Women with GDM have a chronic defect in β-cell function (18
). Although this defect likely antedates the pregnancy (19
), it is first detected clinically in the form of insufficient β-cell compensation for the severe acquired insulin resistance of late pregnancy resulting in the gestational hyperglycemia by which GDM is diagnosed. While the gestational hyperglycemia typically resolves following delivery, it is important to recognize that the β-cell defect in women with GDM is still present in the postpartum. Indeed, several studies have confirmed the presence of chronic β-cell dysfunction (and chronic insulin resistance [19
]) in this patient population many years after the index pregnancy (4
). Furthermore, it has recently been demonstrated that GIGT and even abnormal GCT NGT are both also characterized by β-cell dysfunction (of proportionately lesser severity than that of GDM), and this dysfunction also persists into the postpartum (4
). Accordingly, the concept has emerged that the spectrum of abnormal glucose homeostasis in pregnancy identifies a gradient of chronic β-cell dysfunction that may antedate the pregnancy and translates into a continuum of future risk for the development of type 2 diabetes, with GDM representing the most extreme element followed, in turn, by GIGT (4
). In this context, we sought to determine whether there are metabolic changes in the 1st year postpartum that vary in relation to gestational glucose tolerance status and, hence, may be relevant to this gradient of future diabetic risk.
Four key points arise from the current study. First, the longitudinal design (with two assessments in the 1st year postdelivery) reveals that deterioration of β-cell function is a very early event in women with GDM and GIGT, taking place within the 1st year postpartum. Second, the evaluation of women across the full spectrum of antepartum glucose tolerance shows that the degree of this decline in β-cell function varies in relation to the severity of gestational dysglycemia. Specifically, the decline is greatest in women with GDM followed by those with GIGT, whereas β-cell function does not appear to worsen in women with NGT in pregnancy. Third, this gradient of change in β-cell function in relation to gestational glucose tolerance status occurs in the absence of differential changes between the groups in waist circumference, weight, and insulin sensitivity, respectively (). Last, these data suggest that the deterioration in β-cell function in women with GDM and GIGT appears to precede the worsening of glycemia that must occur for progression to type 2 diabetes. Specifically, β-cell function declined in women with GDM and GIGT despite stable rates of dysglycemia between 3 and 12 months' postpartum (the rates actually decreased slightly in both groups over this period) (supplemental Fig. 1), and GDM remained an independent predictor of declining β-cell function even when the multiple linear regression analyses were limited to only those women with NGT at 3 months' postpartum. Indeed, this observation is consistent with a recent report showing impaired β-cell function at median 7 years' postpartum in 52 women with previous GDM compared with 39 control women with normoglycemia in pregnancy despite similar insulin sensitivity and the maintenance of NGT (22
). Taken together with the current findings, these data suggest that chronic progressive β-cell dysfunction is likely the dominant pathophysiologic defect driving the progression to type 2 diabetes in women with a history of GDM. This idea is further supported by evidence linking the early preservation of β-cell function in response to thiazolidinedione therapy with protection from the development of diabetes in women with a history of GDM (23
In clinical studies, β-cell dysfunction has consistently emerged as an independent predictor of incident type 2 diabetes in several populations (17
) including women with previous GDM (24
). In this context, the model arising from the current data is one where the previously demonstrated gradient of β-cell dysfunction associated with gestational dysglycemia (4
) is mirrored by a gradient of chronic progressive deterioration of β-cell function over time that will ultimately lead to the manifestation of long-term diabetic risk. In other words, as the most extreme element, women with GDM have the most severe β-cell defect at the outset, coupled with the greatest deterioration over the 1st year postpartum, resulting in the highest risk for the development of diabetes. Furthermore, the demonstration of this deterioration within the 1st year postpartum suggests that gestational dysglycemia provides the unique opportunity to identify a patient population in which the early evolution of β-cell dysfunction is unfolding prior to the development of diabetes or even pre-diabetes. It follows from these data that lifestyle modification (previously shown to reduce the risk of type 2 diabetes in women with a remote history of GDM [25
]) potentially should be instituted as early as possible in the postpartum to protect β-cell function, although further study is required.
A limitation of this study is the use of surrogate measures of insulin sensitivity and β-cell function. However, clamp studies would be difficult to implement in a study of this size (n
= 392) given their cost, invasiveness, and time requirements. These issues may be particularly problematic for performing two measurements in the 1st year postpartum in new mothers, a design feature that was integral to the novel demonstration of early deterioration of β-cell function. Furthermore, we have used two established and validated measures for both insulin sensitivity and β-cell function (13
) with consistent results observed in each case. A second limitation is that causality cannot be conclusively established in an observational cohort study owing to the possibility of unrecognized confounding (although the biologic plausibility and consistency of the current data are encouraging). There is likely to be phenotypic and genetic variability within the population that will influence the natural history of β-cell function in the postpartum. The third limitation is that the current study does not provide estimates for the overall population prevalence of postpartum pre-diabetes/diabetes due to the nature of the recruitment strategy, which was designed to enrich the study population for varying degrees of antepartum glucose intolerance. The final study limitation is that the current data cannot determine whether similar mechanisms are responsible for chronic β-cell dysfunction and the increased risk of postpartum metabolic syndrome in women with glucose intolerance in pregnancy (10
), though it is likely that insulin resistance is relevant to both of these outcomes.
In summary, the pattern of change in β-cell function in the 1st year postpartum varies in relation to glucose tolerance status in pregnancy unlike changes in waist circumference, weight, and insulin sensitivity. Indeed, both GDM and GIGT independently predict declining β-cell function between 3 and 12 months' postpartum. It thus emerges that β-cell dysfunction progresses in the early postpartum in women with a history of gestational dysglycemia and is likely a pathophysiologic factor contributing to the development of type 2 diabetes in this at-risk patient population.