Identification of manifest diabetes and complication development in gestational diabetes mellitus. The pursuit for biomarkers

Abstract: Gestational diabetes mellitus (GDM) is a type of diabetes which is first recognised during pregnancy. In the county of Skåne in Southern Sweden, over 2% of all pregnancies are complicated by GDM, a number that is generally several times higher worldwide. Women with GDM during pregnancy are at risk of developing GDM anew in subsequent pregnancies, but also have an increased risk of developing postpartum type 1 or type 2 diabetes. It is not only the mother who is at risk of developing complications due to the increased blood sugar levels in GDM. The foetus responds to the elevated levels of blood sugar by producing more insulin. Aside from lowering the blood glucose levels, insulin also acts as a growth hormone resulting in a larger foetus which in turn can cause birth trauma. Offspring to women with GDM during pregnancy are also at increased risk of developing future obesity and diabetes. GDM is today most commonly diagnosed in late pregnancy. Thus there is a possibility that both the mother and child are exposed to elevated blood sugar levels for a long time before it is recognised which may increase the risk of adverse outcomes. Providing pregnant women with the possibility of earlier screening for hyperglycaemia could help decrease the risk of such complications.The aim with this thesis was to identify proteins soluble in blood in patients with GDM which could improve the diagnosis of GDM in early pregnancy. We also aimed to identify gene variants and soluble proteins capable of indicating women with GDM at increased risk of developing type 1 and type 2 diabetes after delivery.The patients included in our studies presented in this thesis have received the GDM diagnosis following an oral glucose tolerance test at Lund University Hospital, Lund, Sweden 1996-2015. We have also recruited pregnant women without diabetes from the same geographical region in paper II, IV and V to act as controls. Genetic variants of the gene encoding zinc transporter 8 (ZnT8) was compared in women with GDM and female blood donors in paper III.Our results from paper I and III show that women with GDM positive for antibodies against glutamic acid decarboxylase (GAD) during pregnancy have an increased risk of developing type 1 diabetes after delivery. We can also conclude that patients that have a specific subclass of these antibodies (GADA IgG4) have a reduced risk of later type 1 diabetes development compared to patients with (GADA IgG1). In paper II, IV and V soluble proteins was analysed with the aim to improve the diagnosis of GDM. Despite finding interesting results in thesestudies, more studies are required to identify soluble proteins reaching satisfactory precision to improve the diagnosis of GDM.This papers included in this thesis have collectively shown that we better can identify women at increased risk of developing type 1 diabetes after pregnancies complicated by GDM. We have also emphasised the need of finding novel biomarkers capable of improving the diagnosis of GDM during pregnancy, and especially already in early pregnancy. Identifying these women could potentially decrease the risk of developing later complications.