Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes

Abstract

Objective: Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE.

Design: Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset.

Setting: Antenatal clinics.

Population: Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21).

Methods: Maternal serum levels of sRAGE (total circulating pool), N(ε)-(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays.

Main outcome measures: Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-).

Results: In DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P < 0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates.

Conclusions: In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM.

Figure 1

Serum levels of soluble receptor for advanced glycation end-products (sRAGE) (a), N^ε-(carboxymethyl)lysine (CML) (b), hydroimidazolone (c) and nonspecific advanced glycation end-products (AGE) (d) during gestation. Values (means ± SEM) were plotted against the average gestational age at each visit. For illustrative purposes, three groups of women are shown: □, normotensive women without diabetes (DM–) (n = 21); ○, normotensive women with diabetes (DM PE–) (n = 92); ●, women with diabetes and PE (DM PE+) (n = 26). Values significantly different between subject groups are also indicated: the primary analysis compared DM PE+ and DM PE– groups: *P < 0.05; †P < 0.1; two-tailed t-test.

Figure 2

Ratios of soluble receptor for advanced glycation end-products (sRAGE) versus advanced glycation end-products (AGE) during gestation: (a) N^ε-(carboxymethyl)lysine (CML); (b) hydroimidazolone; (c) nonspecific AGE. For illustrative purposes, three groups of women are shown: □, normotensive women without diabetes (DM–) (n = 21); ○, normotensive women with diabetes (DM PE–) (n = 92); ●, women with diabetes and PE (DM PE+) (n = 26). Values significantly different between subject groups are also indicated: the primary analysis compared DM PE+ and DM PE– groups: *P < 0.05; †P < 0.1; two-tailed t-test. Statistical analyses were conducted after logarithmic transformation.