Aberrant Pregnancy Adaptations in the Peripheral Immune Response in Type 1 Diabetes: A Rat Model

Abstract

IntroductionDespite tight glycemic control, pregnancy complication rate in type 1 diabetes patients is higher than in normal pregnancy. Other etiological factors may be responsible for the development of adverse pregnancy outcome. Acceptance of the semi-allogeneic fetus is accompanied by adaptations in the maternal immune-response. Maladaptations of the immune-response has been shown to contribute to pregnancy complications. We hypothesized that type 1 diabetes, as an autoimmune disease, may be associated with maladaptations of the immune-response to pregnancy, possibly resulting in pregnancy complications.MethodsWe studied pregnancy outcome and pregnancy-induced immunological adaptations in a normoglycemic rat-model of type 1 diabetes, i.e. biobreeding diabetes-prone rats (BBDP; 5 non-pregnant rats, 7 pregnant day 10 rats and 6 pregnant day 18 rats) , versus non-diabetic control rats (i.e. congenic non-diabetic biobreeding diabetes-resistant (BBDR; 6 non-pregnant rats, 6 pregnant day 10 rats and 6 pregnant day 18 rats) and Wistar-rats (6 non-pregnant, 6 pregnant day 10 rats and 5 pregnant day 18 rats)).ResultsWe observed reduced litter size, lower fetal weight of viable fetuses and increased numbers of resorptions versus control rats. These complications are accompanied by various differences in the immune-response between BBDP and control rats in both pregnant and non-pregnant animals. The immune-response in non-pregnant BBDP-rats was characterized by decreased percentages of lymphocytes, increased percentages of effector T-cells, regulatory T-cells and natural killer cells, an increased Th1/Th2-ratio and activated monocytes versus Wistar and BBDR-rats. Furthermore, pregnancy-induced adaptations in BBDP-rats coincided with an increased Th1/Th2-ratio, a decreased mean fluorescence intensity CD161a/NKR-P1b ratio and no further activation of monocytes versus non-diabetic control rats.ConclusionThis study suggests that even in the face of strict normoglycemia, pregnancy complications still occur in type 1 diabetic pregnancies. This adverse pregnancy outcome may be related to the aberrant immunological adaptations to pregnancy in diabetic rats.

Peripheral Immunological Cells in Pregnant Women and their Change during Diabetes

“…While type 1 diabetes (T1D) is thought to be a T cell mediated autoimmune disease type 2 diabetes (T2D) and gestational diabetes (GDM) are considered metabolic disturbances. However, recent evidence suggest that aberrant immunological adaptations during pregnancy might play a significant role [1].…”

Impaired trophoblast invasion and increased numbers of immune cells at day 18 of pregnancy in the mesometrial triangle of type 1 diabetic rats

“…We observed decreased litter size, increased fetal resorptions and reduced fetal and placental weight in BBDP-rats compared to healthy control rats [5]. The reduced fetal and placental weight may suggest that the development of the placenta is impaired in pregnant rats with T1D.…”

“…For the present experiments, placentae were used from the pregnant rats used in our previous paper in which we studied the peripheral immune-response during pregnancy [5]. We included pregnant rats, which were sacrificed at day 18 (BBDP: n ¼ 6; W: n ¼ 5; BBDR: n ¼ 6).…”

“…We observed decreased litter size, increased fetal resorptions, and reduced fetal and placental weight in BBDP-rats compared to healthy controls (Supplementary Table 2). This dataset has been previously published under a Creative Commons Attribution [5]. Fig.…”

“…The mechanisms behind the increased incidence of these complications is not fully understood, but hyperglycemic events play a role [3,4]. Recent work from our lab showed that also in an animalmodel for T1D, biobreeding diabetes-prone (BBDP) rats, more complications occurred during pregnancy, even during normoglycemia [5]. This suggests that other mechanisms may be involved.…”