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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2512
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3449-3453
Copyright © 2005 by The Endocrine Society

Exogenous Corticosteroids and in Utero Oxygenation Modulate Indices of Fetal Insulin Secretion

Johan Verhaeghe, Rita van Bree, Erik van Herck and Willy Coopmans

Department of Obstetrics and Gynecology (J.V., R.v.B.), and Laboratorium voor Experimentele Geneeskunde en Endocrinologie (E.v.H., W.C.), Katholieke Universiteit Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Johan Verhaeghe, M.D., Department of Obstetrics and Gynecology, U.Z. Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail: johan.verhaeghe{at}uz.kuleuven.ac.be.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Low birth weight has long-term effects on glucose-insulin homeostasis. Factors that could mediate intra-uterine "programing" of glucose homeostasis include endogenous and exogenous glucocorticoids, adipose tissue-secreted factors such as adiponectin, and in utero hypoxia. Here, we studied 123 fetuses with gestational age (GA) between 25 and 37 wk and birth weight SD score (BW SDS) between –2.79 and 2.42. We measured proinsulin, C-peptide, insulin, and adiponectin in umbilical vein (UV) plasma and calculated the proinsulin to insulin ratio as a measure of ß-cell secretory function. These indices were related to GA, BW SDS, time since the last maternal betamethasone administration, and blood gas data.

Insulin and C-peptide were correlated with BW SDS but not GA, whereas the proinsulin to insulin ratio was inversely correlated with BW SDS. The proinsulin to insulin ratio was raised (P = 0.002) in fetuses with UV PO2 less than or equal to 21.3 mm Hg (i.e. the 50th percentile) compared with those with PO2 more than 21.3 mm Hg, inferring that in utero hypoxia engenders ß-cell secretory dysfunction. Proinsulin, insulin, and C-peptide were markedly but transiently (<24 h) elevated after maternal betamethasone administration, returning thereafter to concentrations measured in noncorticosteroid-treated fetuses. However, there was considerable variability within the less than 24-h betamethasone group: the indices of insulin secretion were related to UV PO2, suggesting that hypoxia attenuates the responsiveness of fetal ß-cells to corticosteroids. Adiponectin was not related to any of the insulin indices.

In conclusion, we have identified two environmental signals that modulate fetal insulin output: maternal corticosteroids produce a transient surge in fetal insulin synthesis and secretion, whereas in utero hypoxia disturbs the insulin secretory process.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
BIRTH WEIGHT (BW) is an independent correlate of postnatal glucose and insulin metabolism and the risk of type 2 diabetes. Plenty of epidemiological studies point to a negative correlation between BW and the incidence of diabetes later in life, although positive and U-shaped relationships have been reported as well (1). Low BW is the result of preterm birth, inadequate in utero growth, or both. Insulin sensitivity was found to be decreased in prepubertal children either born prematurely (2) or born at term but small for gestational age (SGA) (3), as shown by frequently sampled intravenous glucose tolerance tests and euglycemic hyperinsulinemic clamps, respectively. However, the effect of BW on insulin secretion is controversial (1). A recent study, using hyperglycemic clamps, showed no difference in the first- and second-phase insulin response between prepubertal children born at term but SGA and those born appropriate for gestational age (AGA) (4). However, the disposition index during a hyperinsulinemic clamp (i.e. a measure of insulin secretion relative to insulin sensitivity) was reduced by 30% in 19-year-old males born SGA at term (5). A drawback of the foregoing studies is the impact of postnatal events on insulin sensitivity, which appears to be stronger than the impact of BW itself (3, 6).

The mechanism underlying the relationship between BW and insulin homeostasis is uncertain. Activation of cortisol synthesis in nutritionally deprived fetuses might play a role (7), although there is insufficient evidence at this time of intra-uterine "programing" of the hypothalamo-pituitary-adrenal axis (8). It is now standard practice to administer a course of corticosteroids in pregnancies at risk for preterm birth to enhance fetal lung maturation, but this may affect insulin homeostasis; indeed, corticosteroid administration to preterm neonates was found to induce insulin resistance (IR) (9). Hormonal factors produced by adipose tissue (adipokines) such as adiponectin may also be involved: both preterm and SGA fetuses have less fat mass and lower circulating adiponectin compared with term and AGA fetuses, respectively (10, 11); in addition, postnatal catch-up growth is associated with reduced adiponectin concentrations (10). Persistently low adiponectin levels in children born SGA may predict visceral fat accumulation, IR, and ß-cell dysfunction (12, 13). Finally, hypoxemia may also play a role: uterine artery ligation in gravid rats, a validated experimental method to produce in utero hypoxia, resulted in a decrease in the number of granulated ß-cells and lower insulin concentrations in their fetuses or pups (14, 15).

Herein, we evaluated insulin homeostasis in preterm or/and SGA fetuses at the time of birth, to discern the effects of gestational age (GA) and in utero growth. To assess ß-cell function, we measured intact proinsulin, C-peptide, and insulin, and we calculated the proinsulin to insulin molar ratio; this ratio is frequently used as a marker of inappropriate intracellular processing of prohormone to insulin and, by extension, ß-cell secretory dysfunction (16). The C-peptide to insulin molar ratio was calculated as an index of insulin clearance. IR was assessed by the homeostasis model assessment (HOMA). From a mechanistic viewpoint, we studied the relationship between the above parameters and maternal corticosteroid treatment, adiponectin concentrations, and in utero oxygenation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study protocol was approved by the Ethical Committee of the Katholieke Universiteit Leuven, Faculty of Medicine. We collected 123 clean umbilical vein (UV) blood samples at birth from fetuses less than 38 wk GA. All fetuses were singletons; specific exclusion criteria were known anatomic or chromosomal abnormalities, known fetal infection, and maternal pregestational or gestational diabetes. The reason for delivery less than 38 wk was as follows: maternal hypertensive disease in 46 cases (preeclampsia in 28); in utero growth retardation (IUGR) without hypertensive disease but related to smoking or uteroplacental insufficiency (n = 12); antepartum hemorrhage (n = 14); preterm labor or preterm rupture of the membranes (n = 48); or poor obstetric history (n = 3). Delivery was by cesarean section in 77 fetuses. Additional data are shown in Table 1Go. BW SD score (SDS) was calculated as (BW – mean BW for any given GA)/BW SD for that GA, with mean and SD values obtained from recently updated Flemish BW charts derived from more than 429,000 births; in addition, SGA (≤10th percentile), AGA (11th to 90th percentiles), and large for gestational age (>90th percentile) fetuses were stratified from these charts (17). Antenatal corticosteroid administration consisted of two im injections of 12 mg betamethasone, 12 or 24 h apart; we recorded the time (in hours) since the last injection. The umbilical blood gases (pH, PO2, O2 saturation, PCO2, HCO3–, and base excess/deficit) in the umbilical artery and vein were measured in heparin-containing syringes within minutes after delivery on a ABL 700 Analyzer (Radiometer Medical A/S, Brønshøj, Denmark); for the study, we recorded only the values that came without a question mark on the outprint. Placental pathology, specifically addressing the absence/presence of placental tissue infarcts (17), was available in 96 cases.


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  		TABLE 1. Characteristics of fetuses at birth (n = 123)

 
Assays

All blood samples were centrifuged as rapidly as possible, and the plasma was aliquoted and frozen at –80 C; more than one freeze-and-thaw cycle was thus avoided. Glucose was measured by the glucose-oxidase method with a YSI 2300 Stat Plus Glucometer (Yellow Springs Instruments, Yellow Springs, OH); within-assay coefficient of variation (CV) is 1.2%. Total proinsulin was measured by solid-phase two-site enzyme immunoassay (Mercodia AB, Uppsala, Sweden) using a mouse monoclonal antibody. The cross-reactivity with insulin is less than 0.03% and with C-peptide less than 0.006%. The detection limit is less than or equal to 0.5 pmol/liter (0.47 pg/ml); within-assay CV is less than 3.3%, and between-assay CV is less than 5.3%. The assay was calibrated against the International Reference Reagent for human proinsulin (IRR 84/611). C-peptide was measured by RIA with purified human C-peptide as standard and a guinea pig antiserum (Linco Research, St. Charles, MO); this assay shows less than 4.0% cross-reactivity with proinsulin. The detection limit is 0.1 ng/ml (0.033 nmol/liter); within-assay CV is less than 6.5%, and between-assay CV is less than 9.4%. Insulin was measured by an in-house RIA, with recombinant human insulin as standard and a rabbit antiserum (18); the detection limit is 2.5 µU/ml (15 pmol/liter), and between-assay CV is 3.2–5.9%. Adiponectin was measured by RIA with recombinant human adiponectin as standard and a rabbit antiserum (Linco Research); the detection limit is 1 ng/ml (33.3 pmol/liter), within-assay CV is less than 6.3%, and between-assay CV is less than 9.3%.

Data analysis was performed using the NCSS (Kaysville, UT) software, version 2004. The HOMA-IR was calculated as [insulin(µU/ml) x glucose(mg/dl)]/22.5. Analyses included the following: two-sample tests for comparisons between two groups after checking the data for normality and variance, using the equal-variance t test, the Aspin-Welch test, the Wilcoxon rank-sum test, or the Kolmogorov-Smirnov test; one-way ANOVA for overall comparisons between more than two groups, followed by Tukey-Kramer’s multiple-comparison test to compare individual groups; and pairwise Spearman rank correlations.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 2Go shows the correlations between GA, BW SDS, and time since betamethasone and the metabolic indices in the UV. Adiponectin concentrations were strongly correlated with GA, increasing from 3.9 ± 4.4 (SD) ng/ml at 25 wk (n = 4) to 56.0 ± 35.7 ng/ml at 37 wk (n = 7); but none of the other parameters was related to GA. BW SDS was correlated with glucose, insulin, C-peptide, HOMA-IR and adiponectin concentrations; the proinsulin/insulin molar ratio was negatively related to BW SDS, whereas the C-peptide to insulin molar ratio was not related to BW SDS. The time since the last betamethasone administration was negatively correlated with proinsulin, C-peptide, insulin, and HOMA-IR. We found no differences between female and male fetuses in any of the metabolic indices (data not shown).


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  		TABLE 2. Spearman rank correlations between GA, BW SDS, and time since last betamethasone administration and metabolic parameters in UV plasma

 
Insulin and C-peptide were significantly correlated with glucose (r = 0.32 and r = 0.27, respectively), as expected, but also with blood gas values (n = 92–102): insulin was correlated with UV pH (r = 0.40), PO2 (r = 0.20), O2 saturation (r = 0.23), and HCO3– (r = 0.22) and negatively correlated with PCO2 (r = –0.40); and C-peptide was significantly correlated with pH (r = 0.40) and HCO3– (r = 0.26) and negatively with PCO2 (r = –0.38). In contrast, the proinsulin to insulin ratio was negatively correlated with UV glucose (r = –0.25), UV pH (r = –0.33), PO2 (r = –0.26), O2 saturation (r = –0.32), and HCO3– (r = –0.26) but positively correlated with PCO2 (r = 0.30). These correlations were present to a less significant extent with blood gas values in the umbilical artery (data not shown). The UV PO2 was lower in hypertensive than in nonhypertensive pregnancies [17.7 ± 7.5 (SD) vs. 24.8 ± 8.0 mm Hg; P < 0.0001] and in fetuses delivered by cesarean section than in those born vaginally (P = 0.044).

Table 3Go demonstrates that SGA fetuses had lower C-peptide and insulin concentrations and a higher proinsulin to insulin ratio than AGA fetuses, suggesting ß-cell secretory dysfunction in SGA fetuses. Comparable results were obtained when two groups of fetuses were compared on the basis of their UV PO2 value. Fetuses whose placentas showed infarcts (n = 36) also had slightly higher proinsulin to insulin ratios than those without placental infarcts (n = 60) [0.30 ± 0.13 (SD) vs. 0.25 ± 0.13; P = 0.089].


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  		TABLE 3. Proinsulin, C-peptide, and insulin concentrations and proinsulin/insulin molar ratio in SGA vs. AGA fetuses and in two groups according to the UV PO2 value (≤50th percentile vs. >50th percentile)

 
Figure 1Go shows the proinsulin and C-peptide concentrations and HOMA-IR in four betamethasone groups according to the time since the last injection (<24, 25–48, 49–168, and >168 h), as well as in the group that had not received betamethasone. All parameters were significantly elevated in the first 24 h since the last administration but with considerable individual variability. In this subgroup (n = 23), we found no relationship between proinsulin, C-peptide, and HOMA-IR concentrations and GA, BW SDS, or gender (data not shown), but they were correlated, again, with blood gas values in the UV (pH, pO2, O2 saturation, HCO3–, and base excess/deficit). For example, UV PO2 was correlated with proinsulin (r = 0.47; P = 0.038), C-peptide (r = 0.66; P = 0.002), and HOMA-IR (r = 0.64; P = 0.002); in contrast, UV PO2 was negatively correlated with the proinsulin to insulin ratio (r = –0.45; P = 0.045). When comparing fetuses with UV PO2 less than or equal to 21.3 mm Hg or more than 21.3 mm Hg (i.e. the 50th percentile in the entire group; see Table 3Go) within this particular subgroup, we found that fetuses with PO2 less than or equal to 21.3 mm Hg vs. those with PO2 more than 21.3 mm Hg had lower insulin [26.2 ± 23.0 (SD) vs. 70.5 ± 63.0 µU/ml; P = 0.049] and C-peptide (2.13 ± 1.41 vs. 6.07 ± 4.20 ng/ml; P = 0.019) concentrations and showed a trend for a higher proinsulin to insulin ratio (0.32 ± 0.20 vs. 0.18 ± 0.09; P = 0.092). These results suggest that the UV PO2 modulated the fetal insulin secretory response to maternal betamethasone treatment.



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  		FIG. 1. Proinsulin (top), C-peptide (middle), and HOMA-IR (bottom) in UV plasma according to the time since the last betamethasone administration. Data are shown as box plots. Conversion to SI units: for proinsulin, multiply by 1.065 (pmol/liter); for C-peptide, multiply by 0.331 (nmol/liter). One-way ANOVA analysis for proinsulin, C-peptide, and HOMA-IR; all P values <0.00001. Differences between individual groups were assessed by Tukey-Kramer’s multiple-comparison test; groups that are significantly different from one another are denoted by different letters (a, b). In the less than 24-h subgroup, 14 fetuses were delivered by cesarean section; delivery occurred or the pregnancy was terminated within a clinical setting of preterm labor (n = 10), maternal hypertensive disease (n = 7), antepartum hemorrhage (n = 5), or IUGR (n = 1).

 
Adiponectin concentrations were not correlated with glucose, insulin, or C-peptide concentrations, nor with any of the blood gas values in the UV or umbilical artery (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We identified two environmental signals that affect fetal ß-cell function. First, we produced evidence that fetal insulin synthesis and secretion, as reflected by proinsulin, C-peptide, and insulin concentrations, are transiently (<24 h) elevated after maternal betamethasone administration, presumably in response to the corticosteroid-induced IR, as reflected by the transient increase in HOMA-IR. Second, we produced suggestive evidence that in utero oxygenation, directly or indirectly, modulates fetal insulin secretion: C-peptide and insulin concentrations were related to UV PO2 values, whereas the proinsulin to insulin molar ratio, a potential marker of insulin secretory dysfunction, was raised in fetuses with low PO2 values. Relative hypoxemia was also associated with lower insulin and C-peptide concentrations, but a higher proinsulin to insulin ratio, in the less than 24-h betamethasone subgroup.

Betamethasone, like dexamethasone, is a poor substrate for fetoplacental 11ß-hydroxysteroid dehydrogenase, the enzyme that inactivates maternal glucocorticoids. Repeated sc injections of dexamethasone during week 3 of gestation in rats lowered BW; in addition, at 6 months of age, glucose and insulin responses to a glucose load were higher than in control offspring (19). Although our data would indicate that no long-term effects of a single course of betamethasone on insulin homeostasis are to be expected in human fetuses, this may be different with repeated corticosteroid courses, which have a deleterious effect on BW (20).

Our second finding extends cordocentesis data showing a decrement in the insulin to glucose ratio in SGA fetuses (21). Uterine artery ligation in rats repressed fetal insulin concentrations in late gestation (14) and the percentage of granulated ß-cells in d 1 pups (15). A study in deceased human IUGR fetuses found no abnormalities of the ß-cell fraction or the percentage of ß-cells within islets (22). However, this does not exclude subtle insulin secretory dysfunction, which would require ultrastructural assessment of insulin granulation in the ß-cells; alternatively, complex in vivo procedures (e.g. hyperglycemic clamps) in SGA newborns are necessary to buttress our findings. Strongly suggestive evidence of insulin secretory dysfunction was obtained by hyperinsulinemic clamps in 19-year-old Danish men born SGA at term, in whom insulin secretion was reduced by 30% when expressed relative to insulin sensitivity (5). Rather similar data were reported in adult Pima Indians with normal glucose tolerance and a history of low birth weight (23).

Any factors that may explain the possible link between in utero hypoxia and impaired ß-cell function are speculative at this time. We have reported that SGA fetuses have decreased circulating IGF-I but increased IGF-binding protein-1, which are correlated with the PO2 in both umbilical artery and vein (17). Mice overexpressing a rat IGF-binding protein-1 transgene had reduced BW and developed hyperglycemia postnatally, whereas their pancreatic insulin content declined faster than in normal mice (24, 25). Other factors may be involved, e.g. cytokines such as interleukin-6, which is markedly increased in plasma and cerebrospinal fluid of hypoxic fetuses (26) and appears to affect glucose homeostasis.

The HOMA-IR index was positively, not negatively, correlated with BW SDS, whereas there was no relationship with GA. Although HOMA-IR was calculated here without taking the maternal fasting/prandial state into account, our findings do not support the hypothesis that the insulin insensitivity documented in prepubertal children born preterm or SGA (2, 3) is initiated in utero. No difference in insulin sensitivity was found between SGA and AGA preterm newborns at 7 ± 3 (SD) days of age, using an abbreviated frequently sampled intravenous glucose tolerance test (9). Studies in children (6, 27) and experimental animals (28) indicate that postnatal dietary factors amplify the negative effects of BW on insulin sensitivity; in fact, multiple regression of HOMA-IR in 477 8-year-old Asian Indian children failed to show a residual effect of BW (6). These studies have led pundits to introduce the paradigm of the "inadequate predictive adaptive response", i.e. children become insulin resistant as they transition from a "thrifty" or deprived in utero environment to a metabolically adequate postnatal environment (29) rather than becoming insulin resistant in the deprived in utero environment.

UV adiponectin concentrations rose 14-fold between 25 and 37 wk GA and were correlated with BW SDS, in line with previous data (10, 11). However, adiponectin was not related to insulin or C-peptide concentrations, as was also demonstrated in term fetuses (30), and we did not confirm a previously reported (11) gender difference nor an effect of maternal corticosteroids when GA was controlled for. Hence, UV adiponectin concentrations appear to be a sensitive marker of adipose tissue development. Any additional role in intra-uterine glucose or lipid metabolism needs careful assessment, because mice with a disrupted adiponectin gene had a normal BW and maintained normal glucose and insulin concentrations until adulthood, at least when fed a normal diet (31).

This study does have limitations. We were unable in our observational study to differentiate between acute (e.g. during labor), subacute, or chronic in utero hypoxia and their possibly dissimilar association with fetal ß-cell function. Hypoxia is accompanied by changes in nutrient availability (including lower glucose and altered amino acid profile), which may play a contributing or even predominant role in the observed ß-cell dysfunction. In addition, the proinsulin to insulin ratio and the C-peptide to insulin ratio have not been validated previously in fetuses or newborns. Finally, longitudinal studies are mandatory to evaluate the fetal/neonatal insulin trajectory after maternal corticosteroid administration.

In conclusion, fetal insulin synthesis and secretion are transiently raised after maternal corticosteroid administration, whereas in utero hypoxia is associated with an apparently defective insulin secretion and an attenuation of the ß-cell responsiveness to maternal corticosteroids.


   Footnotes
 
This work was supported by Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Belgium) Grant G.0221.03 and Katholieke Universiteit Leuven Onderzoekstoelage OT/02/48.

First Published Online March 1, 2005

Abbreviations: AGA, Appropriate for gestational age; BW, birth weight; CV, coefficient of variation; GA, gestational age; HOMA, homeostasis model assessment; IR, insulin resistance; IUGR, in utero growth retardation; SDS, SD score; SGA, small for gestational age; UV, umbilical vein.

Received December 22, 2004.

Accepted February 22, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. A. Owens, K. L. Gatford, M. J. De Blasio, L. J. Edwards, I. C. McMillen, and A. L. Fowden
Restriction of placental growth in sheep impairs insulin secretion but not sensitivity before birth
J. Physiol., November 1, 2007; 584(3): 935 - 949.
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V. E. Murphy, R. Smith, W. B. Giles, and V. L. Clifton
Endocrine Regulation of Human Fetal Growth: The Role of the Mother, Placenta, and Fetus
Endocr. Rev., April 1, 2006; 27(2): 141 - 169.
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