Long-term tracking of glycosylated hemoglobin levels across the lifespan in type 1 diabetes: from infants to young adults

Sujin Kim; Seo Jung Kim; Kyoung Won Cho; Kyungchul Song; Myeongseob Lee; Junghwan Suh; Hyun Wook Chae; Ho-Seong Kim; Ahreum Kwon

doi:10.6065/apem.2346180.090

Ann Pediatr Endocrinol Metab > Volume 29(4); 2024 > Article

Kim, Kim, Cho, Song, Lee, Suh, Chae, Kim, and Kwon: Long-term tracking of glycosylated hemoglobin levels across the lifespan in type 1 diabetes: from infants to young adults

Original Article

Annals of Pediatric Endocrinology & Metabolism 2024;29(4): 242-249.

Published online: August 31, 2024

DOI: https://doi.org/10.6065/apem.2346180.090

Long-term tracking of glycosylated hemoglobin levels across the lifespan in type 1 diabetes: from infants to young adults

Sujin Kim¹

, Seo Jung Kim¹

, Kyoung Won Cho¹

, Kyungchul Song¹

, Myeongseob Lee¹

, Junghwan Suh¹

, Hyun Wook Chae¹

, Ho-Seong Kim¹

, Ahreum Kwon²

¹Department of Pediatrics, Severance Children's Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea

²Dr Kwon's Growth Clinic, Seoul, Korea

Address for correspondence: Ahreum Kwon Dr Kwon's Growth Clinic, Banpo-daero, Seocho-gu, Seoul 06506, Korea Email: armea@naver.com

Received August 11, 2023 Revised November 2, 2023 Accepted December 12, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

Glycosylated hemoglobin (HbA1c) is commonly used as a monitoring tool in diabetes. Due to the potential influence of insulin resistance (IR), HbA1c level may fluctuate over a person's lifetime. This study explores the long-term tracking of HbA1c level in individuals diagnosed with type 1 diabetes mellitus (T1DM) from infancy to early adulthood.

Methods

The HbA1c levels in 275 individuals (121 males, 43.8%) diagnosed with T1DM were tracked for an average of 9.4 years. The distribution of HbA1c levels was evaluated according to age with subgroups divided by gender, use of continuous glucose monitoring (CGM), and the presence of complications.

Results

HbA1c levels were highest at the age of 1 year and then declined until age 4, followed by a significant increase, reaching a maximum at ages 15–16 years. The levels subsequently gradually decreased until early adulthood. This pattern was observed in both sexes, but it was more pronounced in females. Additionally, HbA1c levels were higher in CGM nonusers compared with CGM users; however, regardless of CGM usage, an age-dependent pattern was observed. Furthermore, diabetic complications occurred in 26.8% of individuals, and the age-dependent pattern was observed irrespective of diabetic complications, although HbA1c levels were higher in individuals with diabetic complications.

Conclusions

HbA1c levels vary throughout the lifespan, with higher levels during adolescence. This trend is observed regardless of sex and CGM usage, potentially due to physiological IR observed during adolescence. Hence, physiological IR should be considered when interpretating HbA1c levels during adolescence.

Keywords: Type 1 diabetes mellitus, Adolescents, HbA1c, Age, Sex, Insulin resistance

Highlights

· In individuals with type 1 diabetes mellitus, glycosylated hemoglobin levels often peak during puberty and then decline, regardless of sex, continuous glucose monitoring (CGM) use, or complications.

· The physiological insulin resistance during adolescence makes glucose management challenging.

· Proactive strategies, including the use of CGM, are essential for achieving glycemic targets and preventing complications during this critical period.

Introduction

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by destruction of insulin-producing beta cells in the pancreas, resulting in a lifelong dependence on insulin therapy [1]. Strict glycemic control is essential for reducing the risk of complications, mortality, and morbidity related to diabetes [2-4]. This control is predominantly monitored through glycosylated hemoglobin (HbA1c) levels. Despite limitations in assessing glycemic variability due to fluctuations in blood sugar levels, measuring HbA1c is currently considered the gold standard for assessing long-term glycemic control in diabetic patients, as it provides an average glycemic level [5]. Numerous studies have demonstrated that HbA1c levels less than 7% significantly reduce both microvascular and macrovascular complications associated with diabetes [6]. However, in young children (aged <6 years), individualized glycemic targets are necessary to balance the risks of hypoglycemia and the developmental burdens of intensive treatment plans. The American Diabetes Association (ADA) recommends special consideration to the risk of hypoglycemia in children younger than 6 years, as they are often unable to recognize, articulate, and manage hypoglycemia [7].

Meanwhile, variations in insulin sensitivity based on age and gender in children and adolescents have been documented [8]. During adolescence, it is presumed that fluctuations in sex hormone secretion [9] and growth hormone (GH)/insulin-like growth factor I (IGF-I) levels [10,11] occur due to growth, leading to insulin resistance (IR) [12]. In other words, significant changes in GH/IGF-I and sex steroid levels during adolescence can result in physiological IR, regardless of obesity, leading to a decrease in insulin sensitivity by approximately 25%–30% [13]. Additionally, females show higher IR and homeostasis model assessment of IR values compared with males from prepubertal to pubertal stages [14-16]. Insulin sensitivity and resistance are critical factors influencing glycemic control in individuals with T1DM. Consequently, in such pediatric patients, the presence of physiological IR at different ages may contribute to variations in HbA1c based on age, puberty, and sex, even among those who have been effectively managing their diabetes [17].

In this study, we investigated the longitudinal trajectory of HbA1c levels in individuals diagnosed with T1DM from infancy to early adulthood, specifically between the ages of 6 months and 30 years, to analyze the pattern of HbA1c levels across age groups. The pattern was analyzed using continuous glucose monitoring (CGM). Additionally, we investigated whether there were differences in HbA1c patterns between participants with and without diabetic complications.

Materials and methods

1. Design and study population

From November 2005 to November 2022, 279 participants with T1DM were recruited from the Pediatric Endocrinology Department at Severance Children's Hospital in South Korea. Two participants with syndromic diseases and 2 participants who had malignant tumors were excluded (Fig. 1). Therefore, the final study population comprised 275 participants, ranging in age from 6 months to 30 years, who were diagnosed with T1DM. The study focused on individuals with a minimum follow-up period of 6 months after diagnosis. HbA1c levels were measured at regular intervals, ranging from 3 to 6 months, between November 2005 and November 2022. HbA1c levels obtained at the time of initial diagnosis and within 3 months after diagnosis were excluded from the datasets. The distribution of HbA1c values was analyzed based on age. To evaluate the mean HbA1c levels across the lifespan, individuals were classified based on age at the time of HbA1c measurement regardless of body mass index (BMI) to include longitudinal datasets.

Moreover, this study investigated the average HbA1c values across age groups, considering sex and utilization of CGM as contributing factors. Additionally, longitudinal trajectories of HbA1c levels were monitored in subgroups categorized based on the presence of complications, including diabetic retinopathy, nephropathy, and neuropathy.

2. Measurements

HbA1c levels were measured at the outpatient clinic using the third-generation Roche Diagnostics immunoturbidimetric inhibition method (TINIA) and the Cobas c 513 instrument (Roche Diagnostics, Mannheim, Germany) following the manufacturer's guidelines.

Diabetic complications encompass ophthalmological, nephrological, and neurological complications. Diabetic retinopathy is diagnosed by an ophthalmologist based on the examination of 2 fundus photographs per eye, with one centered on the optic disc and the other on the macula. Diabetic nephropathy is defined as an estimated glomerular filtration rate less than 60 mL per minute per 1.73 m2 and/or the presence of proteinuria and/or albuminuria. Albuminuria, which includes both microalbuminuria and macroalbuminuria, is defined as the presence of any of the following criteria: (1) urine albumin/creatinine ratio greater than 3 mg/mmol, (2) 24-hour total urine albumin exceeding 30 mg/24 hours, or (3) spot urine albumin exceeding 30 mg/L. Proteinuria is determined by either a 24-hour total urine protein greater than 3.5 g/day or an albumin/creatinine ratio greater than 30 mg/mmol. Neurological complications are assessed through autonomic nerve function tests and sensory and motor nerve conduction velocity tests using appropriate reference standards [18].

3. Statistical methods

The results are presented as mean (percentage) with standard deviation using IBM SPSS Statistics ver. 26.0 (IBM Co., Armonk, NY, USA). An independent 2-sample t-test was used for continuous variables, and the Rao-Scott chi-square test was used for categorical variables. All P-values were calculated using the 2-tailed t-test, and P-values lower than 0.05 indicated significant differences. The figures in this study were generated using R ver. 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria), and the longitudinal trajectory curves for HbA1c were smoothed using the locally weighted scatterplot smoothing (LOESS) method.

4. Ethical statement

This study was approved by the Institutional Review Board of Yonsei University College of Medicine (approval number: 2023-1548-001) and was conducted according to the tenets of the Declaration of Helsinki.

Results

1. Baseline characteristics

A total of 275 participants (121 males, 43.8%) was enrolled. Table 1 presents the baseline characteristics of the participants. The mean age at diagnosis was 7.5±4.0 years (males, 7.7±4.1 years; females, 7.4±3.9 years). The total follow-up duration was 9.4±7.5 years (males, 9.0±7.7 years; females, 9.8±7.4 years). The average number of HbA1c measurements per individual was 22.3±14.3, totaling 6,135 HbA1c measurements in the study population. Among the study participants, 36.2% (n=100; males, 46.0%) utilized CGM, and 74 (26.8%) experienced complications related to diabetes. These complications included retinopathy, nephropathy, and neuropathy with respective incidences of 11.2%, 10.9%, and 12.7%. The duration from diabetes onset until complication occurrence was 15.2±6.0 years for retinopathy, 9.2±6.0 years for nephropathy, and 9.6±6.7 years for neuropathy (Table 1).

2. HbA1c levels across age groups

Mean HbA1c level was measured at various ages, ranging from 0–30 years, and is depicted in Fig. 2A and the Supplementary Table 1. The highest average HbA1c value observed was 9.2% (n=17) at the age of 1 year. Subsequently, HbA1c levels declined until the age of 4 years, reaching 7.7%. Thereafter, there was a significant increase in HbA1c levels, peaking at greater than 9% at ages of 15–16 years. Following this peak, HbA1c levels gradually decreased until age 30, with values near ~7% between 25–30 years. These data suggest that HbA1c levels are low during childhood, gradually increase during adolescence to a peak at ages 15–16, and gradually decrease thereafter.

3. HbA1c levels by sex

Fig. 2B depicts the trajectory of HbA1c levels stratified by sex. The patterns of changes in HbA1c levels across ages were similar to those shown in Fig. 2A, where HbA1c levels were low during childhood, gradually increased and peaked during adolescence, and exhibited a gradual decrease thereafter. However, the changes were more pronounced in females. Particularly, among females, there was a significant increase in HbA1c levels between the ages of 9 and 12 years. At the peak point, which occurred at the age of 15, HbA1c levels in females reached 9.3%, which was higher than in males (8.6%). After the age of 15 to 16 years, both males and females exhibited a decrease in HbA1c levels. Overall, these observations indicate that HbA1c levels increase in both adolescent males and females and decrease afterward, but this pattern is more pronounced in females.

4. HbA1c levels according to CGM use

The study divided participants into 2 groups based on use of CGM and compared HbA1c levels different age groups, as shown in Fig. 3. In the group using CGM, HbA1c values were consistently lower across all age groups. Notably, the difference in HbA1c levels between the 2 groups was most pronounced in infants and prepubertal individuals. However, a similar pattern was observed in the 2 groups, as depicted in Fig. 2A, where the highest value was reached at the age of 15, followed by a gradual decrease. In summary, HbA1c levels increased during adolescence and subsequently decreased in early adults, regardless of CGM use, which can significantly reduce HbA1c levels.

5. HbA1c levels based on diabetic complications

Fig. 4 illustrates the trajectory of HbA1c levels in participants with and without diabetic complications. Individuals with any diabetic complications consistently exhibited elevated levels of HbA1c compared with those without complications, regardless of age (Fig. 4A). However, the overall trend in HbA1c levels in relation to age was similar to that observed in Fig. 2. We conducted further analysis to assess the progression of complications by categorizing them into retinopathy, nephropathy, and neuropathy. Among participants with retinopathy (Fig. 4B), HbA1c levels were initially lower or comparable before the age of 10, but there was a tendency toward higher HbA1c levels after puberty onset. In participants with diabetic nephropathy, the overall HbA1c levels were higher compared with participants without complications (Fig. 4C). Furthermore, in participants with diabetic neuropathy, HbA1c levels were elevated between the ages of 5 and 16 years, followed by a convergence of levels thereafter (Fig. 4D). Taken together, these findings suggest that HbA1c levels rise during adolescence regardless of diabetic complications.

Discussion

We generated a longitudinal trajectory of HbA1c levels across distinct age groups and stratified the data into subgroups based on sex, CGM use, and the presence of diabetic complications. Longitudinal tracking of HbA1c levels over time illuminates the dynamic nature of glycemic control in individuals with T1DM, with a notable increase in HbA1c levels during adolescence. This study demonstrates that the pattern of HbA1c levels remains consistent across subgroups of sex and CGM use. Furthermore, the increase in HbA1c levels during adolescence was consistent regardless of future occurrence of complications. Nevertheless, it is crucial to carefully regulate HbA1c levels during adolescence to minimize fluctuations, as this measure plays a significant role in preventing potential diabetic complications.

IR tends to increase during puberty, typically between the ages of 10 and 13 years [19]. It is presumed that variations in the secretion of sex hormones [9] and GH/IGF-I [10,11] occur in adolescence as the body grows, leading to IR [12]. In other words, pubertal children experience reduced insulin-stimulated glucose metabolism, leading to physiological IR [14,15,20]. The insulin response in pubertal children has been reported to be 30% lower than those in prepubertal children and adults [12]. Likewise, adolescents with T1DM also experience IR during puberty [14,15,20]. Physiological IR during puberty may exert an influence on high HbA1c levels. In a study examining factors influencing HbA1c in healthy children without diabetes, HbA1c levels increased with age, and the most significant difference was observed during pubertal development in both males and females. In females, HbA1c levels particularly increased during the transition from Tanner stage II to III [21].

It is hypothesized that HbA1c levels increase during adolescence not only due to physiological IR, but also due to the influence of various social factors. This critical period, particularly between the ages of 14 to 18 years, usually entails greater individual responsibility for diabetes management. Parents often reduce their oversight of glucose monitoring, insulin adjustments, and injections during this period, leading to diminished compliance and self-care practices [22]. These sociological aspects, along with IR observed during puberty, likely contribute to elevated HbA1c levels. Pinhas-Hamiel et al. [23] similarly found that 75% of patients in the pubertal age group had higher HbA1c levels compared with the recommendations provided by the ADA. The elevated HbA1c levels during adolescence, which were also observed in the present study, may be attributed to physiological IR during puberty and various social factors influencing diabetes management in adolescence. Hovestadt et al. [21] also found that HbA1c levels were significantly lower even in healthy adolescents in high socioeconomic status groups. These findings indicate that many external factors can be responsible for fluctuations in HbA1c levels throughout life.

The pattern of HbA1c increase during adolescence exhibited a consistent trend even when analyzed by sex. Nonetheless, this trend was more pronounced in females. In males, HbA1c levels were generally higher than in females younger than 10 years, with a slight increase during puberty. In contrast, in females, a substantial increase in HbA1c levels from ages 10 to 12 years was observed, reaching a peak at 14 and 15 years, and this increase was more pronounced in females than males. These findings are consistent with previous studies [8,23] that also found elevated HbA1c levels in females compared with males. The observed differences in HbA1c levels between sexes may be attributed to the increased degree of IR in females during puberty compared with males [24-26]. The observed sex disparity in IR is often attributed to variations in adiposity or the timing of pubertal development. However, even after accounting for these factors [25,27], a significant unexplained difference in IR between sexes remained. Consequently, higher IR in females relative to males leads to elevated HbA1c levels. The findings of this study further support the consistent presence of this trend in T1DM. In other words, among adolescents with T1DM, HbA1c increases in both males and females due to physiological IR. However, because IR is higher in females than in males, this tendency is believed to be more pronounced in females. We also analyzed HbA1c pattern based on age at the time of diagnosis, but there was no significant difference.

Recently, CGM use in individuals with T1DM has increased from 7% in 2010–2012 to 30% in 2016–2018 [28]. CGM implementation has been shown to significantly decrease HbA1c levels compared with blood-glucose self-monitoring [29], and it has also been associated with a reduction in severe hypoglycemic events among individuals with T1DM [30-32]. Mean HbA1c level among CGM users was significantly lower compared with nonusers. However, both CGM users and nonusers exhibited the observed HbA1c increase pattern from early childhood to adolescence. In other words, while CGM use can decrease the magnitude of HbA1c and aid in glucose control management in T1DM, it may not mitigate physiologic IR during adolescence.

Fig. 4A demonstrates that HbA1c levels are consistently higher in patients with diabetic complications across all measured ages. However, there is a pattern of increase from 5 years to 15 years, followed by a decline and a subsequent stable trend after 25 years of age. This pattern is similar in patients without complications, indicating that the characteristic age-related pattern observed in HbA1c levels is maintained regardless of diabetic complications. High HbA1c levels have consistently been associated with an increased risk of chronic diabetic complications [33-35]. Furthermore, when analyzing each subgroup of complications, distinct characteristics can be observed. In patients with diabetic retinopathy, HbA1c levels showed a significant increase from ages 10–15 years during puberty, even though lower HbA1c levels were observed in individuals younger than 10 years (Fig. 4B). Puberty is considered one of the risk factors contributing to diabetic retinopathy [36,37], suggesting that the combination of challenges in glycemic control in this age group, along with concurrent hormonal changes, accelerates the risk of diabetic retinopathy during puberty [37-39]. In patients with diabetic nephropathy and neuropathy, higher HbA1c levels were observed across all age groups, especially for individuals 5–15 years old (Fig. 4C and D), compared with those without these complications, underscoring the importance of blood-glucose management. Patients who have both diabetic nephropathy and neuropathy account for 10.8% of individuals with diabetic complications. At the time of HbA1c measurement, average HbA1c was higher than that of the total complications group (9.5%±2.8% vs. 8.8%±2.2%, P<0.01). Elevated HbA1c may contribute to higher values in younger individuals. However, because complications studies typically begin after the 5-year post-diagnosis point or when the patient is 10 years old or older, the dataset for HbA1c values for individuals 8 years old or younger who also have complications may be relatively limited, which would result in insufficient statistical adjustments, potentially leading to an overestimation of HbA1c values. In diabetic retinopathy, puberty has also been implicated in development of diabetic nephropathy and neuropathy [40]. From this perspective, despite the potential increase in HbA1c levels during puberty due to IR, it is crucial to strictly adhere to guidelines for effectively preventing diabetic complications.

The strength of this study lies in its ability to provide clinicians with a longitudinal HbA1c track in T1DM across age groups. This allows clinicians to assess glycemic control in comparison to guidelines and to observe similar patterns across ages, regardless of sex and CGM use. Additionally, by analyzing HbA1c patterns in patients with diabetic complications, it becomes possible to identify specific time points when greater attention should be given to glycemic control.

However, some limitations should be considered. First, we measured HbA1c levels in patients of different ages without considering height, weight, and BMI to include extensive longitudinal datasets. In future research, incorporating BMI values into the analysis of the longitudinal HbA1c trajectory would likely enable a more comprehensive investigation. Second, we analyzed HbA1c levels across ages without considering specific individual Tanner stages and socioeconomic background. We included longitudinal data to the fullest extent possible to mitigate these factors. Third, regarding diabetic complications, particularly retinopathy, there were some patients who did not undergo regular examinations. As a result, there is a possibility of delayed diagnosis; however, it is presumed that the majority of cases was detected early, and significant bias is not expected.

In conclusion, in individuals with T1DM, HbA1c levels peak during puberty and then decline regardless of sex, CGM use, or presence of diabetic complications. This suggests that maintaining proper sugar levels may be challenging due to physiological IR during adolescence. Nevertheless, it is crucial to acknowledge that inadequate blood-glucose control during this phase can increase the risk of diabetic complications. Therefore, proactive interventions are essential for achieving glycemic targets during puberty, with CGM potentially playing a pivotal role in facilitating glycemic control and preventing complications.

Supplementary Material

Supplementary Table 1 can be found via https://doi.org/10.6065/apem.2346180.090.

Supplementary Table 1.

Mean level of glycosylated hemoglobin (HbA1c) at the age of measurements according to sex

apem-2346180-090-Supplementary-Table-1.pdf

Notes

Conflicts of interest

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

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Data availability

The data that support the findings of this study can be provided by the corresponding author upon reasonable request.

Author contribution

Conceptualization: AK, SK; Data curation: SK, SJK, KS; Formal analysis: ML, HWC; Methodology: JS, HSK; Project administration: ML, HSK; Visualization: SK, KWC; Writing - original draft: SK, AK; Writing - review & editing: SK, AK, HSK.

Fig. 1.

Study selection and baseline population. DM, diabetes mellitus; MODY, Maturity-Onset Diabetes of the Young.

Fig. 2.

Trajectory of HbA1c levels across age groups. (A) Total participants. (B) Groups divided by sex. HbA1c, glycosylated hemoglobin.

Fig. 3.

Trajectory of HbA1c levels across age groups according to CGM use. HbA1c, glycosylated hemoglobin; CGM, Continuous glucose monitoring.

Fig. 4.

Trajectory of HbA1c levels across age groups according to diabetic complications. (A) Diabetic complications. (B) Diabetic retinopathy. (C) Diabetic nephropathy. (D) Diabetic neuropathy. HbA1c, glycosylated hemoglobin.

Table 1.

Baseline characteristics of the participants

Characteristic	Total (n=275)	Male (n=121, 43.8%)	Female (n=154, 56.2%)	P-value
Age at diagnosis (yr)	7.5±4.0	7.7±4.1	7.4±3.9	0.12
Follow-up period (yr)	9.4±7.5	9.0±7.7	9.8±7.4	0.31
HbA1c (%)	8.4±1.9	8.2±1.9	8.6±1.9	<0.01*
HbA1c measurement (n)	22.3±14.3	22.0±14.4	22.6±14.1	0.24
CGM	100 (36.2)	46 (38.0)	54 (35.1)	0.61
Diabetic complication	74 (26.8)	27 (22.3)	47 (30.5)	0.15
Retinopathy	31 (11.2)	9 (7.4)	22 (14.3)	0.20
Age at diagnosis (yr)	23.0±4.4	22.7±4.3	23.2±4.5	0.37
Duration until diagnosis (yr)	15.2±6.0	12.4±6.1	16.0±6.0	0.22
Nephropathy	30 (10.9)	10 (8.3)	20 (13.0)	0.17
Age at diagnosis (yr)	19.2±17.8	19.1±5.4	19.3±5.1	0.98
Duration until diagnosis (yr)	9.2±6.0	10.3±5.6	8.6±6.2	0.48
Neuropathy	35 (12.7)	15 (12.4)	20 (13.0)	0.09
Age at diagnosis (yr)	18.5±5.2	19.7±5.4	17.6±5.0	0.27
Duration until diagnosis (yr)	9.6±6.7	11.4±7.2	8.3±6.2	0.01*

Values are presented as mean±standard deviation or number (%).

HbA1c, glycosylated hemoglobin; CGM, continuous glucose monitoring.

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