| | Clinical assessment of insulin action during late pregnancy in women at risk for gestational diabetes: Association of maternal glycemia with perinatal outcomeReceived 1 September 2009; accepted 16 December 2009. published online 18 January 2010. Abstract ObjectiveWe prospectively evaluated differences in fasting- and oral glucose tolerance test (OGTT)-derived indices of insulin action in Caucasian (Cau) and African-American (AA) pregnant women and compared them with obstetric outcomes. Study designIRB-approved prospective study in 171 pregnant women undergoing a 3-h OGTT. Mathematical modeling was used to evaluate insulin response, insulin activity and glucose tolerance in fasting and postglucose ingestion state. Insulin sensitivity indices derived from fasting (HOMA-IR) and glucose-stimulated values (SIOGTT) were compared. An insulin sensitivity-secretion index (IS-SI) was calculated from the product of the SIOGTT and early-phase insulin secretion. ResultsForty-nine patients had gestational diabetes (GDM), 28 had gestational impaired glucose tolerance (GIGT) and 94 had normal glucose tolerance after an abnormal glucose challenge test (NGT-abnGCT). Insulin sensitivity was lowest in women with GDM. In all groups, pregnant AA women were significantly more insulin resistant than Cau women, based on both HOMA-IR and SIOGTT, but had enhanced insulin secretion compared to their Cau counterparts. The mean IS-SI progressively improved for all women from GDM to GIGT to NGT-abnGCT. Women with NGT-abnGCT had a higher prevalence of large-for-gestational age (LGA) newborns and significantly higher cesarean section rate. DiscussionInsulin measures along with glucose determinations during OGTT testing in pregnant women at risk for diabetes provide valuable information that varies according to race. We observed that pregnant women with a lesser degree of glucose tolerance abnormality during pregnancy who receive no intervention have a higher risk for LGA infants and significantly increased C-section rate (ClinicalTrials.gov number, NCT006874791). 1. Introduction  Pregnancy is a diabetogenic condition characterized by insulin resistance with a compensatory increase in β-cell response and hyperinsulinemia [1]. Normal women compensate for insulin resistance by increasing insulin secretion to maintain normal glucose tolerance [2]. Gestational diabetes mellitus (GDM), defined as carbohydrate intolerance with onset or first recognition during pregnancy, occurs when insulin secretion is insufficient to compensate for the insulin resistance of pregnancy. Women with GDM have a limited ability to increase their insulin secretion [3], [4], [5], [6]. As a result, they have very blunt glucose-stimulated insulin responses compared with the augmented insulin responses of normal pregnant women [1], [7], [8]. Women with GDM are at an increased risk of cesarean delivery, while their infants tend to experience higher rates of macrosomia and shoulder dystocia [9]. Abnormal fetal growth in diabetic pregnancy seems to occur with any elevation in the maternal glucose level [10]. Pregnant women with elevated glucose levels have a higher risk of delivering increased birth weight infants, even when their glucose levels are below those diagnostic of GDM [10], [11]. Pregnant women with impaired glucose tolerance exhibit insulin resistance comparable to women with GDM, and have an increased risk of macrosomic infants and other morbidities [11]. It has been suggested that even minor degrees of increased glucose intolerance during pregnancy in women without GDM are related in a continuous and graded pattern with a significantly increased incidence of macrosomia, cesarean section, pre-eclampsia and an increased need for neonatal intensive care unit admission, as well as greater length of maternal and neonatal hospital stay [12], [13], [14], [15], [16]. Women of ethnic minority populations are at a greater risk for developing GDM [17], [18]. Solomon et al. [17] found that the risk of GDM increased among non-Caucasian women in the Nurses’ Health Study Cohort II. A significant interaction between glucose status and race was identified by Saldana et al. [19], so their analyses were stratified by race looking at African-American (AA) and Caucasian (Cau) mothers separately. Obesity-related risks during pregnancy were also found to vary by race, with obese AA women more likely to have adverse outcomes than obese Cau women [20]. Other researchers report the racially disparate effects of impaired glucose tolerance and glucose levels on birth outcomes, with these conditions leading to higher levels of macrosomic babies among AA women, but not among Cau women [19], [21]. Gravidas with GDM generally demonstrate higher degrees of post-pregnancy insulin resistance, β-cell dysfunction, higher BMI, central obesity, and exaggerated hyperlipidemia, which suggest that GDM is a transient manifestation of longstanding metabolic dysfunction [7], [8]. The oral glucose tolerance test (OGTT) in pregnancy can provide valuable insights into the underlying metabolic phenotype and risk potential of young, otherwise healthy women. Notably, the diagnosis of GDM, based on glucose values from an antepartum OGTT, identifies a population of young women at elevated risk of developing diabetes later in life [22]. Investigators have often used fasting glucose and insulin levels or levels after glucose administration as indicators of insulin sensitivity. Kirwan et al. [4] reported that insulin sensitivity estimated from glucose and insulin levels during an OGTT was significantly improved compared with fasting values in pregnant women with normal glucose tolerance and GDM. This study examined the use of fasting- and OGTT-derived indices to measure insulin sensitivity and secretion in pregnant women in southern Louisiana with varying degrees of glucose tolerance. We further explored the potential use of these measures to define racially diverse risk profiles for these pregnant women and compare them with obstetric and perinatal outcomes. 2. Materials and methods 2.1. Treatment protocol The Institutional Review Board of the Woman’s Hospital Foundation approved the protocol, and all participants gave written informed consent. Pregnant women were asked to participate if they met all of the following criteria: (1) gestational age between 20–30 weeks, (2) at least 18years of age, (3) were either Cau or AA and (4) had an otherwise uncomplicated pregnancy. Women with known pregestational type 1 or type 2 diabetes or women of a different ethnicity were excluded from this study. The women were screened for carbohydrate intolerance by performing a standard 1-h, 50-g oral glucose challenge test (GCT) between the 20th and 28th week of gestation. If the plasma glucose level was greater than 135mg/dL (GCT positive), they then underwent a 3-h, 100-g oral glucose tolerance test (OGTT). Study participants consisted of 176 pregnant women (135 Cau, 41 AA) attending outpatient obstetrics clinics, who had been referred for OGTT testing. All OGTTs were performed in the early morning (7:00–9:00 AM) after a 10- to 12-h overnight fast at the outpatient Woman’s Hospital Pathology Laboratory. On the morning of the test, demographic, anthropometric and clinical data (maternal age, race/ethnicity, family history of diabetes, obstetric history, and prepregnancy BMI) were collected by an interviewer-administered questionnaire. Venous blood samples were drawn for measurement of glucose and insulin at fasting and 30, 60, 120, and 180min after oral ingestion of 100g glucose load. Five women (4 Cau, 1 AA) were unable to complete the test, because of vomiting after glucose intake. Based on the GCT and OGTT, participants were stratified into the following three glucose tolerance groups: 2.2. Laboratory measurements and physiologic indexes Determinations of glucose and insulin levels in the fasting state and during an oral glucose load were performed, as previously described [24]. Insulin secretion and sensitivity were expressed using glucose and insulin, measured in conventional units (milligrams per deciliter and microunits per milliliter, respectively). The homeostasis model of assessment for insulin resistance (HOMA-IR) was calculated from fasting values as described by Matthews et al. [25]. The HOMA-IR generally provides a partial estimate of body insulin sensitivity because it mainly correlates with basal hepatic insulin resistance [26]. This is why we also evaluated dynamic insulin sensitivity using the OGTT insulin sensitivity (ISOGTT) model of Matsuda and DeFronzo, which correlates with total glucose disposal, as extensively validated vs. the glucose clamp in various pathophysiological conditions [26]. In pregnant women, ISOGTT exhibits better correlation with insulin sensitivity, derived using the glucose clamp, than did the HOMA-IR model [3]. Insulin secretion was estimated after oral glucose loading by two methods; (1) the corrected insulin response at glucose peak (CIRgp) [27] and (2) the insulinogenic index divided by HOMA-IR (IGI/HOMA-IR) [28], [29] which have been applied previously in pregnant women with and without GDM [30]. The insulinogenic index (IGI) was calculated as the ratio of change in insulin concentration to change in glucose during the first 30min of the OGTT [31]. The early-phase insulin release calculated by the IGI is used as a surrogate marker of first-phase insulin secretion measured during the glucose clamp. β-Cell compensatory capacity was calculated using the insulin sensitivity-secretion index (IS-SI) defined as the product of SIOGTT and first-phase insulin release index (IGI). The IS-SI expresses the overall ability of the β-cell to increase its release rate relative to insulin resistance in response to a glucose stimulus and reveals the progressive loss of β-cell function in individuals with IGT and GDM that was originally demonstrated using the disposition index calculated from the glucose clamp [29]. An analogous mathematically derived measure; the insulin sensitivity secretion index (ISSI) has been utilized previously in both pregnant diabetic and nondiabetic women [32]. 2.3. Obstetrical and perinatal outcomes Obstetrical outcome information was obtained from a database that tracks labor and delivery data for all deliveries at the Woman’s Hospital. Each woman’s demographic information such as age and race was obtained from the computerized hospitalization record and confirmed with self-reported information. Neonatal data were abstracted by the review of maternal and newborn medical records. We recorded maternal prepregnancy weight, parity, age, race, maternal drug or tobacco use, delivery mode, and obstetric history (previous GDM, delivery mode), and infant’s weight and height, gestational age at delivery, and birth weight for gestational age. According to the gestational age-specific weight distribution of the study population, infants were considered large-for-gestational age (LGA) if their sex-specific birth weight for gestational age exceeded the 90th percentile of the US population fetal growth curves, or small for gestational age (SGA) if their birth weight was below the 10th percentile. 3. Results 3.1. Participants and prevalence of gestational diabetes Of the 176 consented participants, five pregnant women were excluded because of vomiting after the glucose load. Of the remaining 171 patients completing the OGTT, 131 (76.6%) were Cau and 40 (23.4%) were AA (Table 1). Table 1 reveals that 49 (29%) and 28 (16%) women were diagnosed with GDM and GIGT, respectively. Of the remaining 94 participants, 72 were Cau (55%) and 22 were AA (56.4%). There were no significant differences among glucose tolerance groups with respect to age, weeks’ gestation tested for the condition, prepregnancy BMI, or parity. As seen in Table 1, AA women had a higher pregravid BMI (P<0.003) and increased parity (P<0.001) compared with their Cau counterparts. (Table 1). | a Overall differences between three glucose tolerance groups: 1NGT vs. GDM. bOverall main effect of race – AA vs. Cau. cNGT vs. impaired (combined GDM and GIGT). dOverall differences across diagnosis groups for birth weight rates for gestational age. |
3.3. Metabolic measures Metabolic characteristics pertaining to insulin action for the three glycemic tolerance groups are summarized in Table 2. Evaluation of fasting insulin resistance demonstrated the greatest sensitivity in the NGT-abnGCT group wherein GIGT had HOMA-IR values similar to GDM (P<0.001; Table 2). In AA women, both GDM and GIGT were significantly less sensitive than NGT-abnGCT, whereas in Cau women, the sensitivity progressively declined from NGT-abnGCT to GIGT to the GDM group (P<0.02). As shown in Fig. 1A, glucose-stimulated measures revealed a different overall pattern with the highest SIOGTT index in the NGT-abnGCT group, followed in turn by the GIGT and GDM groups, respectively (P<0.01). Consistent with fasting measures, in AA women, both GDM and GIGT SIOGTT values differ from NGT-abnGCT but not each other, whereas in Cau women, both NGT-abnGCT and GIGT subjects were significantly more sensitive than the GDM subjects (P<0.003; Table 2). Pregnant AA women were less sensitive than their Cau counterparts overall as illustrated in Fig. 1A. Evaluation of overall insulin secretion supported the observed glycemic trends across the three study groups. For all pregnant women, CIRgp was highest in NGT-abnGCT, followed by GIGT and then GDM (P < 0.002; Fig. 1B). Fig. 1B illustrates that in pregnant Cau women CIRgp was highest in NGT-abnGCT compared to GIGT and GDM that are not different from each other. In pregnant AA women, CIRgp was highest in GIGT and NGT-abnGCT groups whereas in CIRgp was significantly lower in GDM (P<0.007). Nondiabetic AA women have significantly greater CIRgp compared to Cau whereas there is no racial difference in diabetics which is shown in Fig. 1B. Table 2 shows the differences in β-cell function in pregnant women assessed by IGI/HOMA-IR; insulin secretion was highest in the NGT-abnGCT group compared with GDM (P<0.0001) and GIGT groups (P<0.006). The IGI/HOMA-IR was significantly higher in AA pregnant women compared to the corresponding Cau subjects (P<0.03). The relationship between insulin sensitivity and insulin secretion demonstrated a racial dissimilarity as is evident in Fig. 1C. The insulin sensitivity-secretion index (IS-SI) of NGT-abnGCT AA women was significantly higher than Cau counterparts (P<0.02) whereas mean IS-SI in GDM or GIGT groups showed no racial disparity (Fig. 1C). 4. Discussion In current clinical practice, women with GDM are identified on the basis of hyperglycemia on routine glucose tolerance testing in pregnancy. We report our institutional experience with the 100-g OGTT in which glucose and insulin levels were evaluated in the fasting state and after an oral glucose load in a cohort of pregnant women across the glycemic spectrum. Adding insulin levels to the OGTT provided a clearer picture of the subtle metabolic abnormalities in both insulin sensitivity and β-cell function in this at-risk pregnant population. Other investigators suggested the use of fasting measure, such as HOMA-IR as an alternative but sensitive screening test for GDM, which avoids oral administration of glucose-containing solutions [33]. While the HOMA-IR was correlated with the OGTT-derived insulin sensitivity assessment, we found the HOMA-IR provided a weaker predictive index compared to the glucose-stimulated ISOGTT measure. Furthermore, based on OGTT-derived indices of insulin secretion, it was quite clear that β-cell function progressively deteriorates with worsening of glucose tolerance, consistent with results obtained in other studies [30], [32]. Similar to the ISSI index first reported by Retnakaran et al. [32], we calculated an IS-SI for each pregnant patient as a novel integrated measure of insulin sensitivity relative to insulin secretion. Specifically, we found that compared with NGT-abnGCT, women with GDM and GIGT had lower insulin sensitivity, poorer insulin secretion, and greater glycemia. Poor β-cell compensation for insulin resistance was evident in all pregnant women with GDM. A limitation of this study is that only women who failed the GCT underwent OGTT assessment and therefore all the pregnant women studied had some subtle impairment in insulin action. A further limitation is that the estimates of insulin action have been made on calculations based on the OGTT, and not by a “gold standard” test, euglycemic clamp study. The indices are being used in population studies as the clamp studies are not feasible in large numbers. Racial differences in basal and post-stimulation glucose homeostatic regulation were present over the spectrum of glucose tolerance. Nondiabetic pregnant AA women were more insulin resistant but had higher baseline and glucose-stimulated insulin levels compared to Cau counterparts, findings that are consistent with earlier observations [34]. One limitation to this finding of ethnic differences is the modest size (n=40) of the AA pregnant group compared to the Cau group (n=131) studied. However, these differences are not unique to pregnancy; AA children have higher fasting insulin, greater glucose-stimulated insulin levels and lower insulin sensitivity as assessed by a variety of methods [35]. As was observed by other investigators [18], we found that pregnant AA women were more obese than pregnant Cau women in all glucose tolerance groups that might account for the increased insulin resistance. Even so, with further adjustments for obesity and body fat distribution, nondiabetic African-Americans continued to have lower insulin sensitivity but higher fasting and 2-h insulin levels and acute insulin response to glucose than whites [18]. Although maternal GDM has long been associated with fetal macrosomia, our data support a growing number of studies that report a continuous effect of maternal glucose levels, even in the absence of GDM, on offspring birth weight and pregnancy outcomes [10], [11], [12], [13], [14], [15], [16], [36], [37], [38], [39]. Hillier et al. [36] observed among women with both normal and abnormal GDM screenings, increasing level of maternal glucose was linearly related to macrosomia risk. Undetectable glucose intolerance and a resistance to insulin are supposed mechanisms for this subgroup of patients. Retnakaran et al. [37] demonstrated that women with NGT-abnGCT are clearly distinct from those with NGT-normal GCT on the basis of lower insulin sensitivity and greater glycemia. We found that pregnant women who failed only the GCT showed a higher prevalence of delivering high birthweight infants and were significantly more often delivered by cesarean section than GDM and GIGT mothers. Similarly, Lapolla et al. [38] found that the newborns of false positives screening test (NGT-abnGCT) mothers were heavier than those with NGT or GDM. Others have also reported that increasing maternal glucose levels within the normal nondiabetic range were consistently related to larger offspring birth size (large-for-gestational age, LGA) and increased risk of interventional deliveries [10], [30]. In a prospective study of greater than 6000 women, Yogev et al. [39] found a gradual increase in the rate of macrosomia, LGA and cesarean section in relation to increasing GCT severity categories in women without GDM. Moreover, they demonstrated that increased fetal weight and cesarean section rates in both obese and non-obese women are associated with higher degrees of carbohydrate intolerance [39]. In this study, NGT-abnGCT patients had a complication rate that was worse than patients diagnosed and/or treated as GDM. However, all pregnant women with GDM and GIGT at our institution receive interventional glucose-lowering therapy (diet, oral medication, insulin) to improve obstetrical outcome. Standard obstetrical practice at our institution generally does not precipitate any specific intervention or treatment recommendations for women with normal glucose tolerance results after an abnormal GCT. 5. Conclusions In summary, antepartum OGTT screening identifies carbohydrate intolerance that occurs when insulin secretion is insufficient to compensate for the insulin resistance of pregnancy. The work presented here argues that insulin measures along with glucose determinations during oral glucose tolerance testing provide valuable screening test information which is racially disparate and future work should examine the predictive value of derived insulin action indices for the diagnosis of GDM risk in a large prospective ethnically-diverse cohort. Hyperglycemia during pregnancy, less severe than overt DM, is associated with increased risk of adverse maternal and fetal outcome that is independently related to the degree of metabolic disturbance. Pregnancy glycemia, insulin sensitivity, and insulin secretion all contribute to offspring adiposity and macrosomia, and may be separate targets for intervention to optimize birth outcomes and later offspring health. Acknowledgements We wish to thank the Pathology Laboratory technicians for their unrelenting efforts in patient recruitment. 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a Woman’s Health Research Department, Woman’s Hospital, Baton Rouge, LA, United States b Woman’s Pathology Laboratory, Woman’s Hospital, Baton Rouge, LA, United States  Corresponding author. Address: Woman’s Health Research Department, Woman’s Hospital, 9050 Airline Highway, Baton Rouge, LA 70815, United States. Tel.: +1 225 231 5278; fax: +1 225 924 8225.
PII: S1877-5934(09)00063-0 doi:10.1016/j.ijdm.2009.12.006 © 2009 International Journal of Diabetes Mellitus. Published by Elsevier Inc. All rights reserved. | |
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