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Published online August 17, 2007
Diabetes 56:2697-2704, 2007
DOI: 10.2337/db07-0662
© 2007 by the American Diabetes Association
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Inflammation and Endothelial Activation Is Evident at Birth in Offspring of Mothers With Type 1 Diabetes

Scott M. Nelson1, Naveed Sattar1,2, Dilys J. Freeman1, James D. Walker3, and Robert S. Lindsay2

1 Division of Developmental Medicine, Reproductive and Maternal Medicine, University of Glasgow, Glasgow, U.K
2 British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, U.K
3 Department of Diabetes, St. John's Hospital, Livingston, U.K

Address correspondence and reprint requests to Dr. Scott M. Nelson, Reproductive and Maternal Medicine, Division of Developmental Medicine, University of Glasgow, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow, G31 2ER, U.K. E-mail: s.nelson{at}clinmed.gla.ac.uk

Abbreviations: CRP, C-reactive protein; ICAM, intracellular adhesion molecule; IL, interleukin; LMP, last mentrual period; LPL, lipoprotein lipase; NEFA, nonesterified fatty acid; OT1DM, offspring of type 1 diabetic mothers


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE— Offspring of mothers with diabetes are at risk of obesity and glucose intolerance in later life. In adults, markers of subclinical inflammation (C-reactive protein [CRP] and interleukin [IL]-6) and endothelial activation (intracellular adhesion molecule [ICAM]-1) are associated with obesity and higher risk for incident type 2 diabetes. We examined whether these biomarkers were elevated at birth in offspring of type 1 diabetic mothers (OT1DM).

RESEARCH DESIGN AND METHODS— Umbilical cord plasma CRP, IL-6, and ICAM-1 were measured in 139 OT1DM and 48 control offspring, with analysis relative to fetal lipids and hormonal axes.

RESULTS— OT1DM had higher median (interquartile range) CRP (OT1DM 0.17 mg/l [0.13–0.22] vs. control subjects 0.14 mg/l [0.12–0.17], P < 0.001) and ICAM-1 (OT1DM 180 ng/ml [151–202] vs. control subjects 166 ng/ml [145–187], P = 0.047). IL-6 was not different after necessary adjustment for mode of delivery. Birth weight was unrelated to inflammatory indexes; however, leptin was correlated with CRP (control subjects r = 0.33, P = 0.02; OT1DM r = 0.41, P < 0.001) and with IL-6 (r = 0.23, P < 0.01) and ICAM-1 (r = 0.29, P < 0.001) in OT1DM. In OT1DM, CRP correlated with maternal glycemic control (A1C at 35–40 weeks; r = 0.28, P = 0.01). In multivariate analysis, leptin was a determinant of CRP (P < 0.001), ICAM-1 (P = 0.003), and IL-6 (P = 0.02) in OT1DM. Inflammatory measures demonstrated positive relationships with triglycerides in OT1DM (CRP, IL-6, and ICAM-1 P < 0.05) and control subjects (ICAM-1 P = 0.001).

CONCLUSIONS— Inflammatory markers are increased in OT1DM and are related to measures of fetal adiposity, particularly leptin, and maternal glycemia. Subclinical inflammation is a novel component of the diabetic intrauterine environment and should be considered a potential etiological mechanism for in utero programming of disease.

Maternal diabetes is associated with adverse consequences to mother and baby. Rates of macrosomia and fetal adiposity are higher, resulting in substantive increases in intrapartum complications, independent of increased background risk of perinatal morbidity and mortality. In the longer term, offspring have increased risk of obesity and type 2 diabetes (1,2) in high-risk populations, reflecting potential in utero programming of disease. In adults, inflammatory markers—in particular C-reactive protein (CRP), intracellular adhesion molecule (ICAM)-1, and interleukin (IL)-6—are associated with adiposity, altered glucose tolerance, and, prospectively, with later risk of development of type 2 diabetes and vascular disease (3–8). In animal models, intrauterine exposure to cytokines, including IL-6, have been associated with increases in fat mass and insulin resistance in later life (9). Changes in inflammatory markers have not been extensively studied in offspring of type 1 diabetic pregnancies at birth; however, gestational diabetes mellitus has been associated with an alteration in the placental transcriptome with a dominance of genes regulating inflammatory responses and endothelial function (10). This suggests the hypotheses that short-term complications and, more speculatively, the longer-term metabolic sequelae of maternal diabetes for offspring of type 1 diabetic mothers (OT1DM) may be partially attributable to the intrauterine environment.

The objective of the present study was to evaluate whether baseline plasma levels of the inflammatory markers CRP, ICAM-1, and IL-6 were increased in OT1DM at birth and whether they were related to birth weight, measures of fetal adiposity, fetal insulinemia, and maternal metabolic control. Finally, we have also investigated the relationship of inflammatory measures to fetal lipids.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Recruitment and collections of cord bloods.
Recruitment, which began in January 1999 and ended in May 2001, took place in eight hospital-based antenatal centers in Scotland. A total of 250 women with type 1 diabetes consented to participate in the study (a 94% participation rate of those enrolled in and planning to deliver in the centers), and cord blood samples were obtained from 200 women (80%). No differences in gestation at delivery, maternal age at delivery, years of diabetes duration, fetal sex, or maternal A1C (where available) were found between those with and without cord samples. Because sample hemolysis results in increased degradation of insulin and because pilot studies indicated significant (>10%) degradation of insulin in which either samples were not collected from cord for >20 min or there was delay between sample collection and freezing for more than 60 min, samples not fulfilling these criteria were excluded from the main data analysis. Thus, the 200 samples were further restricted to those in whom 1) there was no evidence of hemolysis of cord blood (17 excluded), 2) cord blood had been collected within 20 min (12 exclusions: collection time for remaining samples median [interquartile range] 2 min [1–7]), 3) cord blood had been centrifuged and plasma frozen within 60 min (17 exclusions: time from collection to freezing for remaining samples 17 min [11–26]), 4) antenatal glucocorticoids had not been administered in the 24 h before birth (15 excluded), and 5) childbirth occurred before 33 weeks’ gestation (5 excluded).

A convenience sample of control mothers, who had no history of obstetric or metabolic disease and in whom routine screening for gestational diabetes melllitus (using national guidelines [http://www.sign.ac.uk/guidelines/fulltext/55/section8.html]) was negative, were recruited from routine obstetric follow-up clinics after the 34th week of pregnancy in the same centers. Of the 145 women who gave initial consent, cord samples were attempted in 75 and obtained in 70 women. Forty-eight collections met the above restriction criteria, and samples were available for fetal lipids in all 48.

Data on clinical outcome including Caesarean section, intercurrent medical conditions, and hypertensive conditions of pregnancy were obtained by case note review. Gestational ages were calculated from estimated dates of delivery from chart review. This date was derived from dates of last menstrual period (LMP), where available, or by ultrasound if there was either conflict with dates as assessed by LMP (>6 days) or LMP was unavailable.

Weight was measured at birth and, for offspring born between 33 and 42 weeks of gestation, further expressed as an SD score, as previously described (11). Skinfold thickness at subscapular and triceps was measured with Holtain calipers by pediatricians at each site using a centrally agreed protocol, available in writing at the time of measurement. Skinfolds were not measured in all subjects. However, there were no significant differences in baseline demographic or biochemical measures between those with and without skinfold measurements in either control subjects or OT1DM (data not shown). All mothers gave informed consent, and the local ethical committees approved the protocols.

Cord blood assays.
Plasma insulin, 32–33 split proinsulin, proinsulin, leptin, IGF-1, adiponectin, plasma total cholesterol, triglyceride, nonesterified fatty acid (NEFA), and VLDL, LDL, and HDL cholesterol were assayed as previously described (12–15). All lipid assays were carried out at the Biochemistry Department of Glasgow Royal Infirmary, which is a Centers for Disease Control and Prevention (Atlanta, GA) reference laboratory and accredited by Clinical Pathology Accreditation U.K. Maternal A1C was measured centrally by one laboratory. Plasma IL-6 and ICAM-1 were measured in plasma stored at –80°C using high-sensitivity commercial enzyme-linked immunosorbent assay kits (R&D Systems). CRP was measured using a high-sensitivity, two-site enzyme-linked immunoassay (16).

Statistical analysis.
Data were analyzed using standard software (Minitab 14; Minitab, State College, PA; and Stata version 7; Stata, College Station, TX). In several cases (insulin, leptin, triglyceride, VLDL, NEFA, total–to–HDL cholesterol ratio, CRP, ICAM-1, and IL-6), measures were not normally distributed. Unadjusted values are presented as median (interquartile range) and normally distributed variables as means ± SD. Variables were logarithmically transformed to obtain normal distributions. Intergroup differences were assessed by unpaired t test, ANOVA, or, where further predictor variables were included, by general linear models. Spearman correlation coefficients are reported. Pearson partial correlation coefficients on log-transformed data allowed adjustment of analytes for gestational age. Stepwise logistic regression was performed using an {alpha} of P ≤ 0.15 for adding or removing predictors from the model. Quartiles for CRP, ICAM-1, and leptin were derived for control subjects and OT1DM separately. Assessment of direction across quartiles was performed by {chi}2 test for trend. Statistical significance was determined at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fetal hormonal, inflammatory, and lipid analytes in OT1DM versus control subjects.
Maternal and fetal characteristics for this cohort have previously been described and are included in Table 1. Maternal type 1 diabetes was associated with marked increases in absolute values of cord insulin (12) and leptin (13), with reductions in adiponectin (14), HDL cholesterol, and NEFA (Table 1). All these differences remained significant after adjustment for sex and mode of delivery.


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  		TABLE 1 Characteristics of mothers with type 1 diabetes and their singleton offspring versus control mothers and children

 
In absolute terms, CRP and ICAM-1 were higher and IL-6 lower in OT1DM (Table 1). IL-6 concentrations were related to mode of delivery (Table 2), being lower in babies delivered by elective Caesarean section in both OT1DM (P < 0.001) and control subjects (P = 0.028). After adjustment for mode of delivery, there was no difference in IL-6 between OT1DM and control subjects (P = 0.24) because more OT1DM were delivered by elective Caesarean section. CRP was related to mode of delivery in control subjects, being significantly higher in the six babies delivered by emergency Caesarean section (P = 0.027) (Table 2), but no difference dependent on mode of delivery was observed in OT1DM. CRP remained higher in OT1DM compared with that in control subjects even after adjustment for mode of delivery (P = 0.018). ICAM-1 was not affected by mode of delivery in either group, with overall significantly higher levels in OT1DM (P = 0.047). Fetal sex, gestational age, and birth weight were not significant determinants of IL-6, CRP, or ICAM-1 in control subjects or OT1DM (in a model also including mode of delivery).


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  		TABLE 2 Influence of maternal diabetes on CRP, ICAM-1, and IL-6 with stratification for mode of delivery

 
Fetal inflammatory markers, relationship with fetal adiposity, and leptin.
Initial analysis of the interrelation of each of the inflammatory markers demonstrated that IL-6 and ICAM-1 expression were positively correlated (control r = 0.47, P = 0.002; OT1DM r = 0.2, P = 0.02) and that both CRP (control r = 0.10, P = 0.48; OT1DM r = 0.22, P = 0.01) and ICAM-1 (control r = 0.04, P = 0.80; OT1DM r = 0.37, P < 0.001) were correlated with IL-6 only in OT1DM. Given the higher levels of CRP and ICAM-1 in OT1DM, we further explored the relation of these inflammatory markers to fetal anthropometry and cord hormonal profiles, in particular to measures of fetal adiposity, maternal glycemia, and fetal insulinemia. Inflammation was correlated with various measures of fetal fat mass in control subjects and OT1DM (Table 3) but most consistently with leptin, which was associated with CRP (r = 0.41, P < 0.0001), ICAM-1 (r = 0.29, P < 0.001), and IL-6 (r = 0.23, P = 0.007) in OT1DM (Table 3 and Fig. 1). In addition to these relationships with fetal fat mass, CRP correlated with maternal A1C at 35–40 weeks in OT1DM (r = 0.28, P = 0.01). Despite this association, CRP did not correlate with insulin in control subjects or OT1DM (Table 3). Indeed, insulin demonstrated a negative relationship with IL-6 (r = –0.32, P = 0.01) and ICAM-1 (r = –0.32, P = 0.01) in control subjects. With respect to other hormonal measures, adiponectin was negatively associated with ICAM-1 in control subjects (r = –0.31, P < 0.01) but unrelated to any fetal inflammatory indexes in OT1DM. IGF-1 showed generally negative correlations with the inflammatory measures; however, these relationships were significant only for the association of IGF-1 and IL-6 in control subjects (r = –0.35, P < 0.001) and with CRP (r = –0.23, P < 0.001) in OT1DM. Analysis of the correlations presented in Table 3 after correction of analytes for gestational age produced similar results (data not shown).


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  		TABLE 3 Spearman correlation coefficients (r) of inflammatory markers versus hormonal and lipid measures in cord blood at birth

 

Figure 1
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  		FIG. 1. Unadjusted CRP and ICAM-1 levels relative to group-specific leptin quartiles and unadjusted triglyceride levels relative to CRP and ICAM-1 group-specific quartiles in control subjects and OT1DM. Leptin, CRP, and ICAM-1 quartiles calculated separately for control subjects and OT1DM. Values are geometric means ± SE. Units for y-axes: triglyceride, millimoles per liter; leptin, millimoles per liter. A: CRP across group-specific leptin quartiles for control subjects (ANOVA P = 0.29) and for OT1DM (P = 0.0001). *, **, ***, ****Test for trend across CRP quartiles 1, 2, 3, and 4, respectively, in OT1DM (P < 0.001). B: ICAM-1 across group-specific leptin quartiles for control subjects (ANOVA P = 0.83) and for OT1DM (P = 0.004). *, **, ***, ****Test for trend across ICAM-1 quartiles 1, 2, 3, and 4, respectively, in OT1DM (P < 0.001). C: Triglyceride across group-specific CRP quartiles for control subjects (ANOVA P = 0.58) and for OT1DM (P = 0.002). *, **, ***, ****Test for trend across CRP quartiles 1, 2, 3, and 4, respectively, in OT1DM (P < 0.001). D: Triglyceride across group-specific ICAM-1 quartiles for control subjects (ANOVA P = 0.047) and for OT1DM (P = 0.001). *, **, ***, ****Test for trend across ICAM-1 quartiles 1, 2, 3, and 4, respectively, in control subjects and OT1DM (P < 0.001).

 
To identify the principal associates of inflammation, analysis of the effects of insulin, leptin, adiponectin, IGF-1, mode of delivery, and sex on cord inflammatory markers was performed using a stepwise regression model (Table 4). Most notably, leptin was positively associated with CRP, ICAM-1, and IL-6 in OT1DM. Relationships of cord leptin to CRP and IL-6 were of marginal significance in control subjects (Table 4), but there was a significant association of leptin and CRP in control subjects in similar models, with exclusion of babies delivered by emergency section (contribution to variance 11.8%, P = 0.03). Insulin showed a negative relationship with IL-6 and ICAM-1 in control subjects but was not related to any of the inflammatory markers in OT1DM. Finally, there was a generally negative relationship of IGF-1 to the markers in OT1DM, with the largest effect (contribution to variance 12.8%, P < 0.0001) for CRP in OT1DM. Inclusion of maternal A1C at 35–40 weeks’ gestation as a determinant in these models attenuated the associations of leptin with CRP, IL-6, and ICAM-1 in OT1DM (data not shown).


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  		TABLE 4 Multivariate analysis of predictors of cord inflammatory measures in control subjects and OT1DM

 
Relationship of inflammatory measures to fetal lipids.
An association between inflammation and lipid metabolism was evident in cord blood. Triglyceride was most consistently associated with the inflammatory measures and particularly with ICAM-1 (control subjects r = 0.42, P < 0.001; OT1DM r = 0.35, P = 0.001) (Table 3 and Fig. 1). NEFA was also generally positively correlated with the inflammatory measures but significantly so only in the case of IL-6 (control subjects r = 0.39, P = 0.009; OT1DM 0.43, P < 0.001). Finally, relationships of inflammatory measures with HDL cholesterol were generally but inconsistently negative, with significant correlations between CRP and HDL cholesterol (r = –0.23, P = 0.02) in OT1DM and IL-6 and HDL cholesterol in control subjects (r = –0.33, P = 0.026) (Table 3).

In a multivariate stepwise regression model incorporating log(IL-6), log(CRP), log(ICAM-1), log(insulin), log(leptin), adiponectin, IGF-1, mode of delivery, and sex, all of the inflammatory markers were independent predictors of triglyceride in OT1DM (Table 5). Although there was a small contribution from IL-6 in prediction of NEFA in OT1DM, mode of delivery was the principal predictor of NEFA (Table 5). IL-6 was also associated with HDL cholesterol in OT1DM; however, IGF-1 was the dominant predictor of HDL cholesterol in control subjects and OT1DM (Table 5).


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  		TABLE 5 Multivariate analysis of independent correlates of fetal cord lipids in OT1DM and control subjects

 

   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Maternal type 1 diabetes is associated with significant alteration in cord inflammatory markers in utero. Differences in metabolic, cardiovascular, and inflammatory variables between OT1DM and control subjects have previously been observed in a single study in children as young as 5–11 years old (17). In the current study, we establish that an inflammatory phenotype is present at birth, as ICAM-1 and CRP—accepted markers of systemic inflammation and endothelial dysfunction with previous known associations to obesity, insulin resistance, and type 2 diabetes in children (18–22) and adults (3–7)—are elevated in cord blood. Furthermore, we demonstrate that the known positive interrelationships among the plasma biomarkers CRP, IL-6, and ICAM-1 are established at birth.

IL-6 is one of the most studied cytokines and is considered for the most part to exhibit proinflammatory and proatherogenic activity. It is the main stimulant for hepatic production of CRP and other reactant proteins but also has other important roles leading to increased endothelial cell adhesiveness by upregulating E-selectin, ICAM-1, and vascular cell adhesion molecule-1 and releasing inflammatory mediators, including IL-6 itself (23). IL-6 expression correlates with plasma ICAM-1 expression in control subjects and OT1DM at birth, consistent with in vitro IL-6 upregulation of ICAM-1 expression (24) and the relationships observed in studies in children (25) and adults (26). The positive relationship that we observe between ICAM-1 and CRP may reflect the direct abilities of CRP to induce release of inflammatory cytokines and increase endothelial cell adhesion molecule expression, facilitating endothelial monocyte binding (27,28). The direct effects of CRP on endothelial function have recently been questioned (29,30), and it remains highly likely that elevations in CRP and ICAM-1 simply reflect a more general response to an abnormal environment (31). Although all these proteins form part of the acute-phase response, IL-6 is the most readily inducible, as reflected by the 300% increase in response to vaginal delivery in control subjects and OT1DM. In contrast, ICAM-1 and CRP are much slower to rise, with IL-6 induction of CRP production by liver cells taking at least 24 h (32) and CRP and ICAM-1 levels peaking 4 days after an acute cardiac event (33). Therefore, although IL-6 may be responsible for important mechanistic links with respect to inflammation and endothelial dysfunction, cord blood levels may be reflecting short-term changes—particularly relating to mode of delivery—in line with our findings. In contrast, cord CRP and ICAM-1 are likely to reflect the longer-term changes in the intrauterine environment; thus, their levels are likely to be more informative.

The association of low-grade inflammation with both obesity and type 2 diabetes is well described. CRP and ICAM-1 are increased in adults with obesity (34–38) and type 2 diabetes (39,40), and similar relationships also appear to be present in childhood (19). At birth, OT1DM have increased fat mass and an associated increased circulating leptin concentration (41,42). It is thus of considerable interest that CRP and ICAM-1 are not only increased in OT1DM but also associated with cord leptin and skinfold thickness. Furthermore, leptin is also associated with IL-6 at birth in OT1DM, raising the possibility that fetal adipose tissue is not only responsible for endothelial activation but also induction of a proinflammatory phenotype already evident by the time of birth. In general, relationships of leptin with cord measures of subclinical inflammation were more consistent than relationships of skinfolds to inflammatory measures. This may simply reflect that skinfolds were available for fewer members of the cohort and that skinfold measurement is less precise than cord leptin; nevertheless, we cannot exclude a particular role for leptin. Maternal A1C was also associated with CRP, supporting a role of maternal glycemic control in the inflammatory phenotype at birth.

The mechanistic link between adiposity, endothelial activation, and CRP secretion in utero may be cytokine mediated, including IL-6 (43), as leptin was associated with IL-6 in OT1DM. Although IL-6 levels were not increased in OT1DM, this may be a consequence of the dynamic nature of IL-6 at the time of birth, potentially explaining why we and others have not shown a relationship between cord levels of IL-6 and leptin or anthropometric neonatal measures of adiposity in control subjects (42) despite a relationship being observed in adults (44).

We were also interested in the direct effects of insulin on inflammatory measures at birth. Insulin is capable of stimulating adipocyte IL-6 production in vitro (45); however, there were no significant relationships of insulin to CRP, IL-6, or ICAM-1 in OT1DM. We are well placed to examine the effects of often very high cord insulin concentrations (>300 pmol/l in 14% of our cohort), and our data would not support a substantial stimulatory effect of fetal insulin on IL-6 in utero. Indeed, given the negative relationship of insulin with IL-6 and ICAM-1 in control subjects, one might argue the opposite case, that low-grade inflammation might suppress insulin secretion, as suggested by recent investigation in adults (46) or, conversely, that insulin is in part anti-inflammatory (47).

Lipid metabolism and inflammation are also linked via hepatic lipid metabolism with elevations of plasma triglycerides occurring during acute adult inflammatory responses (48); consequently, CRP and triglyceride are positively related in children (35) and adults (5). We demonstrate that this relationship is present at birth in OT1DM, with markers ICAM-1, CRP, and IL-6 potentially all acting as independent determinants of triglyceride. Underlying this relationship may be lipoprotein lipase (LPL), a pivotal enzyme in lipid metabolism. LPL activity is known to be modulated by various stimuli, including inflammation and adiponectin. In adults, lower adiponectin and higher CRP are associated with lower LPL activity, which is in turn associated with the characteristic diabetic dyslipidemia of low HDL and raised triglycerides (49). One might speculate that our observation of a proinflammatory state in OT1DM and association of CRP with HDL cholesterol and triglycerides in cord blood in OT1DM reflects a similar role of LPL. We have previously demonstrated for this cohort a significant reduction in HDL cholesterol and an increase in total–to–HDL cholesterol ratio in male offspring—established risk factors for coronary heart disease (15).

Clearly, further investigations are needed to examine the longer-term implications of these findings. Inflammatory markers are known to track in childhood (50) and to predict later metabolic (39,40) and vascular (51) disease. A single study has found raised inflammatory markers in offspring of mothers with type 1 diabetes in childhood (17). Our data demonstrate that this inflammatory phenotype is present at birth in OT1DM and that it is particularly related to fetal leptin. Future studies investigating potential long-term effects of this change—including potential programming of inflammatory, metabolic, and even vascular disease phenotypes in OT1DM—are warranted.


   ACKNOWLEDGMENTS
 
This study was supported by grants from the Chief Scientist Office of the Scottish Executive (K/MRS/50/C2726) and Glasgow Royal Infirmary Research Endowment Fund (05REF007).

This study would not have been possible without contributions of many people, including data collection at different centers as previously noted (12). We acknowledge the expert technical help of Dr. L. Cherry, who performed the lipid and inflammatory marker analysis.


   FOOTNOTES
 
Published ahead of print at http://diabetes.diabetesjournals.org on 17 August 2007. DOI: 10.2337/db07-0662.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication May 16, 2007 and accepted in revised form August 12, 2007


   REFERENCES
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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