TYPE Perspective

PUBLISHED 09 November 2023

DOI 10.3389/fendo.2023.1260623

Early detection of type 2

OPEN ACCESS diabetes risk: limitations of
EDITED BY
Roberto Visentin,
University of Padova, Italy
current diagnostic criteria
REVIEWED BY
Patricio Colmegna, Jiale Zhang 1†, Zhuoya Zhang 2†, Kaiqi Zhang 3†, Xiaolei Ge 3,
University of Virginia, United States
Alexander E. Berezin, Ranran Sun 4* and Xu Zhai 3*
Zaporizhia State Medical University, Ukraine
Muhammad Sajid Hamid Akash,
1
Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences,
Government College University, Faisalabad, Beijing, China, 2 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China,
Pakistan
3
Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, China, 4 Dongfang
Hospital, Beijing University of Chinese Medicine, Beijing, China
*CORRESPONDENCE
Xu Zhai
jameszhai34@163.com
Ranran Sun
492660508@qq.com Type 2 diabetes (T2D) is the leading cause of diabetes worldwide and is
†
These authors have contributed
increasing rapidly, especially in youth. It accounts for most diabetes deaths in
equally to this work and share adults ≥20 years old in the Americas, with type 2 diabetes responsible for most of
first authorship the disease burden. The incidence and burden of type 2 diabetes in adolescents
RECEIVED 21 July 2023 and young adults have risen in recent decades globally. Countries with lower
ACCEPTED 23 October 2023
socioeconomic status had the highest incidence and burden, and females
PUBLISHED 09 November 2023
generally had higher mortality and disease burden than males at ages <30
CITATION
Zhang J, Zhang Z, Zhang K, Ge X, Sun R
years. Early diagnosis and management are crucial to delaying progression, but
and Zhai X (2023) Early detection of type 2 current diagnostic criteria based on glucose thresholds and glycated
diabetes risk: limitations of current hemoglobin have limitations. Recent analyses show that prediabetes increases
diagnostic criteria.
Front. Endocrinol. 14:1260623. cancer risk. Better diagnostic criteria are urgently needed to identify high-risk
doi: 10.3389/fendo.2023.1260623 individuals earlier. This article discusses the limitations of current criteria and
COPYRIGHT explores alternative approaches and future research directions.
© 2023 Zhang, Zhang, Zhang, Ge, Sun and
Zhai. This is an open-access article
KEYWORDS
distributed under the terms of the Creative
Commons Attribution License (CC BY). The type 2 diabetes, diagnostic criteria, prediabetes, fasting plasma glucose,
use, distribution or reproduction in other
glycated albumin
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in
this journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.

Introduction
Type 2 diabetes (1) is responsible for most diabetes cases globally and is increasing
rapidly, particularly in young people. Diabetes accounts for 5.9% of all deaths in adults aged
20 or older in the Americas, with T2D accounting for most of the disease burden (2). The
incidence and burden of T2D in adolescents and young adults globally increased from 1990
to 2019. Countries with a low-middle and middle sociodemographic index had the highest
incidence and burden rates. Women generally had higher mortality and Disability-
Adjusted Life Year rates than men at ages <30 years (3). From 2013 to 2016, 34.5% of
American adults had prediabetes (4). According to a 2016 report (5), more than 13 million
adults in California (46% of all adults in the state) are estimated to have prediabetes or
undiagnosed diabetes. In Chinese adults (6), the estimated prevalence of prediabetes is
35.7%. In September 2008, the Canadian Diabetes Association (7) released diagnostic

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Zhang et al. 10.3389/fendo.2023.1260623

criteria for prediabetes: fasting plasma glucose (FPG) level of 6.1-6.9 criteria within this article and explore potential alternative
mmol/L or impaired glucose tolerance (IGT) as demonstrated by modalities and future research focal points.
the oral glucose tolerance test (OGTT). A recent meta-analysis (8)
involving 16 studies and 891,426 participants worldwide showed
that prediabetes increases cancer risk by 15%. 5-10% of prediabetes Insufficiency of current
patients develop diabetes yearly, and an equal proportion of people diagnostic criteria
recover from high blood sugar levels (9). The global incidence of
prediabetes is increasing, and in 2021, the number of people with Current diagnostic criteria for T2D are based on absolute blood
impaired fasting glucose (IFG) reached 298 million, accounting for glucose thresholds and glycated hemoglobin concentration values,
5.8% (10). Experts predict that by 2030, more than 470 million but the hyperglycemic state is a continuous and dynamic process.
people will have prediabetes (9). These limitations may result in misclassification and misdiagnosis,
Therefore, early diagnosis and management are crucial for as the American Diabetes Association (ADA) and World Health
delaying the progression of T2D (11). Generally, HbA1c or Organization (WHO) recommend different glucose thresholds and
patients with blood glucose levels at a subdiabetic level are usually HbA1c levels for diagnosing prediabetes, as shown in Table 1.
diagnosed with moderate hyperglycemia, known as prediabetes, Overall, three main aspects are highlighted.
often called intermediate hyperglycemia. Prediabetes is usually First, hyperglycemia is a dynamic and continuum process, meaning
defined as blood glucose concentration above normal but below that glucose levels are not static but vary with time and other factors. This
the diabetes threshold and is a high-risk state for the development process can range from normal glucose levels progressively rising to
of diabetes (12). Although these two concepts may appear similar, prediabetes and, ultimately, diabetes. Hyperglycemia is not only diabetes
they convey distinct meanings. Prediabetes describes the state but also prediabetes and normoglycemia. 35-50% of prediabetics have a
where blood glucose levels are between normal and diabetic, very high risk of developing diabetes within five years (15). In the
emphasizing the risk of progressing to diabetes in this stage. On development of T2D, fasting, and postprandial glycemia become
the other hand, moderate hyperglycemia is employed to describe abnormally stable. Postprandial 1-hour hyperglycemia correlates
elevated blood glucose levels that are above normal but have not yet closely with subclinical inflammation and target organ damage,
reached the threshold for diabetes, placing greater emphasis on the increasing cardiovascular and microvascular complications and death
continuum between this stage and diabetes. Therefore, it represents risk. Studies (16, 17) show that 1-hour plasma glucose during OGTT has
three groups of individuals: those with impaired fasting glucose enhanced predictive capability for T2D, with 1-hour post-OGTT
(IFG), impaired glucose tolerance (IGT), and elevated glycated hyperglycemia associated with a 4.27-fold increased risk of retinopathy
hemoglobin (HbA1c). The 2023 ADA guidelines (13) still use and a 1.89-fold risk of peripheral vascular complications, plus a 29%
IFG, IGT, or HbA1c levels of 5.7%-6.4% to diagnose prediabetes. higher risk of diabetes mortality. Studies (18, 19) have explored multi-
However, current diagnostic criteria may not detect high blood stage models of diabetes progression, with a basic consensus that
sugar levels until the disease has progressed to a later stage, making compensation, stable adaptation, and early decompensation phases
it difficult to identify high-risk individuals early. In addition, typically occur. Initially, there is a long compensatory phase with
different organizations and institutions provide different insulin resistance, increased insulin secretion, and b-cell hypertrophy.
standards, leading to confusion and uncertainty. Recently, a In the stable adaptation phase, b-cells cannot fully compensate for
commentary (14) published in The Lancet has brought attention increasing insulin resistance, leading to elevated fasting and
to these issues, underscoring the paramount significance of these postprandial glucose levels. The unstable early decompensation phase
aspects. Motivated by previous investigations, we have composed occurs when b-cells fail to match insulin resistance, causing glucose levels
this perspective article. Presently, the conventional standards rely to rise rapidly - typically from prediabetes to manifest diabetes. Research
on absolute values of blood glucose thresholds and HbA1c finds (20, 21) that HbA1c criteria can more accurately identify
concentrations; however, it is crucial to recognize that high blood prediabetes as HbA1c reflects average glucose over 2-3 months while
sugar status represents a continuous and dynamic process. The fasting plasma glucose (FPG) reflects current levels. Additionally, HbA1c
existing diagnostic criteria for T2D prove inadequate in early standards avoid FPG limitations, e.g., patients may eat before testing,
identifying high-risk individuals, leading to delayed diagnoses and affecting accuracy. Besides HbA1c and FPG criteria, 2-hour postprandial
heightened health risks (14). Given the limitations of the current glucose is used to diagnose prediabetes. However, discrepancies exist
diagnostic criteria, we thoroughly examine the insufficiency of these between these standards.

TABLE 1 Diagnostic criteria for prediabetes.

Index ADA 2003 ADA 2010 WHO IEC

Fasting glucose concentration 5.6-6.9mmol/L 5.6–6.9 mmol/L 6.1–6.9 mmol/L NA

2 h glucose concentration after 75 g glucose load 7.8 – 11.0mmol/L 7.8–11.0 mmol/L 7.8–11.0 mmol/L NA

HbA1c NA 5.7–6.4% (39–46 mmol/mol) NA 6.0–6.4% (42–46 mmol/mol)

ADA, American Diabetes Association; WHO, World Health Organization; IEC, International Expert Committee; NA, Not Available or Not Adopted as Criterion.

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There is a lack of consensus on consistent standards and criteria. Clinically, prediabetics can have normal fasting glucose but 2-hour
The ADA and WHO currently provide different glucose thresholds and postprandial glucose between 7.8 and 11.0 mmol/L. HbA1c may be
HbA1c levels for diagnosing prediabetes. The ADA recommends a around 6.0%, below diagnostic cutoffs. Thus, prediabetics can
fasting glucose concentration of 5.6-6.9 mmol/L while WHO defines potentially reverse diabetes through diet, exercise and medications.
6.1-6.9 mmol/L. The ADA also sets a lower HbA1c threshold of 5.7- Many “prediabetics” have intermediate hyperglycemia, not true
6.4% (39-46 mmol/mol) for diagnosing prediabetes. There are prediabetes, so the concept requires a clear definition. Recent papers
differences in the diagnostic criteria for prediabetes. Recently, a (11, 14) suggest that a useful intermediate hyperglycemia definition
Chinese study (22) of 2318 subjects found that fasting plasma requires clinical relevance, sensitivity and specificity. If thresholds are
glucose and HbA1c can diagnose diabetes, but HbA1c should be too high, the definition lacks sensitivity to identify at-risk groups
used cautiously for prediabetes alone. Another Southeast Asian study correctly. If too low, it lacks specificity with high false positives
(23) found significant discordance between fasting plasma glucose and incorrectly classifying healthy individuals. Thus, evidence-based
HbA1c measurements in diagnosing diabetes, with fasting plasma definitions of intermediate hyperglycemia are needed from the
glucose underestimating the burden of undiagnosed diabetes. international community. One study (27) found that the faster
HbA1c-defined diabetes and prediabetes prevalence were 9.7% and fasting glucose levels rise and the higher BMI, blood pressure,
34.6% respectively versus 6.3% and 12.1% for fasting plasma glucose. triglycerides and lower HDL-cholesterol, the greater the risk of
The weighted kappa statistic for HbA1c concordance with fasting diabetes development. This indicates why more research is needed to
plasma glucose was 0.55, with the most discordance in the prediabetes determine optimal diagnostic criteria and strategies, and formulate
group. This suggests that using HbA1c as an adjunct test for diabetes more personalized, precise prevention and treatment plans. However,
diagnosis has significant implications for disease prevalence and clinical in addition to existing concepts, we can delve into a pioneering
practice. Another study (24) found that while HbA1c measurement has theoretical framework called the pan-glycemia theory. Anchored in
advantages like simplicity, standardization and reliability, its pan-vascular diseases, this theory presents a fresh perspective by
performance for screening prediabetes remains debated. Some data integrating moderate hyperglycemia and prediabetes. It underscores
show (25) that HbA1c may miss some patients and be influenced by the significance of a comprehensive and dynamic approach to blood
factors like anemia and kidney dysfunction. In contrast, FPG requires glucose management, aiming to establish a holistic endocrine-vascular
fasting and may be affected by medications. Both metrics have pros and health management framework. The pan-glycemia theory emphasizes
cons; the appropriate test depends on the situation. A Japanese study the entire spectrum of blood glucose management, ranging from the
(26) found that using ADA HbA1c criteria of 5.7-6.4% or IFG to assess early stages of moderate hyperglycemia to prediabetes. It highlights the
prediabetes prevalence and progression to diabetes showed that HbA1c importance of dynamic monitoring and personalized interventions.
screening missed many prediabetics. However, both HbA1c and FPG This all-encompassing management approach holds the potential to
effectively identified high-risk groups with similar predictions. Thus, mitigate the risk of diabetes development while offering more precise
combining tests may better target those at risk of developing diabetes strategies for prevention and treatment. Early identification of
for early intervention. Due to ethnic and regional differences, there is prediabetes and moderate hyperglycemia through dynamic
no consensus on optimal diagnostic standards. Discrepancies in monitoring and individualized interventions enables timely
diagnostic criteria for prediabetes across organizations highlight the intervention and treatment. Treatment plans can be customized
need for unified global standards. To achieve this, we propose an based on glycemic characteristics and adjusted promptly according
international expert committee to systematically review evidence, to continuous monitoring. Sequential surveillance of blood glucose and
conduct meta-analyses, and build consensus through discussions. other markers gauges treatment response, allowing optimized regimens
First, convene a diverse, cross-regional panel of specialists to for better control, lower diabetes risk, and precise management
promote unified criteria development. Second, perform approaches (28). Clinical physicians can develop personalized
comprehensive systematic reviews integrating findings across entities, exercise prescriptions based on patients’ glycemic characteristics and
emphasizing variations in existing criteria and clinical implications. physical conditions. For instance, aerobic exercises such as brisk
Third, enable regular panel discussions to debate diagnostic criteria walking, swimming, or cycling are recommended for insulin-resistant
merits, align theoretical and practical applications, and share patients to improve peripheral tissue glucose uptake. Endurance
experiences. Fourth, leverage sustained deliberations to reach a training, such as weightlifting or high-intensity interval training can
consensus and formulate robust, evidence-based unified criteria for reduce hepatic glucose production for patients with excessive hepatic
population differences. Finally, implement regular evaluations to glucose production. Physicians can improve patients’ glycemic status
update criteria per emerging insights, ensuring continued scientific through individualized exercise prescriptions and provide targeted
rigor and clinical utility. Through such efforts, consistent standards treatment and prevention strategies.
would optimize prediabetes diagnosis and management globally,
thereby improving patient outcomes.
Prediabetes does not necessarily equate to intermediate Importance of early identification
hyperglycemia. Prediabetes is a continuum with gradually rising
glucose levels but does not imply intermediate hyperglycemia. The Type 2 diabetes is a chronic metabolic disease characterized by
physiological fasting and 2-hour postprandial glucose concentrations in hyperglycemia. Long-term high blood glucose can damage multiple
most prediabetic individuals are typically lower than current diagnostic organs, increasing the risk of cardiovascular disease, kidney disease,
thresholds so they may go undetected or undiagnosed as prediabetes. retinopathy and other complications (29). Delayed diagnosis of

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diabetes may increase many health risks. When blood glucose levels published by the American Association of Clinical Endocrinologists
remain above normal for an extended period, multiple organ (AACE) provided a detailed discussion on CGM metrics,
systems can be harmed, raising the risk of cardiovascular, renal, application, and data interpretation for assessing glycemic
neurological and ocular complications (30). In early diabetes, control. Integrating CGM in routine clinical practice improves
symptoms may be absent, making it easy to overlook. Untreated prediabetes management by providing continuous blood glucose
high blood sugar can damage blood vessels and the nervous system, data. Recent advancements in CGM technology (42), such as sensor
leading to various complications. Thus, early identification and improvements and device miniaturization, have made CGM
treatment of diabetes can effectively reduce these risks. Besides systems more reliable and user-friendly. Patients’ increasing
known risk factors, alternative methods can help identify demand for better blood glucose control and quality of life has
individuals at risk for type 2 diabetes. These methods can boosted the acceptance of CGM. However, problems exist, such as
improve early identification and intervention of at-risk high costs limiting its use in certain regions and patient populations
individuals. The following are three potential alternative (43). CGM data requires collaboration and education between
diagnostic approaches for prediabetes: healthcare professionals and patients. Technical issues, like sensor
Glycated albumin (GA): GA is a novel biomarker reflecting drift or data loss, can affect data accuracy. Coverage and
short-term glycemic variations in diabetic patients (31). Like reimbursement policies influence CGM’s application, with
HbA1c, GA measurement reflects average glucose over 2-3 weeks Medicare supporting it in the US, but CGM is not covered by
and can thus monitor and manage diabetes (32). Studies show GA national insurance in China, and patients bear all costs.
testing has been widely researched and applied (33, 34). It has Glycated serum protein (GSP) testing: Glycated serum protein
higher sensitivity and specificity, improving early diabetes diagnosis (GSP) is a novel biomarker that reflects diabetic patients’ glycemic
and treatment (35). The sensitivity of HbA1c plus GA was higher control (44). GSP detection is simple, rapid, reproducible and less
than HbA1c alone (78% vs 50%, P <0.001), detecting nearly 80% of influenced by other metabolic factors. Compared to HbA1c, GSP
African prediabetics. GA≥17.1% could screen most undiagnosed has higher sensitivity and specificity, making it more accurate for
diabetics while measuring fasting glucose plus GA reduced false- diabetes monitoring in conditions like renal dysfunction and
positive screening rates by fasting glucose alone by 33.75% (36). anemia. A study (45) demonstrated a robust positive correlation
Abnormal GA is an important indicator for OGTT screening in between fructosamine levels and HbA1c, indicating that
high-risk groups, especially those with normal fasting glucose. fructosamine and HbA1c may serve as useful glycemic
Continuous glucose monitoring (CGM): CGM is a novel biomarkers for patients with concomitant diabetes and cancer,
technique that continuously records patients’ glucose fluctuations, including those undergoing chemotherapy, utilizing
including postprandial excursions in daily life (37). Compared to glucocorticoids, or with anemia, hypoalbuminemia, or reduced
traditional glucose testing methods, such as fingerstick renal function. GSP testing has potential value in early diagnosis
measurements or periodic blood tests, CGM offers several of diabetes and diabetic complications (46). A 2016 study (47)
advantages. Firstly, CGM provides a complete report of a found GSP performed well in predicting diabetes based on 2h
patient’s glucose profile throughout the day, capturing the glucose and HbA1c levels in overweight and obese youth ages 10 to
dynamic nature of glucose fluctuations. This allows for a better 18. Some research also found that GSP detection has value for
understanding of glycemic variability and identifies specific patterns screening and predicting diabetic complications (48, 49). In
or trends that may be missed with intermittent testing (38). summary, adjunct diagnostic methods may effectively identify
Moreover, CGM devices can detect glucose changes in response individuals at risk for type 2 diabetes. Figure 1 illustrates the
to meals, exercise, stress, and medication, providing valuable advantages of the three alternative placement methods.
insights into how these factors affect blood sugar levels. This Supplemental Material 1 compares cost-effectiveness, availability,
information is crucial for patients and healthcare providers in and practicality among the three methods. However, further
developing personalized treatment plans and making informed research evidence is required to support their clinical application
decisions regarding diet, physical activity, and medication in diagnosis. The validation of diagnostic models for prediabetes is
adjustments. For individuals at risk of developing diabetes, such crucial to ensure the accuracy and reliability of biomarkers,
as those with prediabetes, CGM technology holds potential as a including GA, CGM, and GSP testing. By validating these
diagnostic and management tool. Participants with a fasting blood biomarkers, their effectiveness in capturing short-term glycemic
glucose level below 100 mg/dL experienced impaired glucose variations, monitoring glucose levels continuously, and reflecting
tolerance while continuously monitoring for at least 24 hours glycemic control can be confirmed. Establishing the validity of these
(39). CGM identified an additional 15% of prediabetes and 2%, diagnostic tools enables reliable and accurate prediabetes
suggesting that abnormal glycemia was more prevalent than before identification, subsequently facilitating the implementation of
and that the CGM indicator may be more sensitive (40). The 2022 appropriate interventions and ultimately improving patient
Clinical Practice Guideline for Developing Diabetes Care Plans (41) outcomes. In addition, some studies (50, 51) show post-load and

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FIGURE 1
Three alternative placement methods.

1-hour OGTT glucose levels have higher sensitivity in predicting decisions and provide tailored interventions and management
type 2 diabetes progression than fasting glucose, 2-hour OGTT strategies that address the unique needs of each individual. In
glucose or HbA1c. Thus,1-hour OGTT glucose may identify high- summary, international consensus on prediabetes diagnosis,
risk individuals (52). Moving forward, it is critical to identify strategies, and more personalized, precise prevention and treatment
programs for early identification. plans is critical to addressing rising type 2 diabetes incidence.
Recognizing hyperglycemia as a continuum, not based solely on
glucose/HbA1c cutoffs.
Conclusion
Given rising type 2 diabetes incidence and complications, Data availability statement
identifying and preventing type 2 diabetes early is critical. However,
limitations exist in diagnosing prediabetes, with different cutoffs for The original contributions presented in the study are included
fasting glucose and HbA1c. Thus, other methods are needed to identify in the article/Supplementary Material. Further inquiries can be
high-risk groups. Prediabetes remains challenging to diagnose due to directed to the corresponding authors.
its obscurity (17). Lack of consensus on prediabetes diagnosis poses
challenges in estimating prevalence across populations. Future research
should focus on more sensitive, specific biomarkers. Optimizing Author contributions
glucose and HbA1c thresholds and dynamic monitoring are needed
to diagnose prediabetes accurately. Exploring optimal strategies to JZ: Conceptualization, Writing – original draft. ZZ: Formal
prevent and control prediabetes is important to lower type 2 diabetes Analysis, Writing – original draft, Writing – review & editing. KZ:
risk. In utilizing the new diagnostic model, it is essential to Formal Analysis, Writing – review & editing. XG: Formal Analysis,
comprehensively explain the decision-making process based on the Writing – review & editing. RS: Conceptualization, Funding
model’s output. This process enables determining whether an acquisition, Writing – review & editing. XZ: Conceptualization,
individual belongs to a high-risk group or requires further Funding acquisition, Writing – review & editing.
assessment and management. Several factors influence this decision-
making process, including specific patient characteristics, additional
clinical considerations, and the incorporation of relevant guidelines or Funding
policies. Constructing a comprehensive framework for the decision-
making mechanism facilitates a deeper understanding of the potential The author(s) declare financial support was received for the
diagnostic indicators and their practical application in clinical practice. research, authorship, and/or publication of this article. The work
This framework enables healthcare professionals to integrate various was supported by the Scientific and technological innovation project
factors and considerations, empowering them to make informed of the China Academy of Chinese Medical Sciences (CI2021A00307).

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Zhang et al. 10.3389/fendo.2023.1260623

Conflict of interest organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
The authors declare that the research was conducted in the claim that may be made by its manufacturer, is not guaranteed or
absence of any commercial or financial relationships that could be endorsed by the publisher.
construed as a potential conflict of interest.

Supplementary material
Publisher’s note
The Supplementary Material for this article can be found online
All claims expressed in this article are solely those of the authors at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1260623/
and do not necessarily represent those of their affiliated full#supplementary-material

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