Subclinical inflammation associated with prolonged TIMP-1 upregulation and arterial stiffness after gestational diabetes mellitus: a hospital-based cohort study

Abstract

Background: Gestational diabetes mellitus (GDM) has significant implications for the future health of the mother. Some clinical studies have suggested subclinical inflammation and vascular dysfunction after GDM. We aimed to study whether concentrations of high-sensitivity C-reactive protein (hsCRP), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-8 (MMP-8) and -9, as well as values of arterial stiffness differ between women with and without a history of GDM a few years after delivery. We also investigated possible effects of obesity on the results.

Methods: We studied two cohorts-120 women with a history of GDM and 120 controls-on average 3.7 years after delivery. Serum concentrations of hsCRP were determined by immunonephelometric and immunoturbidimetric methods, MMP-8 by immunofluorometric assay, and MMP-9 and TIMP-1 by enzyme-linked immunosorbent assays. Pulse wave velocity (PWV) was determined using the foot-to-foot velocity method from carotid and femoral waveforms by using a SphygmoCor device. Arterial compliance was measured non-invasively by an HDI/PulseWave™CR-2000 arterial tonometer. All 240 women were also included in subgroup analyses to study the effect of obesity on the results. Multiple linear regression analyses were performed with adjustment for confounding factors.

Results: PWV after pregnancy complicated by GDM was significantly higher than after normal pregnancy, 6.44 ± 0.83 (SD) vs. 6.17 ± 0.74 m/s (p = 0.009). Previous GDM was also one of the significant determinants of PWV in multiple linear regression analyses. On the other hand, compliance indices of both large (p = 0.092) and small (p = 0.681) arteries did not differ between the study cohorts. Serum TIMP-1 levels were significantly increased after previous GDM (p = 0.020). However, no differences were found in the serum levels of MMP-8, MMP-9 or hsCRP. In subgroup analyses, there were significantly higher concentrations of hsCRP (p = 0.015) and higher PWV (p < 0.001) among obese women compared with non-obese ones.

Conclusions: PWV values were significantly higher after GDM compared with normoglycemic pregnancies and were associated with prolonged TIMP-1 upregulation. Cardiovascular risk factors were more common in participants with high BMI than in those with previous GDM.

Keywords: Arterial compliance; Gestational diabetes mellitus; High-sensitivity C-reactive protein; Matrix metalloproteinase-8; Matrix metalloproteinase-9; Pulse wave velocity; Subclinical inflammation; Tissue inhibitor of matrix metalloproteinase-1.

Fig. 1

Serum concentrations of hsCRP in the four subgroups. Median values (minimum, maximum) of hsCRP: among obese GDM women 2.1 (0.0, 12.4) mg/mL, obese control women 2.1 (0.3, 18.5) mg/mL, non-obese GDM women 0.9 (0.0, 32.3) mg/mL, and non-obese control women 0.7 (0.0, 25.7) mg/mL. Values of more than 10 mg/mL were measured by turbidimetric immunoassay. The overall p value is given at the bottom. Individual p values for pairwise comparisons are also presented

Fig. 2

PWV in the four subgroups. Median values (minimum, maximum) of PWV: among obese GDM women 6.8 (5.6, 9.7) m/s, obese control women 6.6 (4.8, 8.5) m/s, non-obese GDM women 6.3 (4.9, 9.2) m/s, and non-obese control women 6.0 (4.5, 7.9) m/s. The overall p value is given at the bottom. Individual p values for pairwise comparisons are also presented

Fig. 3

Large (a) and small (b) artery compliance index values in the four subgroups. a Median values (minimum, maximum) of the large-artery compliance index (C1): among obese GDM women 13.3 (9.1, 21.8) mL/mmHg × 10, obese control women 14.7 (10.2, 23.5) mL/mmHg × 10, non-obese GDM women 15.2 (7.2, 25.2) mL/mmHg × 10, and non-obese control women 15.9 (7.5, 25.7) mL/mmHg × 10. The overall p value is given. b Median values (minimum, maximum) of the small-artery compliance index (C2): among obese GDM women 8.8 (2.8, 15.2) mL/mmHg × 100, obese control women 8.6 (2.2, 17.7) mL/mmHg × 100, non-obese GDM women 8.1 (1.8, 17.6) mL/mmHg × 100, and non-obese control women 8.1 (2.4, 16.0) mL/mmHg × 100. The overall p value is given