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. Author manuscript; available in PMC: 2023 Oct 1.
Published in final edited form as: Obesity (Silver Spring). 2022 Oct;30(10):2014–2022. doi: 10.1002/oby.23533

Effect of Excessive Gestational Weight Gain on Insulin Sensitivity and Insulin Kinetics in Women with Overweight/Obesity

W Todd Cade 1,*, Bettina Mittendorfer 2,*, Bruce W Patterson 2, Debra Haire-Joshu 3, Alison G Cahill 4,6, Richard I Stein 2, Kenneth B Schechtman 5, Rachel A Tinius 1, Katherine Brown 1, Samuel Klein 2
PMCID: PMC9512396  NIHMSID: NIHMS1821888  PMID: 36150208

Abstract

Objective:

Obesity increases the risk for pregnancy complications and maternal hyperglycemia. The Institute of Medicine (IOM) developed guidelines for gestational weight gain (GWG) targets for women with overweight/obesity, but it is unclear whether exceeding these targets has adverse effects on maternal glucose metabolism.

Methods:

Insulin sensitivity (assessed using the Matsuda Insulin Sensitivity Index), β-cell function (assessed as insulin secretion rate in relation to plasma glucose), and plasma insulin clearance rate were evaluated using a frequently-sampled oral glucose tolerance test at 15 weeks and 35 weeks of gestation in 184 socioeconomically-disadvantaged African American women with overweight/obesity.

Results:

Insulin sensitivity decreased, and β-cell function and insulin clearance increased from 15 to 35 weeks of gestation in the entire group. Compared with women who achieved the recommended GWG, excessive GWG was associated with a greater decrease in insulin sensitivity between 15 and 35 weeks. β-cell function and plasma insulin clearance were not affected by excessive GWG.

Conclusion:

These data demonstrate that gaining more weight during pregnancy than recommended by the IOM is associated with functional effects on glucose metabolism.

Keywords: insulin sensitivity, insulin secretion, insulin clearance, beta-cell function, pregnancy

INTRODUCTION

Maternal overweight/obesity is an important public health problem in the United States and other countries because of its high prevalence and causal relationship with adverse medical consequences for both mother and child. About 40 million pregnant women worldwide and about 60% of women who become pregnant in the US have overweight or obesity (1). Women with overweight/obesity at the onset of pregnancy are at increased risk of adverse obstetric outcomes and abnormalities in glycemic control (2, 3). In addition, dysglycemia during pregnancy is associated with increased future risk of prediabetes, diabetes, and cardiovascular diseases, and the risk is proportional to the severity of gestational dysglycemia (4). This issue is of particular concern in socioeconomically disadvantaged (SED) African American women because of their high prevalence of overweight/obesity, which is likely related to a constellation of societal elements, including inequities in housing, income, access to places for physical activity, supermarkets, education and health care, and cultural acceptance of obesity in women (5, 6).

In 2009, the Institute of Medicine (IOM) developed new guidelines for appropriate gestational weight gain (GWG) that recommend less GWG for women with overweight/obesity than for normal-weight women to ensure optimal health of the mother and baby (7). However, it is not known whether exceeding the recommended GWG has adverse effects on the factors that regulate blood glucose (insulin sensitivity, β-cell function, and plasma insulin clearance) and plasma glucose concentration, particularly in the most vulnerable pregnant women with overweight/obesity. The main purpose of the present study was to test the hypothesis that excessive GWG causes adverse effects on maternal glucose metabolism in SED African American women with overweight/obesity at the onset of pregnancy. To this end, we compared fasting plasma glucose concentration, oral glucose tolerance, insulin sensitivity, β-cell function, and basal and postprandial plasma insulin clearance using a frequently sampled oral glucose tolerance test (OGTT) at 15 weeks and 35 weeks of gestation in SED African American women with overweight/obesity at the onset of pregnancy who exceeded the maximum GWG recommended by the IOM (7) or achieved the recommended GWG.

METHODS

Study participants

This study is a secondary analysis of data obtained from a randomized clinical trial conducted at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, Missouri from October 2012 to March 2016 (8) as part of the Lifestyle Interventions For Expectant Moms (LIFE-Moms) consortium. The study was approved by the Washington University Institutional Review Board and registered on the Clinicaltrials.gov website as study number NCT 01768793. A total of 184 women (25 ± 5 years old) participated in this study. Informed consent was provided by all participants. Eligibility criteria included: 1) African American ancestry; 2) SED, defined as being a Medicaid recipient or living in a zip code associated with a median household income below the poverty level; 3) 18 to 45 years old; 4) body mass index (BMI) 25.0 to 45.0 kg/m2 measured at the initial visit during the first trimester; 5) singleton viable gestation at 15 0/7 weeks, established by date of last menstrual period if it was within 5 days of the first trimester ultrasound dating, or by ultrasound itself; 6) weight change between 15 weeks and 35 weeks ≥ 0 kg; and 7) glycosylated hemoglobin < 6.5%. Exclusion criteria included: 1) diabetes or history of diabetes or gestational diabetes; 2) history of bariatric surgery; or 3) use of medications that could affect the study outcomes. A complete list of inclusion and exclusion criteria have been reported previously (8). Among the 184 women who participated in this study, 84 (46%) exceeded the maximum GWG (E-GWG group) and 100 (54%) achieved the recommended GWG (A-GWG group). GWG was determined according to IOM guidelines, taking into account gestational age (7). Study group assignment of participants in the parent study, which randomly assigned participants to one of two groups that either received a standard Parents-As-Teachers (PAT) education curriculum or the PAT education curriculum plus lifestyle counselling (PAT+), was not different between the A-GWG and E-GWG groups. About half of the participants in the A-GWG and E-GWG groups in the present study (46% in the A-GWG and 56% in the E-GWG groups) were assigned to the control (PAT) arm, and half (54% in the A-GWG and 44% in the E-GWG groups) to the “intervention” (PAT+) arm.

Frequently Sampled Oral Glucose Tolerance Test

Participants were admitted to the Washington University Clinical Translational Research Unit in the morning at 15 weeks and 35 weeks of gestation, after they fasted for 10–12 hours overnight. An intravenous catheter was inserted into an antecubital forearm vein for blood sampling. Blood samples were obtained immediately before and at 10, 20, 30, 60, 90, and 120 min after ingesting a 75-g glucose drink to determine plasma glucose, insulin and C-peptide concentrations.

Sample Analyses and Calculations

Plasma glucose concentration was determined using an automated glucose analyzer (Yellow Springs Instruments, Yellow Springs, Ohio). Plasma insulin concentration was determined using a chemiluminescent immunometric method (Immulite; Siemens, Los Angeles, California). Plasma C-peptide concentration was measured using a dual-monoclonal sandwich electrochemiluminescence immunoassay (Roche Diagnostics, IN, USA). The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score, which provides an assessment of insulin sensitivity based on fasting plasma glucose and insulin concentrations, was calculated as the product of plasma glucose (mmol/L) and insulin (mU/L) concentrations divided by 22.5 (9). In addition, insulin sensitivity was assessed using the Matsuda Insulin Sensitivity Index, which provides an assessment of insulin sensitivity during an OGTT (9) that correlates with whole body glucose disposal rate during a hyperinsulinemic-euglycemic clamp procedure in pregnant women (10). The Matsuda Insulin Sensitivity Index was calculated as 10,000 ÷ the square root of the product of fasting plasma glucose (mg/dL), fasting plasma insulin (mU/L) concentration, and the average plasma glucose and insulin concentrations during the OGTT (9). Insulin secretion rate (ISR) was calculated by fitting the plasma C-peptide concentration values during the OGTT to a two-compartment model using a time-variable ISR function in conjunction with population-based C-peptide kinetic parameters (11), which are not affected by pregnancy (12, 13), and volume of distribution values (11). At 35 weeks of pregnancy, the C-peptide volume of distribution was assumed to be 1.4 times the values at 15 weeks, because plasma volume expands by ~40% between 15 weeks and 35 weeks of pregnancy (14, 15). Glucose-stimulated insulin secretion (GSIS) was used to evaluate β-cell function, which was assessed as: i) the ISR in relationship to the plasma glucose concentration during the first 30 min of the OGTT, when plasma glucose was increasing to peak values; ii) the initial (between 0 and 30 min) increase in ISR above basal values (incremental ISR area under the curve, ISR iAUC0–30) in relationship to the increase in plasma glucose concentration above basal values during the same time period (glucose iAUC0–30); and iii) the total ISR (i.e., ISR AUC0–120)-to-total plasma glucose concentration AUC0–120 ratio. Plasma insulin clearance rate (ICR) during basal conditions was calculated by dividing the ISR by the plasma insulin concentration, because ISR equals insulin disposal rate during steady state, basal conditions. The ICR over a given time interval (t1 to t2) after glucose ingestion (i.e., the total volume of plasma that was cleared of insulin between time points) was calculated as the integral of the insulin disposal rate-to-plasma insulin concentration ratio between two time points (16). The insulin disposal rate was calculated from the ISR and the change in the insulin pool size (assuming a distribution volume of 117 mL/kg in women with overweight/obesity (17), D. Polidori personal communication) at 15 weeks, and 1.4 times that value at 35 weeks because of fluid expansion during pregnancy (14, 15).

Statistical Analyses

The statistical significance of differences in age, baseline (15 weeks) body weight and BMI, and baseline metabolic outcomes between the E-GWG and the A-GWG groups was evaluated using the Student’s t test for independent samples. The statistical significance of differences in metabolic outcomes at 35 weeks of gestation between the A-GWG and the E-GWG groups was evaluated using ANCOVA with the 35 week value as the dependent variable, group as the independent variable, and both the 15 week value of the metabolic outcome and BMI at 15 weeks as covariates, because baseline (at 15 weeks) BMI was significantly lower in the E-GWG than in the A-GWG group. We also used a general linear model with parent study treatment (PAT vs PAT+) as an additional factor and found parent study treatment did not affect the results (i.e., there was no statistically significant interaction between parent study treatment and GWG group for the key metabolic outcome measures, including plasma glucose and insulin concentrations, insulin secretion rate, and insulin sensitivity). In addition, we performed regression analysis to determine the contributions of GWG and baseline insulin sensitivity to the change in insulin sensitivity. An α-value of P < 0.05 was considered statistically significant in these analyses. In addition, the relationships between ICR and insulin sensitivity, insulin sensitivity at baseline and the change in insulin sensitivity between 15 weeks and 35 weeks and GWG and changes in metabolic outcome values were evaluated using the Pearson product moment coefficient. Correlations were considered statistically significant at P < 0.05 after correction for multiple comparisons using the Bonferroni correction. Statistical analyses were performed using SPSS® Statistics v26 (IBM).

Primary Study Outcome and Statistical Power

The primary study outcome was insulin sensitivity assessed using the Matsuda Insulin Sensitivity Index. Based on a previous study that found insulin sensitivity decreases by 29 ± 17 % during pregnancy (18) and the number of participants in the A-GWG (n=100) and the E-GWG (n=84) groups in our study, we estimated that we would be able to detect at least an 8.2 percentage point difference in the change in insulin sensitivity (i.e., −29.0% vs −37.2%) between the E-GWG and the A-GWG groups with a two-tailed test, a power of 0.9, and an α-value of 0.05.

RESULTS

About two-thirds of the participants in both the A-GWG and the E-GWG groups had obesity at the beginning of pregnancy (Table 1). At baseline (15 weeks of gestation), age and body weight were not different between the A-GWG and the E-GWG groups (Table 1); however BMI was about 5% lower (P <0.05) in the E-GWG than the A-GWG group (Table 1). By 35 weeks, the E-GWG group had gained more than twice as much weight as the A-GWG group (Table 1).

Table 1.

Metabolic Characteristics during Early and Late Pregnancy of Participants Who Achieved or Exceeded Gestational Weight Gain Recommendations

Outcome variable Achieved GWG Recommendations Exceeded GWG Recommendations ANCOVAc
15 weeksa 35 weeksa Change (95% CI)b 15 weeksa 35 weeksa Change (95% CI)b Differenced P value
N (% with obesity) 100 (66 %) - - 84 (64 %) - -
Age (years) 25 ± 5 - - 26 ± 5 - - N/A N/A
Weight (kg) 88.7 ± 17.4 94.3 ± 15.8 5.6 (5.0 to 6.1) 85.1 ± 12.9 99.2 ± 12.8 14.1 (13.3 to 14.8) N/A N/A
Body mass index (kg/m2) 33.0 ± 5.6 35.1 ± 5.0 2.4 (1.7 to 3.1) 31.4 ± 4.3* 36.5 ± 4.2 5.1 (4.8 to 5.4) N/A N/A
Fasting plasma glucose (mg/dL) 81.7 ± 7.2 78.6 ± 7.4 −3.1 (−4.3 to −1.8) 81.1 ± 5.5 81.0 ± 8.3 −0.1 (−1.8 to 1.6) 2.8 (0.8 to 4.8) 0.005
Fasting plasma insulin (mU/L) 14.1 ± 9.0 16.7 ± 10.3 2.6 (1.3 to 3.9) 11.0 ± 7.9* 18.1 ± 12.9 7.1 (4.6 to 9.6) 4.0 (1.3 to 6.8) 0.004
Fasting plasma C-peptide (ng/mL) 2.0 ± 0.7 2.6 ± 1.0 0.7 (0.5 to 0.8) 1.8 ± 0.7 2.9 ± 1.3 1.1 (0.9 to 1.3) 0.5 (0.2 to 0.7) <0.001
Basal ISR (pmol/min) 173 ± 73 326 ± 139 152 (135 to 170) 157 ± 63 363 ± 161 206 (177 to 235) 62 (31 to 94) <0.001
Basal ICR (L/min) 2.5 ± 1.0 3.7 ± 1.2 0.9 (0.6 to 1.2) 2.7 ± 0.8* 3.8 ± 1.1 1.2 (0.9 to 1.5) - 0.539
Glucose AUC0–120 (mg/dL × min × 10−3) 15.5 ± 1.9 14.9 ± 2.1 −0.6 (−0.9 to −0.2) 15.0 ± 1.8 15.0 ± 2.0 0.0 (−0.4 to 0.4) - 0.086
Insulin AUC0–120 (mU/L × min × 10−3) 14.9 ± 0.9 16.7 ± 1.1 1.8 (0.5 to 3.0) 12.4 ± 6.3* 15.8 ± 1.2 3.4 (1.9 to 4.9) - 0.229
C-pep AUC0–120 (ng/mL × min) 1015 ± 311 1205 ± 410 190 (135 to 244) 954 ± 295 1218 ± 430 264 (185 to 343) - 0.202
ISR AUC0–120 (nmol) 109 ± 37 185 ± 66 76 (67 to 85) 101 ± 32 186 ± 67 85 (72 to 97) - 0.238
ICR AVGOGTT (L/min) 1.5 ± 0.4 2.3 ± 0.6 0.8 (0.7 to 0.9) 1.6 ± 0.4* 2.3 ± 0.6 0.7 (0.6 to 0.8) - 0.076
HOMA-IR scoree 2.9 ± 2.0 3.3 ± 2.3 0.4 (0.1 to 0.7) 2.2 ± 1.7* 3.8 ± 3.4 1.5 (0.9 to 2.2) 1.0 (0.3 to 1.7) 0.006
Matsuda Insulin Sensitivity Indexf 3.3 ± 2.3 2.9 ± 1.7 −0.4 (−0.8 to −0.1) 3.9 ± 2.0* 2.7 ± 1.3 −1.2 (−1.6 to −0.9) −0.5 (−0.8 to −0.1) 0.005
C-peptide AUC0–120/glucose AUC0–120 [(μg/mL)/(mg/dL)] 66 ± 20 81 ± 27 15 (13 to 19) 63 ± 17 81 ± 25 17 (12 to 21) - 0.696
ISR iAUC0–30/glucose iAUC0–30 [(pmol/min)/(mg/dL)] 26 ± 12 39 ± 22 13 (9 to 16) 24 ± 15 39 ± 18 15 (11 to 19) - 0.350
ISR AUC0–120/glucose AUC0–120 [(pmol/min)/(mg/dL)] 7.0 ± 2.3 12.5 ± 4.4 5.4 (4.9 to 6.0) 6.7 ± 1.9 12.3 ± 3.8 5.6 (4.9 to 6.2) - 0.538
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a

Values at 15 weeks and 35 weeks are group averages ± SD.

b

Change values represent the average change in outcome values between 15 weeks and 35 weeks of gestation in each group with the 95% confidence interval.

c

The statistical significance of differences in metabolic outcomes between the A-GWG and the E-GWG groups at 35 weeks of gestation was evaluated using ANCOVA with the 35 week value as the dependent variable, group as the independent variable, and both the 15 week outcome and body mass index values as covariates.

d

Difference represents the adjusted mean difference (i.e., the average change that can be attributed to excess weight gain).

e

The HOMA-IR score was calculated as the product of fasting plasma glucose (mmol/L) and fasting plasma insulin (mU/L) concentrations divided by 22.5.

f

The Matsuda Insulin Sensitivity Index was calculated as 10,000 ÷ the square root of the product of fasting plasma glucose (mg/dL), fasting plasma insulin (mU/L) concentration, and the average plasma glucose and insulin concentrations during the OGTT.

Abbreviations: AUC0–120: area under the curve between 0 min and 120 min during the OGTT; AVG, average; CI, confidence interval; GWG, gestational weight gain; HOMA-IR, homeostasis model assessment of insulin resistance; iAUC0–30: incremental area under the curve between 0 min and 30 min during the OGTT; ICR, insulin clearance rate; ISR, insulin secretion rate; OGTT, oral glucose tolerance test.

*

Significantly different from Achieved GWG value at 15 weeks, p<0.05.

Fasting plasma glucose concentration was not different between the A-GWG and the E-GWG groups at 15 weeks, and was on average 3 mg/dL lower at 35 weeks than 15 weeks in the A-GWG group but did not change in the E-GWG group (Table 1). Fasting plasma insulin concentration at 15 weeks was lower in the E-GWG than the A-GWG group, and increased between 15 weeks and 35 weeks in both the A-GWG and the E-GWG groups, and the increase was significantly greater in the E-GWG than the A-GWG group (Table 1). Fasting plasma C-peptide concentration and basal ISR at 15 weeks were not different between the A-GWG and the E-GWG groups; both fasting plasma C-peptide concentration and basal ISR increased between 15 weeks and 35 weeks in both groups, and the increases were significantly greater in the E-GWG than the A-GWG group (Table 1). Basal ICR at 15 weeks was greater in the E-GWG than the A-GWG group (Table 1). Basal ICR increased from 15 weeks to 35 weeks of gestation in both the A-GWG and the E-GWG groups, and the increase was not different between groups (Table 1).

Plasma glucose concentration AUC0–120 during the OGTT decreased by ~5% between 15 weeks and 35 weeks in the A-GWG group and did not change in the E-GWG group (Table 1 and Figure 1A); however, the difference between the two groups did not reach statistical significance (P = 0.086) (Table 1). Plasma insulin and C-peptide concentration AUC0–120 and ISR AUC0–120 increased between 15 weeks and 35 weeks in both the A-GWG and the E-GWG groups without a significant difference between groups (Table 1 and Figures 1B, 1C, 1D). After glucose ingestion, plasma ICR decreased rapidly from basal values and remained lower during the entire 2-hour OGTT (Table 1 and Figure 1F). Average ICR during the OGTT increased between 15 weeks and 35 weeks in both the A-GWG and the E-GWG groups, without a significant difference between groups (Table 1 and Figure 1F).

Figure 1.

Figure 1.

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Metabolic profile during the oral glucose tolerance test in women who achieved and women who exceeded gestational weight gain recommendations. Panels A-D and F. Plasma glucose (A), insulin (B), and C-peptide (C) concentrations, insulin secretion rate (D), and plasma insulin clearance rate (F) immediately before and for two hours after ingesting 75 grams of glucose. Panel E. Insulin secretion rate in relation to plasma glucose concentration during the first 30 min of the oral glucose tolerance test. Values are mean ± SEM. Abbreviations: A, achieved; E, exceeded; GWG, gestational weight gain; ICR, insulin clearance rate; ISR, insulin secretion rate.

Insulin sensitivity, assessed by the HOMA-IR score and the Matsuda Insulin Sensitivity Index, was better at 15 weeks in the E-GWG than the A-GWG group (Table 1), and the decrease in insulin sensitivity between 15 weeks and 35 weeks was greater in the E-GWG than in the A-GWG group (Table 1). The decrease in insulin sensitivity correlated with the increase in body weight in both groups, and the relationship between the change in insulin sensitivity and the change in body weight was not different between the A-GWG and the E-GWG groups (Figure 2A); GWG accounted for 9.5% of the variation in the change of insulin sensitivity (p < 0.001). In addition, the decrease in the Matsuda Insulin Sensitivity Index between 15 weeks and 35 weeks was inversely related with the index values obtained at 15 weeks, and the decrease in insulin sensitivity at any baseline insulin sensitivity value was greater in the E-GWG than the A-GWG group (Figure 2B). Baseline insulin sensitivity accounted for 48% and 52% of the variation (both p <0.001) in the change of insulin sensitivity in the A-GWG and E-GWG groups, respectively. In multiple linear regression analysis with baseline BMI, baseline Matsuda Insulin Sensitivity Index, and gestational weight gain as predictors, only baseline insulin sensitivity and gestational weight gain, but not BMI, were significant predictors of the change in insulin sensitivity, and together accounted for 54% of the variation (50% and 4%, respectively due to baseline insulin sensitivity and GWG) of the change in insulin sensitivity.

Figure 2.

Figure 2.

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Relationships between the pregnancy-induced change in insulin sensitivity and both gestational weight gain and baseline insulin sensitivity in women who achieved and women who exceeded gestational weight gain recommendations. Panel A. Relationship between the change in insulin sensitivity, assessed using the Matsuda Insulin Sensitivity Index, and the change in body weight between 15 weeks and 35 weeks of gestation. Panel B. Relationship between the change in insulin sensitivity, assessed using the Matsuda Insulin Sensitivity Index, between 15 weeks and 35 weeks of gestation and the corresponding index value at 15 weeks. Symbols represent individual participants’ data. Abbreviations: A, achieved; E, exceeded; GWG, gestational weight gain. The Pearson product moment coefficient (r-value) in Panel A refers to the entire cohort (all 184 participants) because the relationships were not different between the E-GWG and the A-GWG groups. The Pearson product moment coefficients (r-values) in Panel B refer to the E-GWG group (red font) and the A-GWG group (blue font), respectively.

β-cell function was assessed as both the ISR in relation to the plasma glucose concentration during the first 30 min of the OGTT and the ratio of ISR AUC0–120 to glucose concentration AUC0–120 during the entire OGTT. These measures were not different between the A-GWG and the E-GWG groups at 15 weeks and increased from 15 weeks to 35 weeks in both groups, without a significant difference between groups (Table 1 and Figure 1E).

The incidence of gestational diabetes, defined as either a fasting plasma glucose concentration ≥92 mg/dL or a plasma glucose concentration ≥180 mg/dL at one hour during the OGTT or_≥153 mg/dL at 2 hours during the OGTT, was not different between the A-GWG group (n=14 or 14%) and the E-GWG group (n=16 or 19%) and none of the participants with gestational diabetes were treated with medications. Neonatal outcomes were not part of the a priori hypothesis or purpose of this study and were not assessed.

DISCUSSION

Pregnancy is a metabolically challenging condition that requires an adequate supply of nutrients, particularly glucose, to support the growth of the fetus (19, 20) and additional insulin to support placental growth and function (19) and mammary gland remodeling (21), and to enhance the expansion of adipose tissue as an energy reservoir during pregnancy and later during lactation (22). Although placental hormones cause a marked increase in insulin secretion (23, 24, 25, 26), GLUT4 is not expressed at the maternal side of the placenta so the transport of glucose across the placenta occurs independently of insulin and is mediated by GLUT1 and facilitative diffusion across the maternal-fetal glucose gradient (20, 27). Accordingly, increased maternal insulin secretion does not increase the delivery of insulin to the fetus, but could have adverse effects on the glucose supply to the fetus by decreasing maternal plasma glucose concentration. In addition, increased fluid retention during pregnancy causes nearly a 50% increase in maternal plasma volume between the beginning and end of a full-term pregnancy (14, 15) and dilutes the concentration of glucose in the maternal circulation. Fortunately, placental hormones also cause insulin resistance with respect to glucose metabolism (24, 28, 29), which prevents maternal hypoglycemia and ensures an adequate maternal-fetal glucose gradient. Insulin-resistance is therefore an essential adaptation to pregnancy. However, excessive GWG could alter the metabolic response to pregnancy and cause hyperglycemia, which can cause adverse outcomes in mother and baby (2, 4, 30). Although the IOM developed guidelines for GWG that recommend women with overweight/obesity gain less weight (<11.3 kg and <9.1 kg, respectively) than normal-weight women (<16.0 kg) during pregnancy to ensure optimal health of the mother and baby (7), it was not known whether exceeding the recommended GWG had adverse effects on the factors that regulate glycemia (insulin sensitivity, β-cell function, and plasma insulin clearance) or plasma glucose concentration.

In the present study, we evaluated insulin sensitivity, β-cell function, and plasma insulin clearance at 15 weeks of gestation, when pregnancy has minimal effects on glucose metabolism, and at 35 weeks, when pregnancy-induced alterations in glucose metabolism are most pronounced (31, 32), in women who are at increased risk for hyperglycemia. Insulin sensitivity decreased by ~30% between 15 weeks and 35 weeks of gestation among all women, and the decline in insulin sensitivity was greater in women with excessive GWG than in those who did not exceed the maximum weight gain targets proposed by the IOM. β-cell function, assessed as the ISR in relation to plasma glucose concentration, nearly doubled, and the ICR increased by about 50% between 15 weeks and 35 weeks of gestation, without differences between the A-GWG and E-GWG groups. The rate of plasma insulin clearance increased between 15 weeks and 35 weeks and was unaffected by differences in GWG. Together, these alterations in major glucoregulatory factors caused a ~20% increase in plasma insulin and a small (3 mg/dL) decrease in fasting plasma glucose concentration without a change in glucose tolerance at 35 weeks of pregnancy in the A-GWG group and an even greater increase in plasma insulin with no change in plasma glucose concentration in the E-GWG group. These data demonstrate that pregnancy causes profound changes in both insulin sensitivity and insulin kinetics, but only minimally alters fasting and postprandial plasma glucose concentrations. Moreover, even though the decline in insulin sensitivity was greater in the E-GWG than the A-GWG group, this did not result in an increase in fasting or postprandial plasma glucose concentrations in the E-GWG group; however, it prevented the decrease in plasma glucose observed in those who achieved the IOM guidelines for GWG.

A decrease in insulin sensitivity with respect to glucose metabolism is a normal adaptation to pregnancy (24, 28, 29). Our data demonstrate that the magnitude of the change in insulin sensitivity during pregnancy in women with overweight/obesity is influenced by both the change in body weight and the severity of insulin resistance at baseline. We found a direct linear relationship between the decrease in the Matsuda Insulin Sensitivity Index and the amount of weight gained among all participants. We also found a direct linear relationship between the decrease in the Matsuda Insulin Sensitivity Index from 15 to 35 weeks gestation and the value at 15 weeks in both the E-GWG and the A-GWG groups. Together, GWG and baseline insulin sensitivity accounted for 54% of the variation in the change in insulin sensitivity, and baseline insulin sensitivity was the predominant factor in this association. Therefore, there was a much greater decline in insulin sensitivity in women who were the most insulin sensitive than those who were the most insulin resistant at baseline. Nonetheless, at any given Matsuda Insulin Sensitivity Index value at baseline, the decrease in insulin sensitivity from 15 weeks to 35 weeks gestation was generally greater in the E-GWG than the A-GWG group. These findings suggest that weight gain during pregnancy is an important driver of pregnancy-induced insulin resistance, but the decline in insulin sensitivity is attenuated in women who are already insulin resistant at baseline.

β-cell function, assessed as the ISR in relationship to plasma glucose concentration during the OGTT, markedly increased between 15 weeks and 35 weeks gestation, but the increase was not different between the A-GWG and E-GWG groups. Although excess adiposity increases β-cell function in non-gravid women (33, 34), our findings suggest factors other than body weight gain are primarily responsible for the pregnancy-induced increase in β-cell function. Presumably placental hormones, which are known to increase both β-cell mass and β-cell glucose sensitivity (25, 26), were responsible for the increase in β-cell function in our participants who were already overweight or obese at the beginning of pregnancy.

Plasma insulin clearance was much greater at 35 weeks than at 15 weeks of gestation, but the increase in insulin clearance was not different between the A-GWG and E-GWG groups. Although the pregnancy-induced increase in plasma ICR has been observed previously (13, 24, 35), the underlying mechanism(s) for this metabolic adaptation is not clear. It is likely that placental insulin uptake is an important contributor to the increase in insulin clearance associated with pregnancy. The placenta is rich in insulin receptors (20, 27) and binds and degrades insulin (24, 36). Assuming the placenta takes up about 100 pmol of insulin per min (37), we estimate that ~30% of the basal insulin secretion rate was taken up by the placenta at 35 weeks of gestation.

The differences in the changes in the HOMA-IR score and the Matsuda Insulin Sensitivity Index between our A-GWG and the E-GWG groups were similar in magnitude to the differences in insulin sensitivity observed in people with obesity that are associated with important physiological effects, including differences in the HOMA-IR score between people with impaired glucose tolerance and people with normoglycemia (38), and the changes in the HOMA-IR score induced by a 6% weight gain (39) or a 5% weight loss (40). However, the greater decline in insulin sensitivity in the E-GWG than in the A-GWG group did not have adverse effects on fasting plasma glucose concentration or oral glucose tolerance, which did not change during pregnancy in the E-GWG group. Therefore, in contrast with the adverse metabolic effects associated with differences in insulin sensitivity in people with obesity who are not pregnant, it seems unlikely that the greater deterioration in insulin sensitivity in the E-GWG than the A-GWG group was of clinical importance.

Our study has some limitations. First, we used the HOMA-IR score and the Matsuda Insulin Sensitivity Index to evaluate insulin sensitivity. Although these measures of insulin sensitivity do not provide a direct assessment of insulin action, they correlate with measures of insulin sensitivity obtained using the hyperinsulinemic-euglycemic clamp procedure in both pregnant and non-gravid women (9, 10). Moreover, the decrease in insulin sensitivity we observed between 15 weeks and 35 weeks of gestation is consistent with the decrease in insulin sensitivity reported in studies that used the hyperinsulinemic-euglycemic clamp procedure (10, 18, 41). Second, we calculated insulin kinetics using an estimated plasma volume, not a measured plasma volume. The correction factor we used was based on previous studies in pregnant women (14, 15), and the increases in both ISR and ICR between 15 weeks and 35 weeks of gestation in our study are consistent with those reported previously in both preclinical models and in people (12, 24, 25, 26, 31), including the increase in ICR observed previously using a hyperinsulinemic-euglycemic clamp procedure that involves an estimate of ICR that is independent of plasma volume (31). Third, our study is unable to determine whether greater increases in body weight than that observed in our E-GWG group would have had greater effects on our metabolic outcomes.

SUMMARY AND CONCLUSION

Excessive GWG in SED, African American women with overweight/obesity is associated with a greater decline in insulin sensitivity than in women who gain weight within the IOM guidelines, whereas oral glucose tolerance, β-cell function, and insulin clearance are not different between women who gain excess amounts of weight and those who gain the recommended amounts. In contrast with the adverse cardiometabolic implications of insulin resistance in people who are not pregnant, insulin resistance in pregnant women represents a beneficial adaptive response that helps prevent maternal hypoglycemia. Although women with excessive GWG have a greater decline in insulin sensitivity than women who gain weight within the IOM guidelines, this does not have adverse effects on fasting or postprandial glycemia.

STUDY IMPORTANCE QUESTIONS.

What is already known about this subject?

  • Obesity increases the risk of pregnancy complications and maternal hyperglycemia.

  • Although the Institute of Medicine (IOM) proposed guidelines for appropriate gestational weight gain (GWG) during pregnancy, it is not known whether excessive GWG has adverse effects on oral glucose tolerance or the factors that regulate blood glucose (insulin sensitivity, β-cell function, and plasma insulin clearance) in women with overweight/obesity.

What are the new findings in this manuscript?

  • Compared with women who achieved the recommended guidelines for GWG, excessive GWG was associated with a greater decrease in insulin sensitivity and higher fasting plasma glucose and insulin concentrations in women with overweight/obesity, without a difference in β-cell function or plasma insulin clearance rate between groups.

How might your results change the direction of research or the focus of clinical practice?

  • These data provide functional metabolic evidence in pregnant women with overweight/obesity that support the IOM’s guidelines for GWG.

ACKNOWLEDGMENTS

The authors thank the staff of the Center for Human Nutrition at Washington University School of Medicine and the Clinical and Translational Research Unit for assistance in conducting the metabolic studies and their technical assistance in processing the study samples, and the study participants for their participation.

Funding:

This study was supported by National Institutes of Health (NIH) grants U01 DK094416, P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK092950 (Washington University Center for Diabetes Translation Research), P30 DK20579 (Washington University Diabetes Research Center) and UL1 TR002345 (Washington University Clinical and Translational Science Award) and was part of the Lifestyle Interventions For Expectant Moms (LIFE-Moms) consortium, which is supported by NIH grants U01 DK094418, U01 DK094463, U01 DK094416, U01 DK094466, U01 HL114344, U01 HL114377, U01 HD072834, the National Center for Complementary and Integrative Health, the NIH Office of Research in Women’s Health, the Office of Behavioral and Social Science Research, the Indian Health Service, and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.

Footnotes

Disclosure: The authors declared no conflict of interest.

Clinical Trials Registration: ClinicalTrials.gov: NCT01768793

REFERENCES

  • 1.Chen C, Xu X, Yan Y. Estimated global overweight and obesity burden in pregnant women based on panel data model. PLoS One 2018;13: e0202183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Paredes C, Hsu RC, Tong A, Johnson JR. Obesity and Pregnancy. Neoreviews 2021;22: e78–e87. [DOI] [PubMed] [Google Scholar]
  • 3.Saldana TM, Siega-Riz AM, Adair LS, Suchindran C. The relationship between pregnancy weight gain and glucose tolerance status among black and white women in central North Carolina. Am J Obstet Gynecol 2006;195: 1629–1635. [DOI] [PubMed] [Google Scholar]
  • 4.Retnakaran R, Shah BR. Glucose screening in pregnancy and future risk of cardiovascular disease in women: a retrospective, population-based cohort study. Lancet Diabetes Endocrinol 2019;7: 378–384. [DOI] [PubMed] [Google Scholar]
  • 5.Fryar C, Carroll M, Fryar C, Ogden C. Prevalence of Overweight, Obesity, and Extreme Obesity Among Adults Aged 20 and Over: United States, 1960–1962 Through 2015–2016. National Center For Health Statistics 2018. [Google Scholar]
  • 6.Barrington DS, James SA, Williams DR. Socioeconomic correlates of obesity in African-American and Caribbean-Black men and women. J Racial Ethn Health Disparities 2021;8: 422–432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Institute of Medicine. In: Rasmussen KM, Yaktine AL (eds). Weight Gain During Pregnancy: Reexamining the Guidelines: Washington (DC), 2009. [PubMed] [Google Scholar]
  • 8.Cahill AG, Haire-Joshu D, Cade WT, Stein RI, Woolfolk CL, Moley K, et al. Weight Control Program and Gestational Weight Gain in Disadvantaged Women with Overweight or Obesity: A Randomized Clinical Trial. Obesity 2018;26: 485–491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Hannon TS, Kahn SE, Utzschneider KM, Buchanan TA, Nadeau KJ, Zeitler PS, et al. Review of methods for measuring beta-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium. Diabetes Obes Metab 2018;20: 14–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Kirwan JP, Huston-Presley L, Kalhan SC, Catalano PM. Clinically useful estimates of insulin sensitivity during pregnancy: validation studies in women with normal glucose tolerance and gestational diabetes mellitus. Diabetes Care 2001;24: 1602–1607. [DOI] [PubMed] [Google Scholar]
  • 11.Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes 1992;41: 368–377. [DOI] [PubMed] [Google Scholar]
  • 12.Homko C, Sivan E, Chen X, Reece EA, Boden G. Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus. J Clin Endocrinol Metab 2001;86: 568–573. [DOI] [PubMed] [Google Scholar]
  • 13.Katz AI, Lindheimer MD, Mako ME, Rubenstein AH. Peripheral metabolism of insulin, proinsulin, and C-peptide in the pregnant rat. J Clin Invest 1975;56: 1608–1614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Aguree S, Gernand AD. Plasma volume expansion across healthy pregnancy: a systematic review and meta-analysis of longitudinal studies. BMC Pregnancy Childbirth 2019;19: 508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Verkeste CM, Slangen BF, Dubelaar ML, van Kreel BK, Peeters LL. Mechanism of volume adaptation in the awake early pregnant rat. Am J Physiol 1998;274: H1662–1666. [DOI] [PubMed] [Google Scholar]
  • 16.Gastaldelli A, Abdul Ghani M, DeFronzo RA. Adaptation of insulin clearance to metabolic demand is a key determinant of glucose tolerance. Diabetes 2021;70: 377–385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Utzschneider KM, Kahn SE, Polidori DC. Hepatic Insulin Extraction in NAFLD Is Related to Insulin Resistance Rather Than Liver Fat Content. J Clin Endocrinol Metab 2019;104: 1855–1865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Alvarado FL, O’Tierney-Ginn P, Catalano P. Contribution of Gestational Weight Gain on Maternal Glucose Metabolism in Women with GDM and Normal Glucose Tolerance. J Endocr Soc 2021;5: bvaa195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Dumolt JH, Powell TL, Jansson T. Placental function and the development of fetal overgrowth and fetal growth restriction. Obstet Gynecol Clin North Am 2021;48: 247–266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Brett KE, Ferraro ZM, Yockell-Lelievre J, Gruslin A, Adamo KB. Maternal-fetal nutrient transport in pregnancy pathologies: the role of the placenta. Int J Mol Sci 2014;15: 16153–16185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Neville MC, Webb P, Ramanathan P, Mannino MP, Pecorini C, Monks J, et al. The insulin receptor plays an important role in secretory differentiation in the mammary gland. Am J Physiol Endocrinol Metab 2013;305: E1103–1114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Herrera E. Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus. Eur J Clin Nutr 2000;54 Suppl 1: S47–51. [DOI] [PubMed] [Google Scholar]
  • 23.Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, et al. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 2010;53: 2167–2176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Freinkel N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes 1980;29: 1023–1035. [DOI] [PubMed] [Google Scholar]
  • 25.Salazar-Petres ER, Sferruzzi-Perri AN. Pregnancy-induced changes in beta-cell function: what are the key players? J Physiol 202;600:1089–1117. [DOI] [PubMed] [Google Scholar]
  • 26.Rieck S, Kaestner KH. Expansion of beta-cell mass in response to pregnancy. Trends Endocrinol Metab 2010;21: 151–158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Illsley NP, Baumann MU. Human placental glucose transport in fetoplacental growth and metabolism. Biochim Biophys Acta Mol Basis Dis 2020;1866: 165359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Nielsen JH, Haase TN, Jaksch C, Nalla A, Sostrup B, Nalla AA, et al. Impact of fetal and neonatal environment on beta cell function and development of diabetes. Acta Obstet Gynecol Scand 2014;93: 1109–1122. [DOI] [PubMed] [Google Scholar]
  • 29.Hill DJ. Placental control of metabolic adaptations in the mother for an optimal pregnancy outcome. What goes wrong in gestational diabetes? Placenta 2018;69: 162–168. [DOI] [PubMed] [Google Scholar]
  • 30.HapoStudyCooperativeResearchGroup, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358: 1991–2002. [DOI] [PubMed] [Google Scholar]
  • 31.Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol 1999;180: 903–916. [DOI] [PubMed] [Google Scholar]
  • 32.Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol 2007;50: 938–948. [DOI] [PubMed] [Google Scholar]
  • 33.Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. Beta-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care 2013;36: 111–117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Mittendorfer B, Patterson BW, Smith GI, Yoshino M, Klein S. Beta-cell function and plasma insulin clearance in people with obesity and different glycemic status. J Clin Invest 2022; 132:e154068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Catalano PM, Drago NM, Amini SB. Longitudinal changes in pancreatic beta-cell function and metabolic clearance rate of insulin in pregnant women with normal and abnormal glucose tolerance. Diabetes Care 1998;21: 403–408. [DOI] [PubMed] [Google Scholar]
  • 36.Buse MG, Roberts WJ, Buse J. The role of the human placenta in the transfer and metabolism of insulin. J Clin Invest 1962;41: 29–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Challier JC, Hauguel S, Desmaizieres V. Effect of insulin on glucose uptake and metabolism in the human placenta. J Clin Endocrinol Metab 1986;62: 803–807. [DOI] [PubMed] [Google Scholar]
  • 38.Gastaldelli A, Gaggini M, DeFronzo RA. Role of adipose tissue insulin resistance in the natural history of type 2 diabetes: results from the San Antonio Metabolism Study. Diabetes 2017;66: 815–822. [DOI] [PubMed] [Google Scholar]
  • 39.Fabbrini E, Yoshino J, Yoshino M, Magkos F, Tiemann Luecking C, Samovski D, et al. Metabolically normal obese people are protected from adverse effects following weight gain. J Clin Invest 2015;125: 787–795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Magkos F, Fraterrigo G, Yoshino J, Luecking C, Kirbach K, Kelly SC, et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab 2016;23: 591–601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Sivan E, Chen X, Homko CJ, Reece EA, Boden G. Longitudinal study of carbohydrate metabolism in healthy obese pregnant women. Diabetes Care 1997;20: 1470–1475. [DOI] [PubMed] [Google Scholar]

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