In this study, IS estimated by QUICKI did not differ between the offspring of pre-eclamptic and normotensive mothers at age 12 years. The same was true for the serum concentrations of adiponectin, HMW adiponectin, IGF-I, IGF-II, IGFBP-1, leptin, and SHBG. Our data show that the children in the PRE group with low
Table 5. Variables related to IS in the PRE and non-PRE groups with the lowest (low QUICKI) and higher IS (high QUICKI) tertiles at age 12 years
Variables PRE, low QUICKI
QUICKI 0.325 (0.321-0.328) 0.365 (0.359-0.372) <0.001 0.331 (0.327-0.335) 0.362 (0.356-0.368) <0.001
Serum
mmHg 120.0 (116.5-123.4) 114.3 (111.7-116.9) 0.019 115.6 (112.0-119.2) 112.7 (109.7-115.8) 0.269 BMI, kg/m2 19.0 (18.0-20.1) 18.9 (17.8-20.0) 0.433 21.5 (19.6-23.5) 17.9 (16.9-18.9) 0.001
WHtR 0.43 (0.41-0.46) 0.44 (0.42-0.45) 0.826 0.46 (0.43-0.50) 0.42 (0.41-0.44) 0.014
Data are mean (95% confidence intervals).
*Mann-Whitney test for differences.
Abbreviations: BMI, body mass index; BP, blood pressure; HDL, high-density lipoprotein; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor-binding protein; LDL, low-density lipoprotein; QUICKI, Quantitative Insulin Check Index; SHBG, sex hormone-binding globulin, WHtR, waist-to-height ratio
Table 6. Factors associated with low IS (the lowest QUICKI tertile) in the PRE group
Covariates Regression
coefficients p-value OR 95% CI for OR
High systolic BP
(10 mmHg) 0.753 0.024 5.8 1.3-26.5
High serum leptin
(ng/ml) 0.145 0.009 1.2 1.0-1.2
High serum triglycerides (9 mg/dl; 0.1 mmol/l)
0.206 0.040 1.2 1.0-1.5
High serum IGF-I
(10 ng/ml) 0.108 0.031 1.1 1.0-1.2
Results of the binary logistic regression analysis (n = 60) adjusted for sex, pubertal stage (Tanner B/G 1-5), BMI, and birth weight (SDS); variation explained by the model, 51.5%.
Abbreviations: BP; blood pressure; IGF, insulin-like growth factor
QUICKI values (i.e., lower IS) had significantly higher systolic BP and serum IGF-I, leptin, and triglyceride levels and lower IGFBP-1 levels compared with those with higher QUICKI values (i.e., better IS).
The association of pre-eclampsia and IR has been reported previously (Laivuori et al. 1996, Kaaja et al. 1999). Using the minimal model technique, Kaaja et al. (1999) showed that previously healthy women with pre-eclampsia developed IR during pregnancy, and that the insulin-resistant state persisted for at least 3 months after delivery. Type 1 and 2 diabetes and gestational diabetes (Carty et al. 2010, Steegers et al. 2010), as well as the metabolic syndrome, are considered risk factors for the development of pre-eclampsia during pregnancy (Barden et al. 1999, Magnussen et al. 2007). Consequently, the potential causal relationship of IR and pre-eclampsia is unclear at present. Libby et al. (2007) examined whether pre-eclampsia is associated with a future risk of type 2 diabetes in both the mothers and their offspring. The women with previous pre-eclampsia were at increased risk of type 2 diabetes, but in the offspring the risk was influenced only by LBW, specifically by a history of being born SGA (Libby et al. 2007). Miettola et al. (2013) found no differences in insulin and glucose concentrations or lipid profile in 16-year-old offspring of mothers with pre-eclampsia compared with those of normotensive mothers. These results are in accordance with our findings, although Miettola et al. (2013) did not report IS indices.
In addition, Lazdam et al. (2010) found no significant differences in glucose or insulin levels in 24-year-old offspring born preterm from hypertensive or normotensive pregnancies.
In our study, in the PRE group QUICKI was significantly lower and serum insulin, IGF-I, and leptin levels were higher in the girls than the boys, despite their similar BMI. These sex differences could be explained by the earlier pubertal development in the girls. Moran et al. (2002) showed in euglycaemic
hyperinsulinemic clamp studies that during puberty, IGF-I levels are closely related to IR independent of body fat percentage. IGF-I level and IR peak at Tanner stage 4 in both sexes. Thus, the physiological elevation of the GH/IGF-I axis is associated with the IR of puberty (Moran et al. 2002). Subsequently, Moran et al. (2008) reported that during the second decade of life, males become more insulin-resistant than females, possibly owing to subtle sex-related differences in sex hormones and central fat distribution. In our study, the higher serum leptin levels in the girls than boys in the PRE group could result from the earlier onset of puberty in the girls. At the onset of puberty, leptin levels begin to increase in girls but decrease in boys, reflecting sex-dependent changes in body composition (Ahmed et al. 1999).
Serum SHBG, which has been suggested to predict IS and metabolic risk during puberty (Sørensen et al. 2009), did not indicate decreased IS in the PRE group compared with the non-PRE group. Moreover, IGFBP-1 levels did not differ between the 2 groups. However, low IGFBP-1 levels were related to low QUICKI in both groups, confirming the previously reported association between circulating IGFBP-1 level and IS (Yki-Järvinen et al. 1995). Furthermore, higher serum triglyceride, leptin, and IGF-I levels were related to low QUICKI values in both groups. In the PRE group, these associations were seen independent of BMI. In the PRE group, the children in the lowest QUICKI tertile had also significantly higher systolic BP. Several studies have reported an association between maternal pre-eclampsia and elevated BP in the offspring (Palti and Rothschild 1989, Seidman et al. 1991, Tenhola et al. 2003, 2006, Ferreira et al. 2009, Øglænd et al. 2009, Davis et al. 2012, Fraser et al. 2013). In this study, we found a subgroup of PRE subjects with low QUICKI values and higher systolic BP and serum triglyceride, leptin and IGF-I levels.
A strength of the present study is its case-control design, with the PRE and non-PRE groups carefully matched by age, sex, and gestational age. In addition, a possible influence of birth weight on IS was controlled for by adjustments in the regression analyses. In the statistical analyses, the age of participants was challenging, because of the variable timing of pubertal development. However, a comparison of the PRE and non-PRE groups (and the respective low and high QUICKI subgroups) did not reveal any significant differences in pubertal development. Even when controlling for several confounding factors, the 1-time measurement of IS could be a potential limitation. In addition, fasting insulin and IS or IR indices derived from single fasting insulin and glucose are not optimal measures for assessing peripheral IS, although they may provide information regarding compensatory hyperinsulinemia and liver insulin metabolism (Levy-Marchal et al. 2010). Furthermore, other factors influencing IS, such as the frequency and intensity of exercise and dietary habits, were not adjusted for.
Maternal pre-eclampsia did not produce decreased IS in the offspring by age 12 years. However, the offspring with the lowest IS had higher triglyceride levels and systolic BP, suggesting that components of the metabolic syndrome may cluster in this subgroup.
6 SERUM IL-1 RECEPTOR ANTAGONIST CONCENTRATIONS ASSOCIATE WITH UNFAVOURABLE METABOLIC FEATURES IN 12-YEAR-OLD CHILDREN
6.1 ABSTRACT
Context: Elevated IL-1Ra concentrations are associated with obesity, IR and CVD risk in adults.
Objective: To determine if serum IL-1Ra and hs-CRP levels are associated with markers of reduced IS and serum lipids in 12-year-old children.
Design and Participants: Of 191 children (n = 109 girls), 78 were categorized as having had birth weight and length AGA, 69 were SGA, and 44 were AGA and from PREs.
Serum markers of low-grade inflammation, IS, and lipids were measured. QUICKI was calculated.
Results: Mean serum IL-1Ra levels did not differ between the sexes or among the gestational categories. Children in the highest IL-1Ra tertile had lower QUICKI, IGFBP-1, SHBG, and HDL-C values; and higher BMI, WHtR, and serum insulin, hs-CRP, leptin, and triglyceride concentrations than those in the lowest IL-1Ra tertile.
Logistic regression analysis showed higher serum hs-CRP and leptin levels, and WHtR were associated with high serum IL-1Ra levels. IL-1Ra concentration could be used to discriminate the children with lowest IS (area under the curve, 0.68; p < 0.001);
hs-CRP level could not.
Conclusion: Children with the highest IL-1Ra levels had lower IS, higher hs-CRP levels and BMI, and a less favourable lipid profile than those with the lowest IL-1Ra levels, suggesting that high IL-1Ra concentrations may be associated with increased CVD risk in 12-year-old children.
Adapted with permission of Oxford University Press from: Seppä S, Tenhola S, Voutilainen R. IL-1 receptor antagonist concentrations associate with unfavorable metabolic features in 12-year-old children. J Endocr Soc 2(8):870-881, 2018. The tables are modified from the original to correspond sequential numbers of this thesis.
6.2 INTRODUCTION
Adipose tissue is a metabolically active organ that secretes a variety of adipocytokines, which are able to modulate immunological responses, energy homeostasis, adipogenesis, and IS (Blüher and Mantzoros 2015). Metabolic stress in the white VAT causes chronic subclinical inflammation, which may induce activation of the innate immune system, leading to dysregulated adipocytokine synthesis, IR, β-cell dysfunction, and type 2 diabetes (Wellen and Hotamisligil 2005, Ballak et al.
2015, Herder et al. 2015, Blüher and Mantzoros 2015). Furthermore, proinflammatory cytokines contribute to vascular endothelial dysfunction and, finally, to atherosclerotic CVD (Herder et al. 2015, Ridker 2016).
The IL-1 cytokine family is a critical regulator of the innate immune responses (Dinarello 2011, Ballak et al. 2015, Ridker 2016). It consists of 11 members (Dinarello 2011), almost all of which are involved in visceral obesity-associated inflammation (Ballak et al. 2015). The proinflammatory cytokine IL-1β induces secretion of other proinflammatory cytokines, inhibits β-cell function, destroys β-cells, and promotes IR (Ballak et al. 2015, Herder et al. 2015). Its natural antagonist is the adipose tissue-derived cytokine IL-1Ra (Juge-Aubry et al. 2003), which acts by blocking the binding site of IL-1β at the IL-1 receptor (Dinarello 2011). IL-1Ra synthesis is induced by many inflammatory factors, including the members of the IL-1 family (Ballak et al. 2015).
IL-1β induces IL-1Ra production; thus, upregulated IL-1Ra levels are considered to reflect higher IL-1β activity (Herder et al. 2017) and predispose to IR and type 2 diabetes (Ballak et al. 2015). In adults, elevated IL-1Ra concentrations are associated with risk for type 2 diabetes (Ruotsalainen et al. 2006, Grossmann et al. 2015, Herder et al. 2015, 2017), the metabolic syndrome and obesity (Ballak et al. 2015), essential hypertension (Peeters et al. 2001) and CVD (Herder et al. 2015, 2017). Furthermore, increased IL-1Ra concentrations in obesity in childhood are a sign of low-grade inflammation (Stoppa-Vaucher et al. 2012). Moreover, IL-1Ra was considered the most sensitive marker of cytokine response in the prediabetic state in the offspring of patients with type 2 diabetes (Ruotsalainen et al. 2006).
The aim of the current study was to determine whether serum IL-1Ra concentrations are associated with other markers of low-grade inflammation, reduced IS, or unfavourable lipid profile in 12-year-old children. Furthermore, we investigated whether IL-1Ra concentrations are associated with LBW or exposure to maternal pre-eclampsia, which are considered to independently predispose to later metabolic and CVDs (Barker et al. 1989, Davis et al. 2012, Stojanovska et al. 2016).
Finally, we compared concentrations of IL-1Ra with hs-CRP in terms of detecting reduced IS and unfavourable lipid profile.