Contribution of Gestational Weight Gain on Maternal Glucose Metabolism in Women With GDM and Normal Glucose Tolerance

Fernanda L. Alvarado; Perrie O'Tierney-Ginn; Patrick Catalano


J Endo Soc. 2021;5(2) 

In This Article


We report that women who developed GDM, despite having a similar pre-pregnancy percentage body fat, had decreased insulin sensitivity before pregnancy compared with NGT women. Furthermore, the absolute and relative changes in body composition and insulin sensitivity were similar between NGT and GDM women. Adjusting for relevant maternal characteristics, Δ body weight contributed to just 9% of the Δ insulin sensitivity. These results may help explain why many of the clinical trials of dietary and lifestyle intervention during pregnancy for mitigation or prevention of GDM have not achieved the desired results.[1,12]

In nonpregnant individuals, increase in weight is associated with the development of obesity, insulin resistance, and type 2 diabetes. Therefore, similar increases in GWG have been assumed to underlie the changes in glucose metabolism during pregnancy. However, in a longitudinal study of nondiabetic Pima Indians, Swinburn et al showed that baseline insulin resistance was inversely correlated with weight gain over a 3.5-year follow-up period.[34] Our results suggest that the pre-pregnancy measure of insulin sensitivity is a stronger determinant of the changes in glucose metabolism during the 40 weeks of a full-term gestation. An approximately 30% decrease in insulin sensitivity by late gestation was seen in both GDM and NGT subjects.

During a normal pregnancy there is an increase in insulin response,[29] however; excessive GWG, preexisting obesity, and certain genetic predisposition may trigger failure of beta-cell adaptation.[35] In our data, the higher the Δ body weight, the lower the Δ in insulin response in GDM women, although this was not statistically significant. This likely points out the development of a beta-cell defect in women with GDM vs NGT, which when combined with insulin sensitivity as the disposition index, becomes significant for women with GDM.

The use of body weight or BMI as a marker of body fat during pregnancy may result in misclassification of obesity in pregnancy because of the varying contribution of total body water to FFM on body weight.[6,36] Berggren et al demonstrated that during pregnancy, fat mass constitutes the greatest variance in GWG.[37] Hence in our analysis, in addition to the change in weight, we assessed the changes in body composition to examine if accumulation of adipose tissue was related to alterations in maternal glucose metabolism. We did not find a correlation of measures of adiposity with either Δ in insulin sensitivity, insulin response, or disposition index.

Our group has reported a 120% increase in insulin sensitivity in the immediate postpartum period in women with GDM compared with late gestation measures.[38]These data support our findings. The placenta, and not maternal GWG, underlies the metabolic changes in pregnancy. The placenta serves as the main interface between the mother and the fetus, and it is a rich source of hormones, cytokines, and adipokines, which are released into the maternal circulation and modulate maternal glucose metabolism during pregnancy.[39,40]

Placental hormones such as progesterone, estradiol, human placental lactogen, prolactin, and cortisol have all been described as possible mediators for pregnancy-induced insulin resistance; however, there is yet no consensus as to the exact mechanism.[41] Cytokines and adipokines such as tumor necrosis factor-α and leptin have been negatively correlated with insulin sensitivity, although the authors of these studies concluded that further studies were needed in order to confirm their findings.[41,42] Recent data suggests that placental exosomes and miRNAs may be involved in changes in maternal metabolic status.[43,44] Despite the obvious association between whole-body insulin resistance in pregnancy and the placenta, the precise mechanism remains poorly understood, and further studies need to be developed.

A major strength of this study is its longitudinal data with measurements from preconception through late pregnancy. The estimates of insulin sensitivity were measured with the gold-standard hyperinsulinemic-euglycemic clamp. Maternal body composition measurements in pregnancy are specific to gestational age. Our study is limited by a small number of subjects and a lack of ethnic diversity. This is particularly true for the GDM group, as 24 samples were needed to achieve 80% power; however, as this was a secondary analysis, we are constrained by the original trial's criteria.

In conclusion, we did not find a clinically significant correlation between changes in components of glucose metabolism and weight or body composition from preconception to late pregnancy. Given that insulin sensitivity improves 120% in the immediate postpartum period,[38] further studies are needed to more easily estimate insulin sensitivity prior to conception or in early pregnancy as well as to understand the potential mediators released by the placenta. Since weight gain explains a relatively small component of the variation in insulin sensitivity, we continue to recommend avoidance of excessive GWG to prevent postpartum weight retention which increases the risk of long-term maternal metabolic dysfunction and increased pre-pregnancy adiposity in subsequent pregnancies.[45] If the effects of these risk factors are chronic rather than acute, then prevention of GDM would ideally require initiating lifestyle interventions before a planned pregnancy.[1]

In summary, we showed that gestational weight gain contributes only 9% of the absolute changes in insulin sensitivity during pregnancy. We hypothesize that this low contribution is the main reason why lifestyle interventions during pregnancy targeting maternal weight have not impacted the progression of insulin resistance during pregnancy.