The Impact of Gestational Weight Gain on Glucose and Insulin Physiology in Pregnancy-Does Timing Matter?

Gestational diabetes (GDM) during pregnancy leads to negative short- and long-term outcomes for both mother and baby. Women who develop gestational diabetes (GDM) are at increased risk of morbidity during pregnancy (including risk of gestational hypertension/preeclampsia) and of complicated deliveries (including cesarean delivery), and they are much more likely to later develop type 2 diabetes (T2D) and cardiovascular disease than women with normoglycemia during pregnancy. Offspring of GDM pregnancies are at increased risk of neonatal morbidity, including excess fetal adiposity, birth trauma, and neonatal hypoglycemia, and of childhood obesity and impaired glucose tolerance. GDM disproportionately impacts women of color, with nearly 7 of every 100 pregnant women who identify as Hispanic being diagnosed with GDM, and the prevalence of GDM is increasing (1). The rising rate of GDM among Hispanic women is of particular importance as Hispanic women’s estimated lifetime risk of developing T2D is already the highest of all ethnicity/gender categories in the United States, with 52.5% of Hispanic women at risk for developing T2D (2). Identifying modifiable risk factors for GDM in pregnancy that are amenable to intervention is of critical importance to improve maternal and child outcomes and reduce ethnic disparities in pregnancy outcomes and long-term glucometabolic health.

GDM results from changes in glucose metabolism that typically begin in the second half of pregnancy, as insulin resistance increases to accommodate the growing fetus. In women who do not develop GDM, augmentation of β-cell insulin secretion compensates for this increased insulin resistance to regulate glucose levels. However, those with GDM have insufficient pancreatic function to overcome the increased insulin resistance. Thus, identifying modifiable factors that impact insulin sensitivity and β-cell secretion across pregnancy, especially among Hispanic women and other people of color, could be key to reversing the trend of increasing GDM rates.

Lindsay et al address this question in their paper “Rate of Gestational Weight Gain and Glucose-Insulin Metabolism Among Hispanic Pregnant Women With Overweight and Obesity” (3). The researchers hypothesized that the rate of gestational weight gain (GWG) would be related to changes in glucose metabolism in pregnancy in a Hispanic population. To test this hypothesis, they conducted post hoc, cross-sectional analyses of data from 33 nondiabetic Hispanic pregnant women with overweight and obesity after screening to confirm they did not have GDM. Using a standardized liquid mixed-meal 2-hour glucose tolerance test, they examined the association between rate of GWG and area-under-the-curve values for glucose and insulin, insulin sensitivity index, and insulin secretion sensitivity index (ISSI)-2. They found that rate of GWG in the second and third trimesters was inversely associated with β-cell function in their sample. They concluded that in this high-risk population, rate of GWG is a potentially modifiable contributor to insufficient β-cell function, which could contribute to hyperglycemia during pregnancy and to long-term development of T2D. However, rate of GWG accounted for only 13.4% of the variance in ISSI-2 after controlling for covariates (maternal age, parity, and pre-pregnancy body mass index [BMI]), indicating that other important factors also influence β-cell function in late pregnancy.

Lindsay et al’s findings provide a valuable contribution to our understanding of glucose metabolism in Hispanic women. However, their cross-sectional study did not evaluate glucose metabolism at 2 critical time points: pre-pregnancy and early pregnancy, leaving open the question of when during pregnancy GWG has the greatest impact on glucose metabolism. There is growing evidence that weight gain in early pregnancy may be a critical modifiable risk factor. First and early second trimester GWG has been shown to relate most strongly to cord blood hormones that are important for glycemic control and somatic growth (4). Furthermore, we recently reported that in a randomized clinical trial of a pre-pregnancy weight loss intervention, incidence of GDM in early pregnancy (mean 12 weeks) was 73% lower for participants in the intervention group (mean weight loss −0.23 kg/week) than among those who received usual care (mean weight loss −0.02 kg/week) (5). This finding is consistent with those of a recent longitudinal study of 46 predominantly White pregnant women, which found that those who developed GDM had lower insulin sensitivity levels prior to pregnancy than those with normal glucose tolerance in pregnancy, while changes in insulin sensitivity and insulin response during pregnancy were not significantly different between women who developed GDM and those who did not (6). The findings of these studies (5, 6) suggest that the metabolic environment in early pregnancy may be critical for preventing GDM, potentially explaining why pre-pregnancy BMI has been more strongly associated with adverse maternal and infant outcomes than GWG (7). This suggests that interventions may need to start in the pre- (or at least early) pregnancy time periods to have a large impact on GDM risk.

There is growing evidence that GDM is a heterogeneous condition made up of several distinct phenotypes, including insulin-resistant GDM, insulin-deficient GDM, and mixed GDM (characterized by both insulin resistance and insulin deficiency) (8). Focused metabolic studies of understudied population subsets, such as the study by Lindsay et al, help to broaden our knowledge about the association between GWG and GDM risk, and can generate hypotheses about how these associations may vary within high-risk populations. More research is needed to give us the broader picture of the complicated changes in glucose metabolism that occur across pregnancy and across diverse US populations. The GO MOMS study (NCT04860336) is currently enrolling more than 2 000 pregnant women who represent a range of BMIs and racial and ethnic groups into a longitudinal study of glycemia at multiple time points across pregnancy. This study will be able to build on the findings of Lindsay et al and others to provide comprehensive data on how weight gain from early pregnancy through delivery relates to changes in glucose metabolism in the full population of pregnant women, as well as in high-risk subgroups.