Impact of pre-gestational and gestational diabetes mellitus on the expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 in human term placenta

Abstract

Purpose: Various studies in placental tissue suggest that diabetes mellitus alters the expression of glucose transporter (GLUT) proteins, with insulin therapy being a possible modulatory factor. The aim of the present study was quantitative evaluation of the expression of glucose transporters (GLUT-1, GLUT-4, GLUT-9) in the placenta of women in both, uncomplicated and diabetic pregnancy. Additionally, the effect of insulin therapy on the expression of selected glucose transporter isoforms was analyzed.

Methods: Term placental samples were obtained from healthy control (n = 25) and diabetic pregnancies, including diet-controlled gestational diabetes mellitus (GDMG1) (n = 16), insulin-controlled gestational diabetes mellitus (GDMG2) (n = 6), and pre-gestational diabetes mellitus (PGDM) (n = 6). Computer-assisted quantitative morphometry of stained placental sections was performed to determine the expression of selected glucose transporter proteins.

Results: Morphometric analysis revealed a significant increase in the expression of GLUT-4 and GLUT-9 in insulin-dependent diabetic women (GDMG2 + PGDM) as compared to both, control and GDMG1 groups (p < .05). Significantly increased GLUT-1 expression was observed only in placental specimens from patients with PGDM (p < .05). No statistically significant differences in GLUT expression were found between GDMG1 patients and healthy controls.

Conclusions: The results of the study confirmed the presence of GLUT-1, GLUT-4 and GLUT-9 proteins in the trophoblast from both, uncomplicated and diabetic pregnancies. In addition, insulin therapy may increase placental expression of GLUT-4 and GLUT-9, and partially GLUT-1, in women with GDMG2/PGDM.

Keywords: Gestational diabetes mellitus; Glucose transporter; Placenta; Pre-gestational diabetes mellitus; Quantitative morphometry.

Fig. 1

Immunohistochemical localization of GLUT in human term placenta at 400x magnification: GLUT-1 (a); GLUT-4 (b); GLUT-9 (c). The respective negative controls (a’), (b’), and (c’) are also presented (magnification 100×). A single visual field observed with the naked eye looks substantially uniformly within each studied group. For that reason, to avoid unjustified overloading with the pictures, only one immunostaining is presented for GLUT-1, GLUT-4, and GLUT-9

Fig. 2

A comparative examination of microvessel density in the placental sections (A—central part, B—peripheral part of the placenta) using the vascular/extravascular tissular index (V/EVTI); the median values (abstract numbers) and IQR. GDMG1 diet-controlled gestational diabetes mellitus, GDMG2, insulin-controlled gestational diabetes mellitus, PGDM pregestational diabetes mellitus

Fig. 3

Intra and inter-observer agreement calculated for each studied GLUT isoform, measured with 95% confidence interval. The observer agreement was considered good (substantial to almost perfect) when the ĸ value was above 0.60

Fig. 4

Expression of the respective glucose transporters (GLUT-1, GLUT-2, GLUT-9) in placental sections: diabetes-complicated pregnancy (non-insulin-dependent [GDMG1—diet-controlled gestational diabetes mellitus] and insulin-dependent [GDMG2—insulin-controlled gestational diabetes mellitus; PGDM—pregestational diabetes mellitus]) vs. vascular density-matched non-diabetic controls. Median of the percent values and IQR. The median value in the respective controls was taken as 100%*. * The value of the median in all controls (GLUT-1, N = 25; GLUT-4, N = 25; and GLUT-9, N = 25) have showed strong coherence with the respective mean value and the differences between the median and the mean under no circumstances did not exceeded ±5%