Skeletal maturity and serum insulin-like growth factor-1 level in growing patients with type 1 diabetes mellitus

INTRODUCTION

Diabetes is a metabolic disease that can be diagnosed by persistent high blood sugar levels and disruptions in the metabolism of lipids, carbohydrates, and proteins. These abnormalities occur as a result of defects in the production and/or function of insulin, as outlined by the World Health Organization (WHO).^[1] Type 1 diabetes mellitus (T1DM) is commonly observed in the pediatric population and is distinguished by its tendency to cause growth impairment and delay at the onset of puberty in young individuals.^[2]

Abd-Alrazak et al.^[3] found differences in developmental disability with respect to children with diabetes, regardless of gender, in accordance with the standard deviation score of the WHO. Further studies showed that the body weight and stature of children with diabetes in Iraq have exhibited a marked deviation with respect to the established benchmarks of optimal physical development.^[4] The assessment of skeletal maturity is of prime importance in the development of an orthodontic treatment regimen, as it is characterized by variances in the tempo of growth.^[5]The assessment of skeletal maturity is of great importance in determining the optimal timing of therapy for children with endocrine disorders, including growth disorders such as constitutional growth retardation and growth hormone (GH) deficiency, congenital adrenal hyperplasia, hypothyroidism, and precocious puberty.^[6]

The utilization of the middle phalanx of the third finger (MP3) has been suggested to estimate the skeletal age of a human being, as suggested by Hägg and Taranger.^[7] Dental X-ray filming, along with the utilization of X-ray exposure limiting technology, may be utilized to rapidly record the anatomical changes occurring in the MP3 area. Therefore, this method may be considered a quick, precise, cost-effective, and efficient method of determining skeletal maturation.^[8]

Biomarkers are preferred compared to conventional radiographs because of the capacity to obtain a precise idea of the physiology of the patient, in addition to the low exposure to radiation and tolerance to magnification errors. A conventional method of laboratory diagnosis may be the evaluation of the constituents of blood serum, including insulin-like growth factor 1 (IGF-1), or the constituents of gingival crevicular fluid, including alkaline phosphatase.^[9-11]

Levels of IGF-1 can be detected in various body fluids, including saliva, urine, and serum. The serum levels of IGF-1 often function as an indicator of GH status, which is recognized as an effective marker of mandibular residual growth. Therefore, it is regarded as an effective tool for the diagnosis of the pubertal status of patients. The serum levels of IGF-1 have been found to be constant throughout the day, as opposed to GH, which often varies with the day. Moreover, the levels of IGF-1 have been found to be unaffected in obese individuals, thereby improving its utility as an effective tool.^[12,13]

The literature focused on mean IGF-1 differences versus controls, relationships with glycemic control, e.g., glycated hemoglobin, or general growth outcomes, without integrating IGF-1 into skeletal maturity. While these studies have extensively documented delayed skeletal maturation in diabetic patients, few studies have quantitatively explored the link between IGF-1 levels and bone age discrepancy.^[14]

The objective of this study is to examine the potential correlation between serum IGF-1 levels and MP3 maturation stages, with the intention of determining whether these levels can serve as a reliable clinical indicator of maturity, and to determine the peak of IGF-1 levels that correspond to the MP3 for the pubertal phases of T1DM.

The novelty of the present study lies in demonstrating a significant association between IGF-1 level and skeletal maturation stages using MP3 staging which is simple and clinically feasible to characterize skeletal maturation patterns in T1DM and to examine whether IGF-1 level varies systemically across MP3 stages, suggesting a potential biological pathway that extends beyond descriptive observations. This approach allows stage-specific interpretation rather than age-only comparison and may improve clinical risk for delayed/altered maturation in T1DM. These findings may support the clinical value of IGF-1 as an adjunct marker in growth assessment among diabetic children.

MATERIAL AND METHODS

Radiographical exposure

An intraoral periapical digital sensor was utilized to capture a radiograph of MP3 on the left hand, due to its cost-effectiveness, widespread availability, and lower radiation exposure compared with orthopantomograms, cephalometric radiographs, and hand-wrist radiographs.^[17]

The procedure involved positioning the hand with the palm facing downward on a level surface that was devoid of any metallic material. The MP3 of the left middle finger was positioned in a manner that ensured its alignment with the central region of the X-ray sensor. The cone of the portable dental X-ray machine, which operates at 60 kilovolts peak and 7 milliamperes, was placed in close proximity to the middle phalanx at a right angle to the dental X-ray film. The duration of exposure was configured at 0.25 s. The MP3 radiograph approach, as introduced by Rajagopal and Kansal,^[18] was employed for the purpose of interpretation as shown in [Figure 1].

Close

Figure 1: Modified middle phalanx of the third finger method stages described by Rajagopal and Kansal. MP3: Middle Phalanx of the third finger, F: Full/Flush, FG: Fusion Gapping, G: Gapping/Capping, H: Half fusion, HI: Incomplete Fusion, I: Islands/Integrated

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RESULTS

Recordings of the MP3 stage for each sample were independently determined by two researchers at different time points. The researchers were not provided with patient data, including personal identifiers, such as name, age, sex, or IGF-1 levels. The MP3 phases were assessed by the lead investigator on two occasions for all samples, with a 15-day gap between evaluations. The observed kappa coefficient of 0.855 and the intra-observer reliability rate of 85% indicate a high level of agreement, one approaching perfection.

As illustrated in [Table 1], the sample was categorized into three distinct groups according to the maturational state of growth. [Table 2] presents descriptive data, namely the MP3 stage distribution and median IGF-1 level for each age group and both genders. Although an early rise in IGF-1 levels was observed during the late pre-pubertal period, the highest median IGF-1 level in boys was recorded during the pubertal stage H, particularly at age 14 (195.527 ng/mL), corresponding to the peak growth phase.

The levels of IGF-1 exhibited a consistent upward trend during the pubertal phase and demonstrated a small drop from the pubertal to the post-pubertal phase, namely between the H and I stages. The median concentration of IGF-1 throughout this period was recorded as 152.466 ng/mL.

As illustrated in [Table 2], in the girls, the concentration of the hormone steadily increased from the pre-pubertal period (96.463 ng/mL) to its peak during the pubertal phase at G, H, and HI stages (168.756 ng/mL) at the age of 12. Gender difference is obvious at the age of 12 and 13 years old (p ≤ 0.05).

The Kruskal–Wallis H test [Table 3] demonstrated a significant difference in the median IGF-1 level among different pubertal stages. The mean rank exhibited an upward trend over time, rising from 23.88 during the pre-pubertal phase to 49.41 during the pubertal phase before finally reaching 58.07 during the post-pubertal period.

[Table 4] illustrates the discernible differences between the MP3 pubertal stages. The distribution of individuals in the post-pubertal phase was found to be much lower compared with the other phase, indicating prominent differentiation between the two periods.

DISCUSSION

The levels of IGF-1 have the ability to exist independently of GH due to the direct stimulation of IGF-1 production by androgens throughout the period of puberty. The IGF-1 levels can be assessed through the analysis of blood, urine, and saliva samples.

The study conducted by Kanbur-Oksüz et al.^[19] has shown that the levels of IGF-1 showed a peak in the later stages of puberty. This showed that the levels of IGF-1 are correlated with sexual maturation as well as chronological age. In the present study, the analysis for IGF-1 has been conducted on serum samples, despite the previous studies conducted by various researchers^[20,21] that had shown the levels of IGF-1 in urinary and salivary samples. This is because the levels of IGF-1 vary considerably throughout the day, and the present study has been conducted based on the suggestions made by Ryan et al.^[20] that the levels of IGF-1 should be measured only in serum samples.

Although previous study^[20] has focused on the stability of IGF-1 and its diagnostic benefits, newer research has shed some light on the matter. IGF-1 is widely used as a biochemical marker of GH action because of its lower short-term variability compared with the pulsatile secretion of GH. However, its measurement is subject to biological variability, methodology, and pre-analytical conditions.^[22,23] Newer developments in the analysis of the peptide have improved the stability and reliability of the measurement of IGF-1 in the clinical setting. Recent advances in the standardization of the measurement of IGF-1 by LC-MS/MS have improved the reliability of the measurement of IGF-1. The role of age and puberty-specific reference values has also come into the spotlight.^[24]

The IGF-1 immunoassay method demonstrated superior accuracy in assessing skeletal maturity compared with alternative radiography techniques. Radiographic procedures are employed as a means to eliminate potential discrepancies among examiners. The estimation of residual mandibular growth can be reliably determined using this methodology.

The findings of this study are in line with previous research,^[10,15,25] which had consistently demonstrated that levels of IGF-1 exhibit a pattern of low concentration during the pre-pubertal stages of MP3, reach their peak during puberty, and, thereafter, exhibit a gradual fall post-puberty. This could be related to the activation of GH release by adrenal and gonadal steroids, as reported by Masoud et al.^[26]

Nevertheless, the findings indicated that IGF-1 levels remained significantly elevated in a number of participants, even after they had reached the stages of MP3HI and MP3I, which are often associated with the completion of growth. This can be confirmed by previous research conducted by Masoud et al.^[26] The apparent elevation observed during the pre- and post-pubertal phase likely reflects individual variability within small age subgroups rather than the true biological peak, which was clearly identified at stage H during puberty.

The present study demonstrated that the median level of IGF-1 within that specific timeframe reached its highest point at 14 years of age for boys and 12 years of age for girls, as shown in [Table 2]. This is in accordance with the findings of Gupta et al.,^[27] in which the highest levels of IGF-1 were observed in male participants at an average age of 14.08 years, which corresponded to the CS4 stage. In female participants, the peak IGF-1 values were observed at CS3, with a mean age of 12.04 years. Studies conducted by Masoud et al.^[10] and Ishaq et al.^[28] almost agreed with this study. It was observed that Chinese and Danish girls reached their highest levels of IGF-1 at the age of 12–14 years, respectively. Similarly, based on a study conducted on the Turkish population, boys reached their peak IGF-1 levels at 14–16 years.

The median of IGF-1 levels in girls was found to be considerably greater during G, H, and HI phases in comparison with the remaining stages. Boys in the FG, G, and H stages demonstrated elevated median IGF-1 levels, which subsequently declined as they advanced to stage I, whereas the girls demonstrated comparable outcomes and attained their maximum serum IGF-1 levels 1 year earlier than boys, as per the study by Ishaq et al.^[28]

The present study found that in different MP3 stages, the median IGF-1 values were slightly higher in boys compared with girls, which is consistent with the findings of a prior study conducted by Sharmada et al.^[29] The results of this research were found to be of poor quality compared to those of the study by Brabant et al.,^[30] which focused on establishing reference values for blood IGF-1 levels for both male and female subjects across different age groups.

The variances of the results from previous studies can be used to explain the variances in chronological ages related to peak IGF-1 levels. The variations may also occur based on the inclusion criteria used by other studies, which may cover T1DM, racial backgrounds, genetic makeup, environmental conditions, and the method used for the research.

The overall pattern of variation of IGF-1, i.e., low levels before puberty, a marked increase during puberty, and subsequent declining levels, is consistent with that reported in normal pediatric populations.^[25]

However, in pediatric populations with T1DM, there is an alteration in the GH-IGF-1 axis, as indicated by decreased portal insulin levels. The lack of insulin affects hepatic GH receptor and IGF-1 synthesis, resulting in a state of GH resistance with high circulating levels of GH.^[31]

Past research on the endocrine system has established that adolescents with T1DM are found to have an abnormal regulation of the GH/IGF axis, including reduced bioactive IGF-1 and feedback mechanisms compared with non-diabetic individuals.^[22] However, the physiological pattern of the pubertal increase in IGF-1 is reportedly normal in T1DM adolescents, although the concentration and regulation of the hormone are different.

This indicates that the temporal pattern of bone maturation appears to be biologically coordinated in T1DM patients, although endocrine modulation might affect the magnitude of IGF-1 levels.

The limitation of the study was that the analysis of gender differences was not conducted within the groups. For this purpose, a larger number of patients would be needed, although difficulties might arise when trying to involve younger patients at the time of the study. It should be noted that the cross-sectional nature of the study, the absence of body mass index and obesity levels, as well as the presence of other factors (e.g., glycemic control, insulin treatment) might be considered as limitations of the study.

Furthermore, the emphasis placed on the inclusion of such investigations within the orthodontic program for the residents appears to be of particular significance to this end.^[32]

CONCLUSION

The use of serum levels of IGF-1 is an additional tool to increase the accuracy of the timing of orthodontic treatment and is an additional tool to evaluate skeletal maturity in children and adolescents with T1DM. Further studies are necessary to validate the use of serum levels of IGF-1 to optimize the timing of orthodontic treatment.