Next Article in Journal
Atrial Functional Tricuspid Regurgitation (AFTR) Is Associated with Better Outcome After Tricuspid Transcatheter Edge-to-Edge Repair (T-TEER) Compared to Ventricular FTR (VFTR)
Previous Article in Journal
Genetic Polymorphism of Zinc Transporter-8 Gene (SLC30A8), Serum Zinc Concentrations, and Proteome Profiles Related to Type 2 Diabetes in Elderly
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Influence of Sex and Age on Irisin Levels in Pediatric Type 1 Diabetes: A Pilot Study

1
The Institute of Pediatric Endocrinology, Diabetes and Metabolism, “Dana-Dwek” Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
2
Faculty of Medicine and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
3
The Endocrine Laboratory, The Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
4
Department of Epidemiology and Preventive Medicine, School of Public Health, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
5
Nursing Services, “Dana-Dwek” Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(3), 793; https://doi.org/10.3390/jcm14030793
Submission received: 26 December 2024 / Revised: 11 January 2025 / Accepted: 21 January 2025 / Published: 25 January 2025
(This article belongs to the Section Endocrinology & Metabolism)

Abstract

:
Background: Irisin is a myokine involved in the browning of adipocytes, the regulation of body composition and the enhancement of glycemic control. Additionally, irisin has been suggested to play a role in signaling mechanisms associated with the onset of puberty. In this study, we aimed to explore the interaction between muscle and adipose indices, urine irisin levels and glycemic control. Methods: This cross-sectional pilot study enrolled 76 consecutive pediatric patients (mean age 11.7 ± 3.8 years) diagnosed with type 1 diabetes (mean disease duration 2.1 ± 1.6 years). Body composition was assessed by bioelectrical impedance analysis (MFR z-score and skeletal muscle mass index). Urine irisin levels and glycemic control parameters (HbA1c, insulin dose-adjusted A1c [IDAA1c]) were evaluated. One linear regression model, stratified by sex, analyzed the sex-specific impact of puberty and age on irisin levels. A second linear regression model explored the associations of selected variables with irisin levels. Results: The first linear regression model revealed that irisin levels rise with age in prepubertal boys and decline with increased age among pubertal boys. The second linear regression analysis revealed no significant associations between irisin levels and metabolic parameters after adjusting for covariates. In contrast to boys, there were no significant interactions found in girls. Conclusions: Our novel findings revealed sex and age differences in the irisin levels of children and adolescents with type 1 diabetes. The dynamics underlying the role of irisin during pubertal development in the pediatric population with diabetes warrant further exploration.

1. Introduction

Irisin is a myokine that arises from the cleavage of fibronectin type III domain 5 (FNDC5) and is released by both adipose tissue and skeletal muscle following exercise [1]. Irisin is proposed to contribute to mediating some of the beneficial effects associated with physical activity, such as weight loss and thermoregulation [2]. Irisin also plays a role in the browning of adipocytes [3], the downregulation of adipogenesis and the reduction of lipid accumulation [4]. It has also been hypothesized to play a role in the hormonal signaling surrounding puberty in healthy children [5]. However, reports on this subject vary, with some studies concluding that irisin levels are higher in pubertal children [6], while others suggest that there is no variation in irisin levels across pubertal stages [7,8].
The influence of exercise on irisin levels can differ based upon factors such as the type, intensity and duration. Sporadic bouts of intense endurance or strength training have been associated with significant but transient increases in circulating irisin, typically peaking shortly after exercise [9,10,11]. Regular exercise may also influence FNDC5 and irisin levels, although responses can vary widely [11,12].
Some studies have linked irisin to the regulation of body composition and to cardiovascular and metabolic diseases in adults and in children [3,13]. However, other studies have yielded conflicting results regarding associations between irisin levels, blood pressure levels, fat mass and muscle mass in the pediatric population [3]. Some studies have reported elevated irisin levels in children with obesity compared to healthy children [14], suggesting an association between irisin levels, body mass index, weight class and waist-to-hip ratio [8,15].
Pediatric patients with type 1 diabetes exhibited higher irisin levels compared to healthy controls [16]. One study on the association between irisin and glycemic control in 96 pediatric patients with type 1 diabetes revealed a negative correlation between irisin levels and HbA1c, serum glucose levels and diabetes duration, suggesting a potential association with better glycemic control [16]. Following type 1 diabetes diagnosis and the initiation of insulin therapy, many patients experience partial clinical remission, characterized by improved glycemic control and lower exogenous insulin requirements due to a temporary recovery in beta cell function [17]. That phase has been linked to better long-term glycemic control [18,19,20] and to a reduction in lipid levels, which can lower the risk of cardiovascular complications [21,22]. Investigating the relationship between irisin and partial clinical remission may suggest its potential as a contributing factor during that phase.
Given the reported relationship between irisin levels and glycemic control [3], as well as the link between the muscle-to-fat ratio (MFR) and glycemic control [23,24,25], we hypothesized that there is a potential bi-directional relationship between irisin levels and MFR. Therefore, in addition to investigating the variables of sex and age in association with irisin levels, our pilot study also examined the interaction between muscle indices, urine irisin levels and glycemic control in pediatric patients with type 1 diabetes.

2. Materials and Methods

2.1. Study Design and Patients

Pediatric patients with type 1 diabetes who were being routinely followed-up on by our outpatient clinic were invited to participate. All children aged 5–18 years with a diabetes duration of <5 years, an available urine sample and same-day body composition assessment were eligible. The study protocol conformed to the Declaration of Helsinki principles (0950-20-TLV) and was approved by the institutional ethics review board. Written consent to participate was obtained from the parents of minors, while individuals aged ≥ 16 years signed an assent form. During 2022, 81 of the 82 consecutive eligible patients with type 1 diabetes agreed to participate in the study, and three adolescent girls were excluded due to menstruation at the time of their visit. The size of this pilot study was restricted due to the cost of FNDC5 ELISA kits. The results of 2 of the 78 urine samples that were assayed were not analyzed due to procedural errors. The 76 patients included in the study were stratified according to sex and pubertal stage.

2.2. Study Protocol

Each participant underwent a complete physical examination including anthropometric measurements, vital signs, pubertal stage according to Tanner, measurements of their capillary HbA1c levels (on a DCA 2000 device from Bayer Diagnostics Inc., Mississauga, ON, Canada, with a 95% confidence interval of 4.3–5.7%) and their body composition (bioelectrical impedance analysis [BIA]).
Data on physical activity were collected by means of self-reported questionnaires on daily activity levels. Physical activity was categorized as “adequate” if participants met the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommendations of ≥60 min of daily physical activity, as shown in Table 1 and Table 2. While this measure provides a general indication of adherence to physical activity guidelines, it does not capture detailed information on the type, intensity or duration of exercise, which can influence irisin release. Due to these limitations and potential for self-reporting bias, physical activity was excluded from the linear regression models to minimize confounding and ensure a more robust analysis.

2.3. Body Composition Assessment

Since 2018, one of the therapeutic goals of our Diabetes Center has been to reduce modifiable cardiovascular disease risk factors. Patients with type 1 diabetes receive comprehensive glycemic control and metabolic risk assessment, including body composition measurement through bioimpedance analysis (BIA; Tanita Body-Composition Analyzer, Tanita MC-780 MA and GMON Professional Software, GMON Pro) during clinic visits as part of the routine standard of care [26]. The measurement takes a few minutes per subject and has been clinically verified as being accurate and reliable [27,28]. BIA measures both whole body and segmental (trunk, upper and lower limbs) fat and muscle. It also provides data adjusted for sex, age and height. Calculated BIA variables include appendicular skeletal muscle mass (ASMM; the sum of muscle mass of four limbs), MFR (the ratio between ASMM and fat mass) and a skeletal muscle mass index (the ratio between ASMM and height in meters squared). The sex- and age-specific reference curves for MFR in healthy white children and adolescents were used for calculation of the z-scores [29].

2.4. Urine Protein Analysis

Fresh urine samples were collected and stored at −80 °C until analysis. The samples were analyzed in duplicate by ELISA for fibronectin type III domain-containing protein 5 (FNDC5), a precursor of irisin by a chemistry analyzer (Cloud-Clone Corp., Katy, TX, USA), which has high sensitivity and specificity for the detection of FNDC5, with a 15.6–1000 pg/mL detection range and an intra-assay coefficient of variability of <10%.

2.5. Definition of Study Variables

Pubertal stage was determined according to the Marshall and Tanner criteria, which categorize physical changes during puberty into five stages (Tanner stages 1–5). Prepubertal individuals were classified as being in Tanner stage 1. Pubertal onset was defined as the appearance of Tanner stage 2 genitalia in boys, with a testicular volume of ≥4 mL, and the development of breast buds in girls [30,31]. The clinical remission phase was defined as insulin dose-adjusted A1C: IDAA1C [A1c (percent)] + [4 × insulin dose (units per kilograms per day)] ≤ 9. This definition, validated by a stimulated C-peptide level > 300 pmol/L, has shown a strong correlation with residual beta cell function and is therefore a useful tool in predicting partial remission [17]. Blood pressure percentiles were calculated with an online age-based pediatric BP calculator [32].

2.6. Statistical Analysis

All analyses were performed using Statistical Package for the Social Sciences software version 28 (SPSS Inc., Chicago, IL, USA). All performed statistical tests were two-sided. The Kolmogorov–Smirnov test or the Shapiro–Wilk test were performed to test the normality of continuous data. Data are expressed as means ± standard deviation (SD) for normally distributed variables and median and interquartile range [IQR] for skewed distributions. Comparisons between groups for continuous variables were made using independent sample t-tests for normally distributed data and Mann–Whitney U tests for skewed distributions. Categorical variables were evaluated by the chi-squared test or Fisher’s exact test as appropriate. One linear regression model, stratified by sex, was used to analyze the sex-specific impact of puberty and age on irisin levels. A second forward linear regression model was used to explore the associations of selected variables on irisin levels.

3. Results

The cohort consisted of 76 children and adolescents with type 1 diabetes, including 48 boys (63.2%) and 28 girls (36.8%). Of the total cohort, 36 participants (47.3%) were prepubertal. The mean age of the cohort was 11.7 ± 3.8 years, with a mean diabetes duration of 2.1 ± 1.6 years. At the time of assessment, the median HbA1c was 7.2% [IQR 6.7, 8.1]. A comparative analysis of metabolic parameters in pediatric patients with type 1 diabetes stratified by sex is provided in Table 1.
The pubertal boys with type 1 diabetes were characterized by significantly higher skeletal muscle mass indices (p < 0.001), MFR z-scores (p = 0.004) and creatinine levels (p = 0.001) compared to the prepubertal boys (Table 2). A linear regression model, stratified by sex, was used to analyze the sex-specific impact of puberty and age on irisin levels. That model found a significant interaction between age and puberty (β= −11.0, SE = 4.2, p = 0.011), while irisin levels rose with increasing age among prepubertal boys, whereas irisin levels declined as age increased among pubertal boys (Table 3, Figure 1). Following these results, a second forward stepwise linear regression analysis was conducted to investigate the relationship between irisin levels and metabolic parameters. First, sex and age were entered into the model as covariates to control for their potential confounding effects. In the second step, the added parameters included the duration of diabetes and the HbA1c, IDAA1c, creatinine, skeletal muscle mass index, MFR z-score and blood pressure levels. The model found no significant associations.
Pubertal girls with type 1 diabetes were characterized by significantly higher skeletal muscle mass indices (p < 0.001) and creatinine levels (p = 0.007) than prepubertal girls (Table 2). Unlike boys, no significant interaction was found between puberty and age in girls. Additionally, no significant association with irisin was found in the model which included duration of diabetes, HbA1c, IDAA1c, creatinine, skeletal muscle mass index, MFR z-score and blood pressure levels.

4. Discussion

To the best of our knowledge, this pilot study is the first to examine interactions between irisin levels in different pubertal stages among pediatric patients with type 1 diabetes. Our findings revealed sex differences in the interaction between irisin and age, with age-related trends differing by pubertal stage solely among boys. Specifically, irisin levels increased as age advanced in prepubertal boys and decreased as age advanced in pubertal boys. There were no comparable pubertal stage-related differences in irisin levels among girls with type 1 diabetes.
Irisin has been hypothesized to play a role in the signaling mechanisms associated with the activation of the hypothalamic–pituitary–gonadal axis and the onset of puberty [5]. Our evidence of the rise in irisin with increasing age among prepubertal boys together with the opposite trend in pubertal boys supports this hypothesis. Interestingly, studies in rodents and primates have shown this mechanism to be more dominant in girls [33,34,35]. The difference between sexes may suggest divergent biological mechanisms with specific roles of estrogen and testosterone, although the limited sample of girls may have also contributed to this difference in our study.
Irisin has been associated with a reduction in insulin resistance [36]. An alternative explanation for the elevated irisin levels within the male prepubertal subgroup could be related to the physiological insulin resistance observed preceding and during puberty [37,38]. The onset of puberty in individuals with obesity is characterized by a supraphysiological rise in insulin resistance, which was associated with an increase in irisin levels [6], highlighting the relationship between insulin resistance and irisin levels in humans. This rise in irisin levels, which was potentially triggered by heightened insulin resistance, may contribute to the patterns observed in our study.
There is contradictory evidence regarding the association between irisin levels and cardiometabolic parameters in the pediatric population. Previous studies have indicated that irisin levels are correlated with cardiometabolic parameters such as blood pressure and BMI, suggesting the potential use of irisin as a surrogate marker for metabolic syndrome [13,39,40]. Conversely, other studies did not find significant associations between these factors [3,41]. Our study aligns with the latter group, providing specific insights into the pediatric population with type 1 diabetes, as we found no association between irisin levels and body composition parameters or blood pressure levels.
We analyzed boys and girls separately in accordance with the findings of studies that documented substantial sex differences in body composition among individuals with type 1 diabetes. Girls with type 1 diabetes were reported to have higher fat and truncal fat percentages, along with lower MFR z-scores compared to boys [23,24]. Furthermore, sexual dimorphism was observed in glycemic control, with girls exhibiting higher HbA1c levels at diagnosis as well as over time [42]. They also reportedly spend less time within the optimal blood glucose range [43]. These findings underscore the importance of sex-specific approaches in managing pediatric patients with type 1 diabetes to optimize clinical outcomes.
Although they are preliminary, our findings suggest potential pathways for improving the clinical understanding of metabolic parameters in children and adolescents with type 1 diabetes. Further investigations into the relationship between irisin levels, glycemic control and metabolic markers may help in guiding the development of more personalized treatment strategies. They could also provide insights into insulin requirements and the early markers of cardiovascular risk, ultimately contributing to the better management of type 1 diabetes in pediatric patients.
Our study has certain limitations. The main ones are related to the small sample size, which necessitates caution when interpreting our findings, and the cross-sectional design, which prevents the establishment of causal relationships. Another limitation is that it may not be generalizable to the entire pediatric population with type 1 diabetes, since the sample comprises children attending a single pediatric diabetes center. Furthermore, physical activity data were excluded from the analysis due to their being self-reported, despite the importance of examining associations between physical activity and irisin. A key strength of this study is the uniformity of medical care delivered by a multidisciplinary team within a single hospital-based diabetes center, as well as the novel approach of exploring the interaction between muscle indices, urinary irisin levels, glycemic control and puberty in this population.
In conclusion, our preliminary findings highlight sex and age differences in irisin levels among children and adolescents with type 1 diabetes. The absence of interactions between urinary irisin levels, muscle indices or glycemic control call for further research to clarify the potential role of irisin in metabolic and hormonal processes during different stages of pubertal development in children and adolescents with diabetes.

Author Contributions

Conceptualization, A.B. and Y.L.; methodology, S.A., A.B. and Y.L.; validation, A.B. and Y.L.; formal analysis, S.A., M.Y.-G., A.B. and Y.L.; investigation, S.A., A.B. and Y.L.; resources, A.B. and Y.L.; data curation, S.A., O.G., I.L., A.D., G.S., A.B. and Y.L.; writing—original draft preparation, S.A. and Y.L.; writing—review and editing, S.A., O.G., M.Y.-G., I.L., A.D., G.S., A.B. and Y.L.; supervision, Y.L. All authors have read and agreed to the published version of the manuscript.

Funding

The irisin kits used in this study and the APC were provided with funding from Sanofi grant number PEDM-12-2024-TLV. The company had no role in the study design, data collection, analysis or interpretation of the results.

Institutional Review Board Statement

The study protocol conformed to the Declaration of Helsinki principles and was approved by the ethics committee of the Tel Aviv Sourasky Medical Center on 18 January 2021 (0950-20-TLV). The data were handled in accordance with the principles of good clinical practice.

Informed Consent Statement

Written consent to participate was obtained from the parents of minors, while individuals aged ≥ 16 years signed an assent form.

Data Availability Statement

The data used to support the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgments

This article is a revised and expanded version of a poster entitled “Sex, age and irisin levels in pediatric type 1 diabetes: a pilot study”, which was presented at ESPE 2024 (17.11.24-18.11.24). [Stewart V. ESPE 2024 Abstracts. Horm Res Paediatr. 2024 Oct 10;97(Suppl. 3):1–737.]. This work was performed in partial fulfillment of Shay Averbuch’s MD thesis requirements of the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. The authors are grateful to the multidisciplinary team of dedicated nurses, dieticians, psychosocial workers and physicians at the Diabetes Center at Dana-Dwek Children’s Hospital, and Esther Eshkol, the institutional medical copyeditor, for editorial assistance.

Conflicts of Interest

Yael Lebenthal is the head of an institute that receives research grants from Medison Pharma, Novo Nordisk, Pfizer and Sanofi. The irisin kits used in this study were provided with funding from Sanofi. The company had no role in the study design, data collection, analysis or interpretation of the results. Yael Lebenthal has also received speaker fees, travel grants and served on advisory boards for Medison Pharma, Novo Nordisk, Pfizer and Sanofi. All other authors declare no conflicts of interest.

References

  1. Waseem, R.; Shamsi, A.; Mohammad, T.; Hassan, M.I.; Kazim, S.N.; Chaudhary, A.A.; Rudayni, H.A.; Al-Zharani, M.; Ahmad, F.; Islam, A. Fndc5/irisin: Physiology and pathophysiology. Molecules 2022, 27, 1118. [Google Scholar] [CrossRef]
  2. Qi, J.-Y.; Yang, L.-K.; Wang, X.-S.; Wang, M.; Li, X.-B.; Feng, B.; Wu, Y.-M.; Liu, S.-B.; Zhang, K. Mechanism of CNS regulation by irisin, a multifunctional protein. Brain Res. Bull. 2022, 188, 11–20. [Google Scholar] [CrossRef]
  3. Elizondo-Montemayor, L.; Mendoza-Lara, G.; Gutierrez-DelBosque, G.; Peschard-Franco, M.; Nieblas, B.; Garcia-Rivas, G. Relationship of Circulating Irisin with Body Composition, Physical Activity, and Cardiovascular and Metabolic Disorders in the Pediatric Population. Int. J. Mol. Sci. 2018, 19, 3727. [Google Scholar] [CrossRef] [PubMed]
  4. Kołodziejski, P.A.; Pruszyńska-Oszmałek, E.; Wojciechowicz, T.; Sassek, M.; Leciejewska, N.; Jasaszwili, M.; Billert, M.; Małek, E.; Szczepankiewicz, D.; Misiewicz-Mielnik, M.; et al. The role of peptide hormones discovered in the 21st century in the regulation of adipose tissue functions. Genes 2021, 12, 756. [Google Scholar] [CrossRef] [PubMed]
  5. Wahab, F.; Shahab, M.; Behr, R. Hypothesis: Irisin is a metabolic trigger for the activation of the neurohormonal axis governing puberty onset. Med. Hypotheses 2016, 95, 1–4. [Google Scholar] [CrossRef] [PubMed]
  6. Reinehr, T.; Elfers, C.; Lass, N.; Roth, C.L. Irisin and its relation to insulin resistance and puberty in obese children: A longitudinal analysis. J. Clin. Endocrinol. Metab. 2015, 100, 2123–2130. [Google Scholar] [CrossRef]
  7. Taş, D.; Akman Öden, A.; Akgül, S.; Metin, Z.E.; Pınar, A.; Kanbur, N. The effect of pubertal stage on the concentrations of the novel adipomyokine, irisin, in male adolescents. J. Clin. Res. Pediatr. Endocrinol. 2020, 12, 168–174. [Google Scholar] [CrossRef] [PubMed]
  8. Jang, H.B.; Kim, H.-J.; Kang, J.H.; Park, S.I.; Park, K.H.; Lee, H.-J. Association of circulating irisin levels with metabolic and metabolite profiles of Korean adolescents. Metab. Clin. Exp. 2017, 73, 100–108. [Google Scholar] [CrossRef]
  9. Nygaard, H.; Slettaløkken, G.; Vegge, G.; Hollan, I.; Whist, J.E.; Strand, T.; Rønnestad, B.R.; Ellefsen, S. Irisin in blood increases transiently after single sessions of intense endurance exercise and heavy strength training. PLoS ONE 2015, 10, e0121367. [Google Scholar] [CrossRef] [PubMed]
  10. Huh, J.Y.; Panagiotou, G.; Mougios, V.; Brinkoetter, M.; Vamvini, M.T.; Schneider, B.E.; Mantzoros, C.S. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and, I.I. mRNA expression and circulating concentrations in response to weight loss and exercise. Metab. Clin. Exp. 2012, 61, 1725–1738. [Google Scholar] [CrossRef] [PubMed]
  11. Cheng, Y.; Ma, J.; Bo, S. Short- and long-term effects of concurrent aerobic and resistance training on circulating irisin levels in overweight or obese individuals: A systematic review and meta-analysis of randomized controlled trials. PeerJ 2024, 12, e17958. [Google Scholar] [CrossRef] [PubMed]
  12. Pekkala, S.; Wiklund, P.K.; Hulmi, J.J.; Ahtiainen, J.P.; Horttanainen, M.; Pöllänen, E.; Makela, K.A.; Kainulainen, H.; Hakkinen, K.; Nyman, K.; et al. Are skeletal muscle FNDC5 gene expression and irisin release regulated by exercise and related to health? J. Physiol. 2013, 591, 5393–5400. [Google Scholar] [CrossRef] [PubMed]
  13. Shim, Y.S.; Kang, M.J.; Yang, S.; Hwang, I.T. Irisin is a biomarker for metabolic syndrome in prepubertal children. Endocr. J. 2018, 65, 23–31. [Google Scholar] [CrossRef]
  14. Nigro, E.; Scudiero, O.; Monaco, M.L.; Polito, R.; Schettino, P.; Grandone, A.; Perrone, L.; Del Giudice, E.M.; Daniele, A. Adiponectin profile and Irisin expression in Italian obese children: Association with insulin-resistance. Cytokine 2017, 94, 8–13. [Google Scholar] [CrossRef]
  15. Binay, Ç.; Paketçi, C.; Güzel, S.; Samancı, N. Serum irisin and oxytocin levels as predictors of metabolic parameters in obese children. J. Clin. Res. Pediatr. Endocrinol. 2017, 9, 124–131. [Google Scholar] [CrossRef]
  16. Faienza, M.F.; Brunetti, G.; Sanesi, L.; Colaianni, G.; Celi, M.; Piacente, L.; D’Amato, G.; Schipani, E.; Colucci, S.; Grano, M. High irisin levels are associated with better glycemic control and bone health in children with Type 1 diabetes. Diabetes Res. Clin. Pract. 2018, 141, 10–17. [Google Scholar] [CrossRef] [PubMed]
  17. Nagl, K.; Hermann, J.M.; Plamper, M.; Schröder, C.; Dost, A.; Kordonouri, O.; Rami-Merhar, B.; Holl, R.W. Factors contributing to partial remission in type 1 diabetes: Analysis based on the insulin dose-adjusted HbA1c in 3657 children and adolescents from Germany and Austria. Pediatr. Diabetes 2017, 18, 428–434. [Google Scholar] [CrossRef]
  18. Passanisi, S.; Salzano, G.; Gasbarro, A.; Urzì Brancati, V.; Mondio, M.; Pajno, G.B.; Alibrandi, A.; Lombardo, F. Influence of Age on Partial Clinical Remission among Children with Newly Diagnosed Type 1 Diabetes. Int. J. Environ. Res. Public. Health 2020, 17, 4801. [Google Scholar] [CrossRef]
  19. Grönberg, A.; Espes, D.; Carlsson, P.-O. Better HbA1c during the first years after diagnosis of type 1 diabetes is associated with residual C peptide 10 years later. BMJ Open Diabetes Res. Care. 2020, 8, e000819. [Google Scholar] [CrossRef] [PubMed]
  20. Fonolleda, M.; Murillo, M.; Vázquez, F.; Bel, J.; Vives-Pi, M. Remission phase in paediatric type 1 diabetes: New understanding and emerging biomarkers. Horm. Res. Paediatr. 2017, 88, 307–315. [Google Scholar] [CrossRef]
  21. Nwosu, B.U.; Rupendu, S.; Zitek-Morrison, E.; Patel, D.; Villalobos-Ortiz, T.R.; Jasmin, G.; Barton, B.A. Pubertal lipid levels are significantly lower in youth with type 1 diabetes who experienced partial clinical remission. J. Endocr. Soc. 2019, 3, 737–747. [Google Scholar] [CrossRef]
  22. Nwosu, B.U. Partial Clinical Remission of Type 1 Diabetes Mellitus in Children: Clinical Applications and Challenges with its Definitions. Eur. Med. J. Diabetes 2019, 4, 89–98. [Google Scholar] [CrossRef] [PubMed]
  23. Brener, A.; Hamama, S.; Interator, H.; Ben Simon, A.; Laurian, I.; Dorfman, A.; Chorna, E.; Yackobovitch-Gavan, M.; Oren, A.; Eyal, O.; et al. Sex differences in body composition in youth with type 1 diabetes and its predictive value in cardiovascular disease risk assessment. Diabetes Metab. Res. Rev. 2023, 39, e3584. [Google Scholar] [CrossRef] [PubMed]
  24. Averbuch, S.; Yackobovitch-Gavan, M.; Ben Simon, A.; Interator, H.; Lopez, A.; Borger, O.; Laurian, I.; Dorfman, A.; Chorna, E.; Oren, A.; et al. Muscle-to-fat ratio in children and adolescents with type 1 diabetes in predicting glycaemic control and partial clinical remission. Diabetes Metab. Res. Rev. 2024, 40, e3767. [Google Scholar] [CrossRef] [PubMed]
  25. Goldberg, T.; Brener, A.; Levy, S.; Interator, H.; Laurian, I.; Dorfman, A.; Chorna, E.; Oren, A.; Eyal, O.; Lebenthal, Y. Association between age at type 1 diabetes diagnosis and metabolic outcome at young adulthood: A real-life observational study. Diabetes Metab. Res. Rev. 2021, 37, e3356. [Google Scholar] [CrossRef] [PubMed]
  26. Brener, A.; Peleg, I.; Rosenfeld, T.; Kern, S.; Uretzky, A.; Elkon-Tamir, E.; Rosen, G.; Levinson, H.; Israeli, G.; Interator, H.; et al. Beyond Body Mass Index—Body Composition Assessment by Bioimpedance in Routine Endocrine Practice. Endocr. Pract. 2021, 27, 419–425. [Google Scholar] [CrossRef] [PubMed]
  27. Ceniccola, G.D.; Castro, M.G.; Piovacari, S.M.F.; Horie, L.M.; Corrêa, F.G.; Barrere, A.P.N.; Toledo Oliveira, D. Current technologies in body composition assessment: Advantages and disadvantages. Nutrition 2019, 62, 25–31. [Google Scholar] [CrossRef]
  28. Chwałczyńska, A.; Jędrzejewski, G.; Lewandowski, Z.; Jonak, W.; Sobiech, K.A. Physical fitness of secondary school adolescents in relation to the body weight and the body composition: Classification according to Bioelectrical Impedance Analysis. Part II. J. Sports Med. Phys. Fitness 2017, 57, 252–259. [Google Scholar] [CrossRef]
  29. McCarthy, H.D.; Samani-Radia, D.; Jebb, S.A.; Prentice, A.M. Skeletal muscle mass reference curves for children and adolescents. Pediatr. Obes. 2014, 9, 249–259. [Google Scholar] [CrossRef] [PubMed]
  30. Marshall, W.A.; Tanner, J.M. Variations in pattern of pubertal changes in girls. Arch. Dis. Child. 1969, 44, 291–303. [Google Scholar] [CrossRef] [PubMed]
  31. Marshall, W.A.; Tanner, J.M. Variations in the pattern of pubertal changes in boys. Arch. Dis. Child. 1970, 45, 13–23. [Google Scholar] [CrossRef] [PubMed]
  32. Shypailo, R.J. Age-Based Pediatric Blood Pressure Reference Charts. Retrieved 3/28/2022 from the Baylor College of Medicine, Children’s Nutrition Research Center, BodyComposition Laboratory. 2018. Available online: https://www.bcm.edu/bodycomplab/BPappZjs/BPvAgeAPPz.html (accessed on 4 November 2024).
  33. Wahab, F.; Khan, I.U.; Polo, I.R.; Zubair, H.; Drummer, C.; Shahab, M.; Behr, R. Irisin in the primate hypothalamus and its effect on GnRH in vitro. J. Endocrinol. 2019, 241, 175–187. [Google Scholar] [CrossRef]
  34. Decourt, C.; Evans, M.C.; Inglis, M.A.; Anderson, G.M. Central irisin signaling is required for normal timing of puberty in female mice. Endocrinology 2022, 164, bqac208. [Google Scholar] [CrossRef]
  35. Ulker, N.; Yardimci, A.; Kaya Tektemur, N.; Bulmus, O.; Ozer Kaya, S.; Gulcu Bulmus, F.; Turk, G.; Ozcan, M.; Canpolat, S. Irisin may have a role in pubertal development and regulation of reproductive function in rats. Reproduction 2020, 160, 281–292. [Google Scholar] [CrossRef]
  36. Bao, J.-F.; She, Q.-Y.; Hu, P.-P.; Jia, N.; Li, A. Irisin, a fascinating field in our times. Trends Endocrinol. Metab. 2022, 33, 601–613. [Google Scholar] [CrossRef]
  37. Skog, O.; Korsgren, O. Aetiology of type 1 diabetes: Physiological growth in children affects disease progression. Diabetes Obes. Metab. 2018, 20, 775–785. [Google Scholar] [CrossRef] [PubMed]
  38. Jeffery, A.N.; Metcalf, B.S.; Hosking, J.; Streeter, A.J.; Voss, L.D.; Wilkin, T.J. Age before stage: Insulin resistance rises before the onset of puberty: A 9-year longitudinal study (EarlyBird 26). Diabetes Care 2012, 35, 536–541. [Google Scholar] [CrossRef]
  39. Gonzalez-Gil, A.M.; Peschard-Franco, M.; Castillo, E.C.; Gutierrez-DelBosque, G.; Treviño, V.; Silva-Platas, C.; Perex-Villarreal, L.; Garcia-Rivas, G.; Elizondo-Montemayor, L. Myokine-adipokine cross-talk: Potential mechanisms for the association between plasma irisin and adipokines and cardiometabolic risk factors in Mexican children with obesity and the metabolic syndrome. Diabetol. Metab. Syndr. 2019, 11, 63. [Google Scholar] [CrossRef] [PubMed]
  40. Kim, S.-H.; Kim, S.E.; Kim, S.; Ahn, M.B.; Cho, W.K.; Cho, K.S.; Jung, M.H. The association of serum irisin with anthropometric, metabolic, and bone parameters in obese children and adolescents. Front. Endocrinol. 2023, 14, 1326851. [Google Scholar] [CrossRef] [PubMed]
  41. Esin, K.; Batirel, S.; Ülfer, G.; Yigit, P.; Sanlier, N. Association of Serum Irisin Levels with Body Composition, Metabolic Profile, Leptin, and Adiponectin Levels in Lean and Obese Children. Medicina 2023, 59, 1954. [Google Scholar] [CrossRef]
  42. Moore, J.M.; Snell-Bergeon, J.K. Trajectories of hemoglobin A1c and body mass index z-score over four decades among 2 to 18 year olds with type 1 diabetes. Pediatr. Diabetes 2019, 20, 594–603. [Google Scholar] [CrossRef]
  43. Cherubini, V.; Bonfanti, R.; Casertano, A.; De Nitto, E.; Iannilli, A.; Lombardo, F.; Maltoni, G.; Marigliano, M.; Bassi, M.; Minuto, N.; et al. Time In Range in Children with Type 1 Diabetes Using Treatment Strategies Based on Nonautomated Insulin Delivery Systems in the Real World. Diabetes Technol. Ther. 2020, 22, 509–515. [Google Scholar] [CrossRef] [PubMed]
Figure 1. A graphical depiction of a linear regression model illustrating that irisin levels increase with age among prepubertal boys and decrease with age among pubertal boys.
Figure 1. A graphical depiction of a linear regression model illustrating that irisin levels increase with age among prepubertal boys and decrease with age among pubertal boys.
Jcm 14 00793 g001
Table 1. Comparative analysis of metabolic parameters in pediatric patients with type 1 diabetes stratified by sex.
Table 1. Comparative analysis of metabolic parameters in pediatric patients with type 1 diabetes stratified by sex.
Boys, n = 48Girls, n = 28p Value
Age, years12.1 ± 3.811.1 ± 3.60.283
Systolic blood pressure (%)61.0 [41.8, 82.0]73.2 [53.0, 83.8]0.365
Diastolic blood pressure (%)58.6 [46.2, 70.7]67.6 [56.4, 79.5]0.118
Adequate physical activity, n (%)25 (52.1)17 (60.7)0.470
Fat, %17.3 [15.4, 24.0]25.5 [22.7, 28.5]<0.001
Truncal fat, %14.2 [11.2, 19.3]18.7 [16.6, 23.5]0.001
ASMM14.9 [8.5, 19.4]11.9 [7.4, 14.6]0.027
ASMM z-score0.03 [−0.53, 0.50]−0.25 [−0.76, 0.66]0.474
Skeletal muscle mass index5.8 [4.6, 6.6]4.8 [4.4, 5.6]0.038
MFR1.62 [1.19, 2.28]1.10 [0.90, 1.23]<0.001
MFR z-score−0.30 [−1.24, 0.24]−0.59 [−0.98, −0.28]0.296
HbA1c, %7.4 [6.7, 8.2]7.1 [6.8, 7.8]0.850
IDAA1c10.3 [9.3, 11.7]10.6 [9.2, 11.7]0.817
Urine irisin, pg/mL50.0 [35.3, 64.2]61.3 [37.7, 88.9]0.275
Serum creatinine, mg/dL0.50 [0.43, 0.64]0.45 [0.40, 0.61]0.274
Data are presented as number (percent), mean ± standard deviation or median [interquartile range]. The Mann–Whitney U test was performed to test non-parametric medians. Self-reported physical activity was considered adequate if it met the ISPAD recommendations of ≥60 min each day. n, number; ASMM, appendicular skeletal muscle mass; MFR, muscle-to-fat ratio; HbA1c, hemoglobin A1c; IDAA1c, insulin dose-adjusted HbA1c. Bold indicates significance.
Table 2. Comparative analysis of metabolic parameters in pediatric patients with type 1 diabetes stratified by pubertal status.
Table 2. Comparative analysis of metabolic parameters in pediatric patients with type 1 diabetes stratified by pubertal status.
Boys, n = 48Girls, n = 28
Prepubertal,
n = 24
Pubertal,
n = 24
p ValuePrepubertal,
n = 12
Pubertal,
n = 16
p Value
Age, years9.0 ± 2.015.2 ± 2.6<0.0017.5 ± 1.413.9 ± 1.9<0.001
Systolic blood pressure (%)64.0
[50.0, 86.1]
56.5
[25.4, 80.5]
0.18373.9
[56.5, 84.7]
70.3 [48.8, 81.9]0.329
Diastolic blood pressure (%)62.2
[44.6, 77.8]
56.8
[46.6, 66.0]
0.69570.8
[57.3, 79.5]
66.0
[53.6, 79.5]
0.010
Adequate physical activity, n (%)9 (37.5)16 (66.7)0.0455 (41.7)12 (75)0.079
Fat, %20.0
[17.2, 25.4]
15.9
[12.4, 17.8]
0.00225.3 ± 3.926.6 ± 5.60.516
Truncal fat, %14.9
[12.6, 20.5]
11.7
[9.0, 17.0]
0.07619.6 ± 4.420.5 ± 6.10.692
ASMM8.5
[6.8, 10.1]
19.6
[16.9, 25.3]
<0.0017.2 ± 1.914.2 ± 2.0<0.001
ASMM z-score0.21 ± 0.850.31 ± 0.740.029−0.18 ± 0.78−0.11 ± 1.030.842
Skeletal muscle mass index4.7 ± 1.26.8 ± 1.1<0.0014.4 ± 0.45.5 ± 0.7<0.001
MFR1.3 [1.1, 1.6]2.3 [2.0, 2.9]<0.0011.1 ± 0.21.1 ± 0.30.629
MFR z-score−0.8 ± 0.70.2 ± 1.40.004−0.82 ± 0.50−0.36 ± 0.760.076
HbA1c, %7.1
[6.7, 8.0]
7.6
[6.3, 8.2]
0.7187.0
[6.8, 8.4]
7.2
[6.8, 7.6]
0.944
IDAA1c9.8
[9.3, 11.2]
10.8
[8.9, 11.9]
0.39810.3
[9.1, 11.8]
10.6
[9.2, 11.6]
0.944
Urine irisin, pg/mL47.1
[28.7, 64.0]
52.3
[40.9, 64.7]
0.25561.2
[35.1, 70.8]
86.9
[49.0, 113.3]
0.180
Serum creatinine, mg/dL0.47
[0.39, 0.50]
0.65
[0.47, 0.75]
0.0010.41 ± 0.120.44 ± 0.120.007
Data are presented as number (percent), mean ± standard deviation or median [interquartile range]. The Mann–Whitney U test was performed to test non-parametric medians. Self-reported physical activity was considered adequate if it met the ISPAD recommendations of ≥60 min each day. n, number; ASMM, appendicular skeletal muscle mass; MFR, muscle-to-fat ratio; HbA1c, hemoglobin A1c; IDAA1c, insulin dose-adjusted HbA1c. Bold indicates significance.
Table 3. A linear regression model, in boys, analyzing the impact of puberty and age on irisin levels.
Table 3. A linear regression model, in boys, analyzing the impact of puberty and age on irisin levels.
βStd. ErrortSig.95% Confidence IntervalPartial Eta Squared
Lower BoundUpper Bound
Intercept127.538.83.290.00249.4205.70.197
Puberty132.549.42.680.01033.0232.00.141
Age−4.42.5−1.750.088−9.490.6810.065
Puberty × Age−11.04.2−2.60.011−19.4−2.610.137
Parameters entered into the model were puberty, age and irisin levels.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Averbuch, S.; Gaiduk, O.; Yackobovitch-Gavan, M.; Laurian, I.; Dorfman, A.; Shefer, G.; Brener, A.; Lebenthal, Y. Influence of Sex and Age on Irisin Levels in Pediatric Type 1 Diabetes: A Pilot Study. J. Clin. Med. 2025, 14, 793. https://doi.org/10.3390/jcm14030793

AMA Style

Averbuch S, Gaiduk O, Yackobovitch-Gavan M, Laurian I, Dorfman A, Shefer G, Brener A, Lebenthal Y. Influence of Sex and Age on Irisin Levels in Pediatric Type 1 Diabetes: A Pilot Study. Journal of Clinical Medicine. 2025; 14(3):793. https://doi.org/10.3390/jcm14030793

Chicago/Turabian Style

Averbuch, Shay, Oxana Gaiduk, Michal Yackobovitch-Gavan, Irina Laurian, Anna Dorfman, Gabi Shefer, Avivit Brener, and Yael Lebenthal. 2025. "Influence of Sex and Age on Irisin Levels in Pediatric Type 1 Diabetes: A Pilot Study" Journal of Clinical Medicine 14, no. 3: 793. https://doi.org/10.3390/jcm14030793

APA Style

Averbuch, S., Gaiduk, O., Yackobovitch-Gavan, M., Laurian, I., Dorfman, A., Shefer, G., Brener, A., & Lebenthal, Y. (2025). Influence of Sex and Age on Irisin Levels in Pediatric Type 1 Diabetes: A Pilot Study. Journal of Clinical Medicine, 14(3), 793. https://doi.org/10.3390/jcm14030793

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop