Changes of Prolactin Sensitivity in Gestational Diabetes

The hypothesis is that gestational diabetes (GDM) is characterized by a reduced sensitivity for the hormones prolactin (Prl) and placenta lactogen (PL). Both of these hormones act through the Prl receptor, a determinant of Prl sensitivity. In the project we aim to identify families where gestational diabetes is common. Blood from mothers with GDM will be used to determine the sequence of the Prl receptor with the intent to look for genetic differences in this receptor compared to women without GDM. The role of Prl will further be studied in cultured beta cells where the aim is to understand how certain genes (SOCS2/mTOR) and certain environmental components (palmitate) affect the Prl receptor sensitivity and beta cell functions. Prl has previously only been regarded to regulate fertility and lactation but new results demonstrate a broader function for this hormone that may include GDM. It is important to better define and prevent GDM because it has both short term and long term consequences for the child.

The hypothesis is that gestational diabetes (GDM) is characterized by a reduced sensitivity for the hormones prolactin (Prl) and placenta lactogen (PL). Both of these hormones act through the Prl receptor, a determinant of Prl sensitivity. In the project we aim to identify families where gestational diabetes is common. Blood from mothers with GDM will be used to determine the sequence of the Prl receptor with the intent to look for genetic differences in this receptor compared to women without GDM. The role of Prl will further be studied in cultured beta cells where the aim is to understand how certain genes (SOCS2/mTOR) and certain environmental components (palmitate) affect the Prl receptor sensitivity and beta cell functions. Prl has previously only been regarded to regulate fertility and lactation but new results demonstrate a broader function for this hormone that may include GDM. It is important to better define and prevent GDM because it has both short term and long term consequences for the child.

Background. Prolactin (Prl) is a pituitary hormone known to be related to fertility and lactation. Recent discoveries demonstrate that human Prl is also made outside of the pituitary gland and might there act as a local growth factor (1). In clinical practice, measurement of serum prolactin (Prl) is used to identify pituitary adenomas. A key point in this application concerns the importance of altered Prl sensitivity and such conditions need not to be associated with altered Prl levels found in the circulation. An important component of Prl sensitivity is the Prl receptor that is expressed in a variety of tissues and this receptor activates the intra-cellular JAK-STAT-SOCS signaling pathway. Previous studies of altered Prl sensitivity have linked the Prl receptor to certain clinical conditions. A Prl receptor mutant, resulting in loss of function, have been found in a family with high Prl levels and conversely, a constitutively active Prl receptor mutant have been found in benign fibromas of the breast (2) (3). Other mechanisms in control Prl sensitivity include SNPs, genes that regulate Prl receptor levels, environmental/infectious agents and hormonal factors. The hypothesis in the present application is that gestational diabetes mellitus (GDM) is associated with a reduced sensitivity for Prl. Gestational diabetes (GDM) is the third form of diabetes, it is different from type I and type II diabetes because it is discovered during pregnancy and is normally reversed following delivery. The diagnosis is made by measurements of glucose in the mother and normally there are no subjective symptoms. The incidence of GDM varies but can be around 10-20% of pregnancies. A dramatic increase in incidence suggests GDM to be related to life style but it is clearly a genetic component as well (4). Because GDM is reversible, the condition has gotten a relative small interest compared to other forms of diabetes (type I and type II diabetes). However, new results show that children of GDM mothers have a marked increased risk to later in life develop diabetes, cardiovascular complications and neuropsychiatric conditions such as ADHD (5-7). The most likely reason for this is that a high fetal exposure to glucose leads to epigenetic effects on the child (8). Obviously, this situation makes it increasingly important to diagnose and to treat GDM mothers. In terms of treatment most women are treated with life style advice (changed nutrition, increase physical activity) but in severe cases insulin is needed. Since the diagnosis depend on blood sugar measurements, the setting of an appropriate cut off value has been widely debated and there is a need to find better diagnostic tools. The hypothesis in this application is that Prl is a key factor in GDM. During pregnancy Prl levels increase and this is also the case for human placenta lactogen (hPL) produced by the placenta. Both of these hormones bind to the Prl receptor and thereby expand insulin producing beta cells during pregnancy in order to adapt to new metabolic demands. Interestingly, a mouse knock out of the Prl receptor, specifically in beta cells has no effect in the normal mouse but during pregnancy these mice all get GDM (9). Different types of investigations suggest that Prl is important in GDM (10). However, studies in human have failed to detect any major changes in circulating Prl or hPL in GDM mothers - subsequently the possibility arises that GDM is a condition of reduced Prl sensitivity. A reduction of Prl sensitivity could hypothetically depend on mutations/SNPs in the Prl receptor gene or be caused by altered functions of genes regulating Prl sensitivity. Prl receptor SNPs have been found to correlate to GDM in a South American population (11). In terms of Prl receptor regulation genes we have previously identified two such genes, encoding SOCS2 and TSC2. Knock out of SOCS2 (increases sensitivity to GH/Prl) leads to increased size of beta cells and a partial resistance to diabetes (12, 13). The overall plan in this application is to analyze Prl sensitivity genes (Prl receptor, SOCS2, TSC2) in GDM patients and to conduct in vitro studies using cultured beta cells to study regulation of Prl receptors in such cells.