Plasma Metabolomic Profiling Suggests Early Indications for Predisposition to Latent Insulin Resistance in Children Conceived by ICSI

Abstract

BackgroundThere have been increasing indications about an epigenetically-based elevated predisposition of assisted reproductive technology (ART) offspring to insulin resistance, which can lead to an unfavorable cardio-metabolic profile in adult life. However, the relevant long-term systematic molecular studies are limited, especially for the IntraCytoplasmic Sperm Injection (ICSI) method, introduced in 1992. In this study, we carefully defined a group of 42 prepubertal ICSI and 42 naturally conceived (NC) children. We assessed differences in their metabolic profile based on biochemical measurements, while, for a subgroup, plasma metabolomic analysis was also performed, investigating any relevant insulin resistance indices.Methods & ResultsAuxological and biochemical parameters of 42 6.8±2.1 yrs old ICSI-conceived and 42 age-matched controls were measured. Significant differences between the groups were determined using univariate and multivariate statistics, indicating low urea and low-grade inflammation markers (YKL-40, hsCRP) and high triiodothyronine (T3) in ICSI-children compared to controls. Moreover, plasma metabolomic analysis carried out for a subgroup of 10 ICSI- and 10 NC girls using Gas Chromatography-Mass Spectrometry (GC-MS) indicated clear differences between the two groups, characterized by 36 metabolites linked to obesity, insulin resistance and metabolic syndrome. Notably, the distinction between the two girl subgroups was accentuated when both their biochemical and metabolomic measurements were employed.ConclusionsThe present study contributes a large auxological and biochemical dataset of a well-defined group of pre-pubertal ICSI-conceived subjects to the research of the ART effect to the offspring's health. Moreover, it is the first time that the relevant usefulness of metabolomics was investigated. The acquired results are consistent with early insulin resistance in ICSI-offspring, paving the way for further systematic investigations. These data support that metabolomics may unravel metabolic differences before they become clinically or biochemically evident, underlining its utility in the ART research.

Long‐term follow‐up of ICSI‐conceived offspring compared with spontaneously conceived offspring: a systematic review of health outcomes beyond the neonatal period

“…Glucocorticoids are important mediators of obesity and insulin resistance, and disruption of the hypothalamic–pituitary–adrenal axis has been proposed as a mechanism for unfavorable metabolic outcomes after in vitro conception (Belva et al ., ). Interestingly, lower salivary and serum cortisol levels have been reported in ICSI‐conceived girls compared to SC girls, although these results were based on single measurements (Belva et al ., ; Gkourogianni et al ., ). Mean salivary cortisol in the Belgium cohort was lower in ICSI‐conceived girls, which remained after adjusting for current characteristics, and early life and maternal factors (Belva et al ., ).…”

“…Mean salivary cortisol in the Belgium cohort was lower in ICSI‐conceived girls, which remained after adjusting for current characteristics, and early life and maternal factors (Belva et al ., ). In a smaller cohort, an extensive review of plasma metabolomics also revealed lower cortisol levels in a subgroup of ICSI‐conceived girls aged 4 to 9 years compared to SC girls, alongside significant differences in 36 metabolites indicating early insulin resistance in the ICSI group (Gkourogianni et al ., ). Another unexpected finding in this latter study was lower inflammatory markers in the ICSI group compared to SC controls including YKL‐40, which normally represents a marker of inflammation, obesity, and insulin resistance (Gkourogianni et al ., ).…”

“…In a smaller cohort, an extensive review of plasma metabolomics also revealed lower cortisol levels in a subgroup of ICSI‐conceived girls aged 4 to 9 years compared to SC girls, alongside significant differences in 36 metabolites indicating early insulin resistance in the ICSI group (Gkourogianni et al ., ). Another unexpected finding in this latter study was lower inflammatory markers in the ICSI group compared to SC controls including YKL‐40, which normally represents a marker of inflammation, obesity, and insulin resistance (Gkourogianni et al ., ). Collectively, these findings have been suggested to reflect an adaptive mechanism to counter the increased insulin resistance after ICSI conception, thereby maintaining metabolic homeostasis (Belva et al ., ; Gkourogianni et al ., ).…”

Associations of cord blood metabolites with perinatal characteristics, newborn anthropometry, and cord blood hormones in project viva

“…Metabolomics analyses in children have found that higher circulating branched chain amino acids (BCAAs) are associated with obesity status (10, 11), as well as subclinical risk factors for metabolic disease like insulin resistance (10, 12). Studies in adults have shown that elevations in serum branched chain amino acids (BCAAs) are detectable several years prior to development of insulin resistance and incident type 2 diabetes (13, 14), even among individuals of similar weight status (13).…”

Research update for articles published inEJCIin 2013

“…In another study by Chen et al [48] peripheral insulin sensitivity as measured by the hyperinsulinemic-euglycemic clamp was significantly lower in IVF vs. naturally conceived young adults. Gkourogianni et al [49] performed a metabolomic analysis on girls conceived by ICSI and revealed significantly increased levels on most metabolites related to obesity, insulin resistance and metabolic syndrome, compared to controls, even before they were biochemically evident.…”