Discussion
To our best knowledge, this is the first study to provide epidemiological evidence that the relationship between circulating IGF-1 and risk of T2D was significantly modified by birth weight. Our data showed an inverse association between IGF-1 and risk of T2D in individuals with birth weight of ≥2.5 kg, but not in those with birth weight of <2.5 kg. Such effect modification was not observed for the GRS of birth weight.
Our findings of the inverse associations between circulating IGF-1 and T2D are consistent with the results from several epidemiological studies.23–25 Null associations were also observed between IGF-1 and T2D.26 27 The discrepant observations might be partly due to the small sample size (less than 800 cases) or failure in excluding baseline T2D prevalent cases. Moreover, a recent Mendelian randomization study showed that the genetic predisposition to elevated IGF-1 levels during adulthood was associated with a higher risk of T2D, suggesting a potentially causal relation.13 However, in this study, some SNPs used as instrumental variables were also related with other traits that may confound the relationship between IGF-1 and risk of T2D, such as hypertension, vascular or heart disease, birth weight of the first child, body fat mass, and height. Hence, caution is needed when interpreting the results of the Mendelian randomization study.
The significant interaction between birth weight and circulating IGF-1 on T2D is in line with our previous findings that birth weight may modify the adulthood risk factors on cardiometabolic disease risk.6 28 Of note, data on the relations between IGF-1 and T2D risk from the previous observational studies are highly conflicting, with findings of inverse,23–25 U-shaped,29 or null associations.26 27 30 31 Such heterogeneous results suggest the potential effect modifications may exist. Our results indicate that birth weight is likely to be an effect modifier on the relation between IGF-1 and T2D.
An inverse association between IGF-1 and T2D was only observed among the participants with birth weight of ≥2.5 kg, while the association between IGF-1 and T2D was attenuated toward null in those with birth weight of <2.5 kg. The putative effect modification by birth weight on the relationship between IGF-1 and T2D might be explained by several potential biological mechanisms. Low birth weight is a widely accepted indicator for prenatal malnutrition and intrauterine growth restriction. Evidence has shown that intrauterine growth restriction may lead to developmental programming of lifecourse IGFs concentrations. It was found that intrauterine growth restriction was associated not only with lower levels of cord IGF-132 but also with decreased levels of IGF-1 in infants,33 preadolescent children without significant ‘catch-up’ growth34 and adults.12 Experimental studies indicate that intrauterine growth restriction can result in persistent reduction of serum IGF-1 through modifying epigenetic characteristics, especially the histone code of the hepatic IGF-1 gene,35 perturbing developmental epigenetics around distal growth hormone response elements on hepatic IGF-1 gene,36 and disturbing the formation of nucleosome-depleted region at the right potion on the IGF-1 gene.37 Moreover, prenatal malnutrition had long-term effects on glucose–insulin metabolism through multiple pathways involving IGFs, including epigenetic modifications, permanent changes in organs’ structure during a sensitive period of development and persistent effects on cellular aging regulation.11 38 Hence, we assumed that the effects of elevated IGF-1 levels could be nullified by these aforementioned alterations caused by prenatal malnutrition and intrauterine growth restriction.
In addition, our data showed the association between IGF-1 and T2D was not modified by genetic predisposition to birth weight. As the GRS used in our study only explained 2% of the variance in birth weight,39 the non-significant interaction may be due to the genetic variations that only account for a small proportion of the variance in birth weight. Further studies are warranted to corroborate our findings on the synergistic effect of GRS of birth weight and IGF-1 levels in adulthood on the risk of T2D.
A body of evidence from animal and human studies suggests that the early life development windows are critical periods when environmental exposure is more harmful to health outcomes throughout the life course.40 In normal condition, IGF-1 can act independently or coordinate with insulin to maintain the glucose homeostasis.41 However, our data showed the potential beneficial effect of elevated IGF-1 in adulthood on T2D might be influenced by the impaired fetal growth. The findings in this present study suggest that improvement of prenatal/postnatal exposures plays a critical role in the prevention and treatment of T2D through the pathway involving IGF-1.
The major strengths of this study include the prospective study design, large sample size, and comprehensively collected information on the lifestyle factors. Moreover, the value of regression dilution ratio derived from the baseline and repeated measurements of IGF-1 indicated that the baseline IGF-1 levels could provide a precise estimate of long-term IGF-1 levels. Our study also has several potential limitations. First, information regarding IGF-binding proteins and IGF-2 was not available in the UK Biobank; hence, we were unable to adjust for these factors as confounders or mediators in the model. We were unable to investigate the interaction between free IGF-1 and birth weight on T2D as well. Second, covariates collected at baseline could have changed over time; however, given the prospective study design, the subsequent misclassification would be non-differential, which would most likely to attenuate the true associations. Third, although data on birth weight was self-reported in our study, a previous study has validated the variable and demonstrated that the self-reported birth weight in the UK Biobank was a reliable measurement.16 Furthermore, as UK Biobank did not collect the information on birth terms, we were unable to further categorize the birth weight on the basis of preterm or full-term birth. Fourth, due to the observational study design, our data could not be used for inference of causality. Finally, evidence has shown that the ethnicity may affect the circulating IGF-1 levels42; hence, studies in other ethnic populations are needed.
Our data indicate that the relation between adulthood IGF-1 and T2D is significantly modified by birth weight. Our findings highlight the importance of early-life risk factors in the development of the lifecourse prevention strategies targeting on IGF-1 and T2D.