Challenging the dogma of homogeneity in gestational diabetes

The number of women who develop diabetes in pregnancy (gestational diabetes) is increasing. Women of South Asian ethnicity are particularly affected. This common disorder which is associated with high blood glucose increases the risk of several pregnancy complications, most of which relate to the baby growing too large. These risks include difficulties during labour and stillbirth. Also, there is increased chance of the mother developing lifelong type 2 diabetes.
At present, all women who develop gestational diabetes receive the same treatment approach. This is because doctors view gestational diabetes as one condition. Research in non-pregnant people with type 2 diabetes is beginning to show that there may be many different types of diabetes. Similarly, evidence is emerging which suggests that doctors should think of gestational diabetes as a group of different disorders, all leading to high blood glucose. This study aims to unpick the different types of gestational diabetes and we shall see if these are the same in South Asian and White European women. If successful we shall then be able to treat each woman according to their type of diabetes, and work towards preventing type 2 diabetes after pregnancy.
This work will begin by defining more accurately two proposed pathways to GDM:-
1. GDM arising from problems of glucose uptake in the liver, fat and skeletal muscle. In one subtype of GDM, it is proposed that the normal transfer of glucose into tissues is reduced because the tissues don't respond to insulin, leading to glucose not being taken up from the blood, resulting in raised blood levels.
2. GDM arising from inefficient secretion of insulin from the beta-cells of the pancreas. In normal pregnancy, all women become a little insulin resistant, but cells in the pancreas (beta-cells) respond by producing more insulin. In this, second type of GDM it is proposed that the pancreatic insulin response is insufficient, and glucose rises in the blood.
We will recruit 750 pregnant women (400 White European, 350 South Asian, calculated on the basis of the likely number of women who will develop GDM) at the time of their first scan (11-15 weeks of pregnancy). As we are interested in glucose levels and how well the body is producing insulin (the hormone that controls glucose) throughout pregnancy, women will undertake two sugar stress tests (the oral glucose tolerance test; OGTT); one in early pregnancy (12-16 weeks), and one at the normal time for diagnosis of gestational diabetes (24-28 weeks), and blood samples will be stored. We will also ask some simple questions and measure glucose using a stick-on glucose sensor (CGM) in addition to following the growth of the baby during pregnancy. We will then undertake a detailed analysis of the blood samples, measuring a range of molecules which we know are associated with diabetes and blood glucose management. By combining this data together we hope to define with accuracy the different ways each of the subtypes develop gestational diabetes, so we can offer each woman the most appropriate treatment. We will look for differences and similarities between women of White European descent and women of South Asian descent. Having achieved a better understanding of the GDM subtypes we will be well positioned to develop specific tests for each type of GDM to help doctors decide on which treatment would work best for each individual. We shall also find out if the same or slightly different tests early in pregnancy can pick up women who will later develop GDM subtypes, so that doctors can intervene to prevent GDM.

The prevalence of GDM has increased globally, but mechanistic understanding of this common pregnancy complication has remained unchanged for decades. Reliance on the inaccurate oral glucose tolerance test (OGTT), and a lack of rigorous scientific investigation has led to empirical treatment strategies, often with sub-optimal outcomes.
This proposal was prompted by reports that GDM may have at least two different aetiologies, paving the way for accurate mechanistic definition, targeted prevention/treatment strategies and better pregnancy outcome. This will be the first rigorous biological investigation of two proposed and predominant subtypes: 1) GDM resulting primarily from insulin resistance and 2) GDM resulting primarily from inadequacy of pancreatic beta-cell function. 750 women will be recruited; 400 of White European descent and 350 of South Asian descent. All will have two OGTTs (12-16 weeks, 24-28 weeks). Known biomarkers of insulin sensitivity and beta-cell function will be profiled in fasting and post-challenge blood samples to inform subtype allocation. Since the origins of beta cell dysfunction in GDM remain enigmatic, implicated pregnancy/placental hormones (eg kisspeptin) will be measured.
Disease subtypes will be elucidated through integration of routine maternal and clinical data with targeted hormonal profiles captured during the two OGTTs, and the gestational glucose profile obtained using continuous glucose monitoring. Differences and similarities will be explored between women of White European and South Asian descent.
To facilitate translation to clinical practice, including improved diagnosis and targeted treatment/prevention we shall work towards tests to discriminate between 1) GDM subtypes in the second trimester, 2) subtypes in early pregnancy before development of GDM, and 3) propose targeted treatment regimes.
This study will lay the foundation for personalised, physiologically targeted therapy for GDM, leading to improved outcomes.