Excessive weight gain, insulin resistance and beta cell dysfunction are all associated with the development of type 2 diabetes, but we don’t know which of the three is most important, particularly in the early stages when normal glucose tolerance (NGT) progresses to dysglycaemia. Identifying this key risk factor could help focus prevention efforts. 

A practical limitation in addressing this question is how best to find a normoglycaemic population to study that is likely to show sufficient rates of progression to prediabetes or diabetes within the time window of a research study. Pregnant women comprise a population that fits the bill because any degree of dysglycaemia in pregnancy increases the risk of future type 2 diabetes, particularly among those who develop gestational diabetes mellitus (GDM). So women with recent gestational diabetes that then reverts to NGT could provide a good model for studying early events in progression to prediabetes and diabetes. 

Ravi Retnakaran at Mount Sinai Hospital in Toronto and colleagues elsewhere have used this approach to rank the contributions made by adiposity, insulin resistance and beta cell dysfunction to the development of prediabetes and diabetes. They carried out metabolic measurements over a period of five years in a cohort of women who reflected the full spectrum of gestational glucose tolerance, from NGT through mild dysglycaemia to GDM. All had reverted to NGT at three months postpartum. 

Metabolic measurements

This study was carried out at Mount Sinai Hospital as part of a prospective observational cohort programme that is looking at the relationship between maternal glucose tolerance in pregnancy and metabolic function in the years after giving birth. All pregnant women are screened for GDM at 24 to 28 weeks with a 50 g glucose challenge test (GCT) followed by an oral glucose tolerance test (OGTT) if the GCT result is abnormal. Women were recruited into this new study before or after the GCT, including those with an abnormal GCT to enrich the cohort with those with varying degrees of dysglycaemia. Therefore, the cohort reflected a broad range of future risk of prediabetes and diabetes. 

Participants had serial metabolic measurements at three months, one year, three years and five years postpartum. They had an OGTT during which blood samples were taken for measurement of glucose and insulin at fasting and at 30, 60 and 120 minutes post-challenge. These measurements allowed assessment of glucose tolerance status, insulin sensitivity/resistance and beta cell function.  

Progressors and non-progressors

There were 302 women in the study of whom 213 maintained NGT over the next five years (non-progressors), while 89 developed either prediabetes or diabetes (progressors), which affected 76 and 12 women respectively. There were no significant differences between the two groups at baseline with respect to age, ethnicity, family history of diabetes or duration of breastfeeding. However, progressors had a higher prevalence of GDM in the recent pregnancy, higher BMI and higher fasting glucose and 2 h glucose, although all the glucose measurements were still in the normal range. They also had greater insulin resistance and poorer beta cell function. And, as the five-year study trajectory progressed, these differences persisted. Insulin sensitivity/resistance actually worsened in both groups, but more so in the progressors. 

What was more striking was a deterioration in beta cell function in progressors over this time, while it remained relatively stable among non-progressors. Further analysis, using various statistical models, was able to identify and rank predictors of progression at baseline. These were, in rank order, 2 h glucose on OGTT, recent GDM, BMI and age. A separate analysis also confirmed that beta cell function at baseline is the predominant pathophysiological determinant of future dysglycaemia. And the measure of beta cell function over the time of the study also emerged as being inversely associated with prediabetes/diabetes. In contrast, time-varying adiposity was not associated with progression and results for insulin resistance gave conflicting findings.   

Focus on beta cell dysfunction

Previous studies have consistently identified excess adiposity, insulin resistance and beta cell dysfunction as pathophysiological factors for type 2 diabetes. However, since all three frequently co-exist, dissecting their relative contributions to the condition has been challenging, leading to conflicting findings. The design of this new study, with a population of postpartum women, some of whom are at risk of developing prediabetes or diabetes within a five-year period, may have the capacity to disentangle the relative contributions of these three risk factors.

Although the generalisability of this study cannot be assumed given that it was focused on pregnant women, the authors say that there are three reasons why it does have clinical relevance. First, the International Diabetes Federation has reported that maternal hyperglycaemia now affects one in six pregnancies around the world. Second, those who do have hyperglycaemia in pregnancy have an increased risk of type 2 diabetes in the future. Finally, women of childbearing age are the group that has experienced the greatest rise in the prevalence of diabetes in Canada (where the study took place) in recent years. Therefore, a better understanding of the pathophysiology of progression from postpartum NGT to prediabetes and diabetes is important in addressing the growing burden of diabetes among women. 

The authors also point out that although adiposity, insulin sensitivity and beta cell function all differed between progressors and non-progressors, only beta cell function showed a differential decline over time in the former group. This is consistent with other research showing a decline in beta cell function prior to a diagnosis of diabetes. This new study adds to these findings by also identifying beta cell dysfunction both at baseline and across the follow-up period as being the main determinant of progression from NGT to prediabetes and diabetes. 

The analysis done in the study also quantifies the magnitude by which beta cell dysfunction exceeds excess adiposity and insulin resistance in this regard. Taken together, these findings support a pathophysiological model where the impact of weight gain and insulin resistance on diabetes risk may ultimately be mediated by how they affect the secretory function of the beta cells. 

This study’s findings have implications for both clinical practice and research. It is usually recommended that women with GDM undergo postpartum assessment of glucose tolerance by OGTT rather than by fasting glucose alone. This is supported by the finding in the baseline analysis mentioned above that, even when normoglycaemic, the 2 h fasting glucose value clearly surpasses the fasting glucose as a predictor of progression to prediabetes/diabetes in the first five years postpartum. It is also notable that the 2 h glucose measurement at three months postpartum also ranked higher than traditional risk factors such as BMI, age and ethnicity. This perhaps supports its use in future surveillance of women with GDM. 

The study also highlights declining beta cell function as the central factor that should be targeted when designing interventions aimed at preventing diabetes in women who have had glucose intolerance in pregnancy. To this end, the authors are conducting a randomised placebo-controlled trial of the SGLT-2 inhibitor empagliflozin for the preservation of beta cell function among women with recent GDM.

To read this paper, go to: Retnakaran R, Ye C, Kramer CK, Hanley AJ, Connelly PW, Sermer M, Zinman B. Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy. Diabetologia 24 August 2023. http://doi.org/10.1007/s00125-023-05994-5

To learn more, enrol on the EASD e-learning course ‘Gestational diabetes mellitus (GDM)’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.