significantly impact fetal β-cell mass [42,43]. Birth weight is associated with the risk and clinical characteristics of T2DM in humans [44,45]. Intrauterine growth retardation has been shown to alter DNA methylation of the Pdx1 promoter in the fetus [46]. Maternal protein restriction during pregnancy can alter the epigenetic landscape of the Hnf4α enhancer region or decrease miRNA-375 expression in fetal pancreatic β-cells, which reduces β-cell proliferation and insulin secretion after birth [43,47]. Dietary intake during the postnatal period can influence β-cell proliferation and maturation [48,49]. The pubertal stage is a critical period during which baseline β-cell mass can be established. After reaching adulthood, β-cell mass remains plastic, making puberty the last period in which one can significantly increase β-cell mass under physiological conditions, aside from pregnancy [50-53]. A histological study based on human samples demonstrated that individuals with a history of childhood obesity tended to have an increased β-cell area and larger islet size [54]. East Asian countries, including Korea, Japan, and China, experienced extreme poverty and famine after World War II. These environmental influences could have contributed to the low functional β-cell mass in this region.
CHANGING EPIDEMIOLOGICAL LANDSCAPE OF T2DM IN EAST ASIANS
Despite clear evidence of low functional β-cell mass in East Asians, recent studies suggest that the characteristics of patients with T2DM in this region may be changing. Rapid economic development and westernization have significantly increased the prevalence of obesity in East Asian countries. In Korea, for instance, the obesity rate is projected to rise from 27.7% in 1998 to 38.4% in 2021. Concurrently, the prevalence of obesity among patients with T2DM has risen from 37.8% in 1998 to 54.4% in 2020 [9,55]. According to the Shiga Diabetes Clinical Survey, the prevalence of obesity in Japanese patients with diabetes increased from 32.1% in 2000 to 40.9% in 2012 [56]. Similarly, in China, the prevalence of obesity rose from 4.2% in 1993 to 15.7% in 2015 [57]. This trend has led to decreased insulin sensitivity among patients with T2DM. Interestingly, although obesity rates continue to climb in Korea, the rapid increase in T2DM cases has recently shown signs of slowing. Specifically, the annual incidence of diabetes in Korea has decreased by 0.1% annually. In China, despite a 170% increase in the prevalence of diabetes from 1990 to 2019, the age-adjusted incidence rate of diabetes remains lower than the global rate, attributed to the aging of the Chinese population rather than to newly developed T2DM [58]. This changing epidemiological landscape raises the question of whether the functional β-cell mass in this region is adapting.
ADAPTATION OF FUNCTIONAL Β-CELL MASS IN EAST ASIAN COUNTRIES
Currently, there is no direct evidence to suggest a recent increase in functional β-cell mass in East Asian countries. However, the environmental changes experienced by individuals in this region during their early life indirectly support this hypothesis (Fig. 1). Rapid economic development has enhanced nutrient availability and improved socioeconomic and health conditions across many East Asian countries [4,59]. Alongside this, there have been significant advancements in pre- and perinatal care and nutrition. Notably, maternal protein supplementation has increased, which may have contributed to better intrauterine health and, consequently, an increase in fetal functional β-cell mass [60]. Environmental changes during adolescence may also have played a role in increasing functional β-cell mass in East Asia. In Korea, for instance, the prevalence of adolescent obesity has risen sharply from 9.7% in 2012 to 19.3% in 2021 [13]. This increase in BMI among adolescents could have contributed to an increase in functional β-cell mass in Korea, potentially influencing the decreased incidence of T2DM. However, these relationships should be interpreted with caution, as there are conflicting reports regarding the link between adolescent obesity and T2DM [61-63].
Evolving characteristics of type 2 diabetes mellitus (T2DM) in East Asia. East Asian patients with T2DM have traditionally been characterized by low functional β-cell mass. However, over the past few decades, environmental changes early in life may have mitigated the rising incidence of T2DM in this population, likely by increasing their peak β-cell mass. In addition to these early-life environmental changes, the growing proportion of foreign residents is expected to reshape the epidemiological landscape of T2DM in East Asia.
Previously, we suggested that changes in insulin resistance, rather than insulin secretory capacity, occurred among Koreans between 1990 and 2000 [16]. In this study, we analyzed OGTT results from a Korean population across various glucose tolerance categories—normal glucose tolerance, prediabetes, and T2DM—from the 1990s and 2000s. The mean age of participants ranged from the early 40s to early 50s across these subgroups, suggesting that their adolescent years likely occurred between the 1950s and 1970s, a period that may not accurately reflect recent environmental changes during adolescence. Additionally, epigenetic changes resulting from the intrauterine environment may persist across several generations [64]. Therefore, the metabolic impacts of enhanced pre- and perinatal care might not have become apparent until more recently. Future research should focus on trends in functional β-cell mass, utilizing OGTT, FSIGT, and histological examinations to further substantiate this perspective.
The number of foreign residents in East Asian countries is rapidly increasing. For instance, in Korea, the proportion of foreign residents has risen to 4.89%, marking a gradual transition from an ethnically homogeneous to a multiracial society [65]. While the genetic traits of East Asian patients with T2DM discussed in this article are likely to remain consistent, it is crucial to understand how these shifts in genetic background, along with environmental factors, affect the characteristics of patients with T2DM. This understanding is an important area for future research (Fig. 1).
CONCLUSIONS
Low functional β-cell mass is a significant trait in East Asian patients with T2DM, likely resulting from a complex interplay of genetic and environmental factors. Epidemiological evidence indicates a potential adaptation of β-cells in this demographic. The rapid changes in environmental conditions, especially concerning maternal nutrition and adolescent obesity in East Asian countries, might have influenced this adaptation. The characteristics of T2DM in this region seem to evolve dynamically rather than remaining static. Given the genetic predispositions, the insulin secretion defect in East Asians might persist; however, the relative impact of this defect on the development of T2DM appears to be in flux. Further research is needed to thoroughly explore and document the alterations in insulin secretion and sensitivity among East Asians.
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
ACKNOWLEDGMENTS
This work was supported by the Research Foundation of Internal Medicine, The Catholic University of Korea. The authors also wish to acknowledge the financial support of the Catholic Medical Center Research Foundation made in the program year 2024.
This work was supported by the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean government (MSIT) (No. 2022-000965, development of diabetes patients’ healthcare digital twin technology based on continuous lifelog variables) and Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HC19C0341) to Kun-Ho Yoon; and National Research Foundation of Korea (2022R1I1A1A01068401) and the Korea Health Industry Development Institute (RS-2024-00408915, RS-2024-00404132) to Joonyub Lee.