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Diabetes Care 29:1345-1350, 2006
DOI: 10.2337/dc05-1677
© 2006 by the American Diabetes Association
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Pathophysiology/Complications
Original Article

Hyperinsulinemia in Cord Blood in Mothers With Type 2 Diabetes and Gestational Diabetes Mellitus in New Zealand

Jenny A. Westgate, FRANZCOG, MD, Robert S. Lindsay, MB, PHD2, Judith Beattie, RM3, Neil S. Pattison, FRANZCOG, MD3, Greg Gamble, MSC4, Lindsay F.J. Mildenhall, FRACP5, Bernhard H. Breier, PHD6 and Frank D. Johnstone, FRCOG, MD7

1 Department of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand
2 Western Infirmary, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, U.K.
3 Department of Women’s Health, Middlemore Hospital, Auckland, New Zealand
4 Clinical Trials Research Unit, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand
5 Department of Newborn Services, Kid First, Middlemore Hospital, Auckland, New Zealand
6 Liggins Institute, University of Auckland and Research Centre for Growth and Development, Auckland, New Zealand
7 Obstetrics Department, University of Edinburgh, Edinburgh, Scotland, U.K.

Address correspondence and reprint requests to Dr. Jenny Westgate, Obstetrics and Gynecology, University of Auckland, Private Bag, 92019 Auckland, New Zealand. E-mail: ja.westgate{at}auckland.ac.nz


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—In genetically diabetes-prone populations, maternal diabetes during pregnancy increases the risk of their children developing diabetes and obesity (the vicious cycle of type 2 diabetes). Fetal hyperinsulinemia at birth acts as a marker of this risk. We therefore examined whether cord insulin and leptin concentrations are increased in offspring of Maori and Pacific Island mothers with type 2 and gestational diabetes mellitus (GDM) and varying degrees of glycemic control (HbA1c).

RESEARCH DESIGNS AND METHODS—Maori and Pacific Island mothers were prospectively recruited at Middlemore Hospital, South Auckland. Cord blood was taken from umbilical vein at birth from singleton babies born after 32 weeks of gestation to 138 mothers with GDM, 39 mothers with type 2 diabetes, and 95 control mothers.

RESULTS—Babies born to mothers with both type 2 diabetes and GDM had higher birth weight and skinfold thickness and markedly higher concentrations of insulin (median [interquartile range] type 2 diabetes 77 pmol/l [42–143], GDM 67 pmol/l [42–235], and control subjects 33 pmol/l [18–62]; P < 0.001) and leptin (type 2 diabetes 39 ng/ml [18–75], GDM 31 ng/ml [17–58], and control subjects 13 ng/ml [8–22]; P < 0.001) in cord blood. Cord insulin concentrations >120 pmol/l were found in 29% of offspring of mothers with GDM and 31% of mothers with type 2 diabetes. Many mothers with GDM had abnormalities of glucose tolerance postpartum (20% type 2 diabetes, 34% impaired glucose tolerance or impaired fasting glucose). Higher cord insulin (57 pmol/l [40–94]) and leptin (26 ng/ml [17–39]) concentrations were found even in offspring of GDM mothers with normal glucose tolerance postpartum.

CONCLUSIONS—Raised cord insulin and leptin concentrations are a common finding in offspring of mothers with type 2 diabetes and GDM in this population.

Abbreviations: GDM, gestational diabetes mellitus • ILM, insulin-like molecule • OGTT, oral glucose tolerance test


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Fetal hyperinsulinemia is characteristic of pregnancy complicated by maternal diabetes and underpins complications such as macrosomia (1). Cord leptin correlates with measures of adiposity at birth (2–4) and is also raised in offspring of mothers with diabetes (3,4). Assessment of insulin and leptin at birth may be a particularly useful way of monitoring whether the fetus has been exposed to abnormally high levels of glucose in utero. Fetal hyperinsulinism may also have potential prognostic implications. Several studies have suggested that the maternal intrauterine environment might result in "programming" of later disease. An increased risk of obesity (5–8) and abnormal glucose tolerance (9–12) are observed when offspring have been exposed to maternal diabetes in utero. Fetal hyperinsulinemia acts as a marker of this increased risk, offspring of diabetic mothers with higher insulin levels in utero being at a higher risk of later metabolic complications (7,8,10).

The Pacific Island and Maori peoples of New Zealand are populations at high risk of both type 2 and gestational diabetes during pregnancy. We measured concentrations of fetal insulin, insulin propeptides, and leptin, together with weight and skinfold thickness at birth, with the following hypotheses: where the mother has type 2 diabetes and gestational diabetes mellitus (GDM), fetal hyperinsulinism is common despite treatment of disease, and fetal leptin and fat mass are similarly increased; and in subgroup analysis, these effects are most pronounced in those women with known preexisting disease and not found in those with GDM and subsequent normal postnatal oral glucose tolerance test (OGTT).


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
The case group comprised Maori and Pacific Island women planning to deliver in Middlemore Hospital, South Auckland, who had either type 2 diabetes known before pregnancy or a positive OGTT during pregnancy. Local criteria for diagnosis of GDM were fasting glucose ≥5.5 mmol/l and/or a 2-h value after a 75-g glucose load ≥9.0 mmol/l. All women delivered between 1 February 1999 and 31 May 2001. A total of 232 women with diabetes were eligible for the study, and 218 (94%) agreed to take part. Twenty-eight women were excluded during pregnancy (12 miscarried, 10 moved out of the area, 3 twin pregnancies, 1 delivery at <32 weeks’ gestation, 1 intrauterine death, and 1 termination of pregnancy for fetal abnormality). To ensure quality of insulin assays (13), 13 case subjects were excluded after delivery if cord blood was not collected or there was gross sample hemolysis (9), if there was a delay >20 min before cord blood collection or >60 min before freezing plasma (4), or if antenatal glucocorticoids had been administered in the 24 h before birth (no exclusions). A total of 138 women with GDM and 39 women with type 2 diabetes were thus included in the analysis.

Control subjects were selected using a pseudo-random number generator (MS Excel) to produce a standardized template that was placed against clinic lists. To avoid overmatching, the only selection criteria were ethnicity (Pacific Islander or Maori), no previous history of diabetes, and no evidence of diabetes in the current pregnancy (a negative screen after 26 weeks’ pregnant). The screen used was the polycose 50-g unfasted test with blood test 1 h later, normal glucose <7.8 mmol/l. One hundred and thirty control subjects were invited to participate, with 17 women declining and 18 excluded (7 twins and 11 no cord blood sample available).

All participants were given information sheets translated into Tongan and Samoan when required, and the study was explained by the research midwife (J.B.) or another member of the clinical team. Participants gave informed consent, and the trial protocol received ethical approval from the Health Funding Authority, Auckland Ethics Committee.

Clinic protocol
Pregnancy care was supervised by a combination of hospital and home visits by diabetes midwives. All women were instructed in home blood glucose monitoring at a first home visit by the diabetes midwives with recommendation to test fasting and 2 h postprandially (five tests daily). All women were routinely seen by an obstetrician and diabetologist in the clinic monthly until 28 weeks, fortnightly until 36 weeks, and weekly until delivery. Insulin, usually as lispro insulin up to three times daily along with Humulin N, was commenced if fasting glucose was ≥5.5 mmol/l on two occasions or postprandial readings were consistently ≥6.5 mmol/l. After commencement of insulin, diabetes midwives maintained twice weekly contact with all women, adjusting doses as necessary. Where daily dosage exceeded 200 units, subcutaneous insulin pumps were the preferred route of administration. No oral hypoglycemic agents were used.

All women with GDM (diabetes with first onset or recognition in pregnancy) were offered a 75-g OGTT at 8 weeks postnatally. Glucose tolerance was classified by 1998 American Diabetes Association criteria (14).

Collection of cord blood and neonatal assessment and assays
Delivery room midwives were trained by a single research midwife (J.B.) in all procedures. After delivery of the baby, but before placental delivery, either the delivering midwife or the operator at cesarean section took 20 ml cord blood from the umbilical vein. Blood was centrifuged in the delivery suite, and plasma was initially stored at –15°C for up to 48 h before final storage at –86°C.

A neonatal pediatrician (L.F.J.M.) or one specified senior neonatal nurse assessed the babies within 24 h of delivery. Crown-heel length and scapular and tricep skinfold thicknesses were measured with a Harpenden neonatometer and Harpenden calipers (Holtain Limited, Dyfed, U.K.), respectively.

Assays were performed either at Addenbrookes Hospital, Cambridge, U.K. (plasma insulin, proinsulin, 32–33 split proinsulin, and glucose) or Auckland University Laboratory, Grafton, Auckland (leptin). The methods used for analysis were as previously described (15). HbA1c (A1C) assays were performed at two local laboratories using either affinity chromatography (Primus, Kansas City, MO) or ion-exchange chromatography (Bio-Rad, Hercules, CA). Regular interlaboratory comparisons were performed to ensure the comparability of results.

Statistical analysis
Differences between groups were analyzed by either {chi}2 test (for categorical variables) or by general linear model and post hoc Student-Newman-Keuls test. Z scores were calculated for babies of 38–41 weeks’ gestation using ethnic-specific birth weight centiles developed from deliveries at National Women’s Hospital, Auckland (16), for babies of Maori, Samoan, and Tongan ethnicity or "other" (other Pacific Island ethnicity including Cook Island) in keeping with the derivation of the centile charts. Simple correlations of insulin-like molecules (ILMs) to fetal and maternal variables were assessed by Spearman’s rank correlation. The hypothesis that correlation coefficients of the ILMs versus birth weight or leptin were different from those of insulin versus birth weight or leptin was assessed by standard methods (17).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
Mothers with both GDM and type 2 diabetes were older, more parous, heavier, more likely to have labor induced, and more likely to be delivered by cesarean section compared with control subjects (Table 1). Mothers with type 2 diabetes were more likely to have had essential hypertension noted before pregnancy (28% type 2 diabetes vs. 4% control subjects and 2% GDM subjects; P < 0.001), and booking blood pressure was higher in both diabetic groups (Table 1). No differences in other medical diagnoses were observed. A1C was significantly higher in mothers with type 2 diabetes compared with GDM subjects at 30 weeks of gestation and at the end of pregnancy (Table 1).


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  		Table 1— Maternal demographic and delivery details

 
Despite being born ~2 weeks earlier than control subjects, offspring of mothers with GDM were ~300 g heavier at birth, and birth weight adjusted for sex and gestation (expressed as birth weight Z score) was significantly greater in offspring of mothers with both type 2 and diabetes and GDM (Table 2). Offspring of diabetic mothers had higher skinfold thickness as well as markedly higher concentrations of insulin, insulin propeptides, and leptin, with median values generally two to three times those of control subjects. These relationships persisted after multivariate analysis controlling for delivery method, sex, and ethnicity and, in the case of insulin, insulin propeptides and leptin even after adjusting for those variables and standardized birth weight. Neither mode of delivery nor use of intravenous dextrose in delivery (recorded for 88% of case subjects and used in 82% of GDM and 95% of type 2 diabetes deliveries) were independent predictors of cord insulin.


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  		Table 2— Neonatal outcomes by maternal diabetes status

 
For most variables, offspring of mothers with GDM and type 2 diabetes were similar (Table 2). In general, concentrations of leptin, insulin, and the insulin propeptides were higher in offspring of mothers with type 2 diabetes, while absolute values of birth weight and Z score of birth weight were higher in the offspring of mothers with GDM. However, none of the differences between the two diabetic groups were significant. Values of all three ILMs (insulin, proinsulin, and 32–33 split proinsulin) were highly intercorrelated. In general, these relationships were strongest between 32–33 split proinsulin and proinsulin (data not shown). ILMs were significantly related to birth weight and leptin in all three groups (Table 3). In general, 32–33 split proinsulin showed a stronger relationship to birth weight and leptin than insulin, but this was only significantly greater in the case of leptin in type 2 diabetes (Table 3). By contrast, insulin was only significantly correlated to cord glucose in offspring of mothers with diabetes (GDM or type 2 diabetes) and more strongly related to cord glucose concentrations than to either 32–33 split proinsulin (in GDM and type 2 diabetes) or proinsulin (in type 2 diabetes).


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  		Table 3— Relationship of ILMs to birth weight, leptin, and cord glucose

 
In mothers with diabetes (data for type 2 diabetes and GDM combined), maternal A1C at the end of pregnancy was significantly correlated with standardized birth weight (r = 0.24, n = 123, P = 0.008), skinfold thickness (triceps: r = 0.39, n = 105, P < 0.001; scapular: r = 0.35, n = 105, P = 0.002), cord insulin (r = 0.30, n = 132, P = 0.004), 32–33 split proinsulin (r = 0.31, n = 135, P = 0.003), and leptin (r = 0.40, n = 136, P < 0.001).

Among mothers with GDM, 107 (79%) underwent postnatal glucose tolerance testing. A high number of mothers (57 of 107) had persisting abnormalities of glucose tolerance (20% type 2 diabetes and 34% impaired glucose tolerance or impaired fasting glucose), suggesting that many women may have had preexisting, but clinically undetected, abnormalities of glucose tolerance before pregnancy. In general, birth weight, skinfold thickness, insulin, insulin propeptides, and leptin were higher in mothers with GDM and abnormal glucose tolerance after pregnancy. In those with GDM, values of A1C were highest in those subsequently found to have type 2 diabetes on OGTT postpartum (A1C at end of pregnancy: postpartum type 2 diabetes 6.5 ± 0.8%, n = 29; postpartum impaired glucose tolerance/impaired fasting glucose 6.0 ± 0.6%, n = 19; postpartum normal OGTT 5.7 ± 0.6%, n = 43; P < 0.0002). Notably, values of insulin, 32–33 split proinsulin, and leptin were higher than in control subjects even in offspring of those GDM mothers with entirely normal glucose tolerance after pregnancy (Table 2).


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
Exposure of the fetus to maternal diabetes results in characteristic changes in birth weight, adiposity, and fetal insulin production. We have used cord insulin and leptin as indicators of exposure to an abnormal intrauterine environment. Notably, birth weight, skinfold thickness, insulin, insulin propeptides, and leptin are significantly increased in our population, not only in offspring of mothers with type 2 diabetes but also offspring of mothers with GDM. Further, cord hormonal measures indicate that insulin and leptin are higher in offspring of mothers with GDM even when glucose tolerance returns to normal postpartum. Fetal hyperinsulinemia is a frequent outcome of pregnancy complicated by diabetes in our population, and this is associated with increased fetal growth and adiposity.

How important is the finding of raised fetal insulin levels at birth? Several studies suggest that exposure to maternal diabetes in utero exerts programming effects to increase the risk of adiposity and type 2 diabetes in early life. In the Pima Indian population of southwestern U.S., maternal diabetes is clearly associated with an increase in risk of type 2 diabetes and obesity in offspring, in keeping with in utero programming of disease (9,18) and forming a "vicious cycle of type 2 diabetes" (19). More recently, studies (20,21) in hepatocyte nuclear factor-1{alpha} mutation carriers (maturity-onset diabetes of the young 3) have supported a role of the intrauterine environment in modifying risk of diabetes. Such studies are of great importance to Pacific Island and Maori women, as these populations are also believed to be at high genetic risk of obesity and type 2 diabetes and therefore likely to be prone to the same programming effects. Importantly, the risk of later adverse metabolic consequences appears to relate to fetal insulin levels (7,8,10). In this context, our finding of increased concentrations of insulin in cord blood offspring of mothers with type 2 diabetes and GDM suggests that such a cycle is also potentially present in Pacific Island and Maori peoples.

Are insulin levels raised to a similar degree as found in these previous studies? Weiss et al. (22) have suggested that cord insulin concentrations >120 pmol/l (20 µU/ml) are indicative of hyperinsulinemia relative to control subjects. Less than 1% of control pregnancies had insulin concentrations >120 pmol/l compared with 21% of offspring of mothers with GDM and 49% of offspring of mothers with type 1 diabetes. In our series, 3 of 91 offspring (3%) of control mothers, 29% of offspring of mothers with GDM, and 31% of offspring of mothers with type 2 diabetes had cord insulin concentrations >120 pmol/l. Results for the control subjects are similar to those of Weiss et al. and would suggest that insulin levels are indeed markedly raised in our offspring of diabetic mothers. Proinsulin and 32–33 split proinsulin have longer half-lives (23–25) and are poorer substrates for insulin-degrading enzymes (26) than insulin. We have previously demonstrated that insulin propeptides are more stable in cord blood than insulin and have closer relationships to fetal growth and leptin concentrations at birth than insulin (13). Insulin propeptides are also raised in offspring of mothers with GDM and comprise ~30–40% of all ILMs. Further, they are significantly correlated with birth weight and cord leptin. In general, 32–33 split proinsulin was more closely related to leptin (but not birth weight) in the diabetic groups. Taken together, these results would confirm that measurement of insulin propeptides are a useful indicator of overall fetal insulinemia with potentially stronger relationships to important fetal outcomes.

The importance of GDM as a clinical entity has recently been demonstrated by an Australian randomized trial in which the identification and treatment of GDM significantly reduced the rate of fetal macrosomia and serious adverse perinatal outcome (27). Our data demonstrating that GDM is associated with fetal hyperinsulinemia in Maori and Pacific Island women provides biochemical confirmation that GDM is associated with an abnormal intrauterine environment that has at least short-term consequences for the neonate. As noted, Pacific Island and Maori women are at high risk of type 2 diabetes, and our results may not be generalizable to other populations. Notably, there was a very high rate of persistent abnormality of glucose tolerance in women with GDM, with 20% subsequently diagnosed as having type 2 diabetes and 34% having persisting impaired fasting glucose or impaired glucose tolerance. A high percentage of those with GDM (defined as first onset or recognition in pregnancy) in our study probably had clinically undetected abnormalities of glucose tolerance before pregnancy. Further, it is a population with high levels of insulin resistance. Over half of the women with preexisting type 2 diabetes (n = 22, 56%) and 13 (9%) of the women with GDM required >200 units of insulin and hence used an insulin pump. This is a warning for clinicians who are not used to such populations and who may be inclined to dismiss the significance of GDM. Cundy et al. (28), describing their extensive experience in Auckland, have already pointed to the poor pregnancy outcome associated with type 2 diabetes, regardless of whether the diagnosis is made before or during pregnancy. In keeping with this birth weight, skinfold thickness and cord insulin and leptin were equivalent in mothers with type 2 diabetes prepregnancy and those with type 2 diabetes diagnosed postnatally. Indeed, these measures were generally higher in mothers with type 2 diabetes diagnosed postnatally, although this did not achieve significance. Our second hypothesis rested on the expectation that the fetal hormonal and biometric data in those women with GDM and a normal postnatal OGTT would not differ from the control population. We postulated that this less-marked abnormality of glucose tolerance would be below threshold stimulus. In fact, this condition does seem to be part of the spectrum of significant disease. These fetuses had significantly raised insulin, insulin propeptides, and leptin concentrations. Cord insulin concentrations were on average double those of the control subjects, and cord insulin was >120 pmol/l in 16% of these offspring. Thus, the finding that fetal hyperinsulinemia is a common outcome of pregnancy in women with GDM in this population would support the importance of detection and careful monitoring of this group and suggests that similar studies might be carried out in other groups. Finally, our study confirms the expected modest but significant relationship of maternal glycemia with birth weight and cord insulin. A1C at the end of gestation correlated with standardized birth weight and cord measures of insulin, insulin propeptides, and leptin in mothers with GDM and type 2 diabetes and is in keeping with previous results in mothers with type 1 diabetes (13). This relationship offers some support for current treatment paradigms and the expectation that careful monitoring and treatment of blood glucose will return these outcomes toward normal. By contrast, birth weights of offspring mothers with type 2 diabetes were lower (although not significantly so) than those with GDM despite slightly higher A1C at the end of pregnancy. It is not clear to what extent this reflects influences of other maternal factors (such as microvascular complications, essential hypertension, or treatment of hypertension) to modify birth weight, although it is of interest that a similar trend was not seen for cord insulin.

In conclusion, hyperinsulinemia was found throughout the spectrum of severity of maternal diabetes. Our study does not demonstrate that the vicious cycle of type 2 diabetes is occurring in this population. Nevertheless, it does demonstrate that maternal diabetes is commonly resulting in fetal hyperinsulinemia at birth in a population genetically prone to obesity and diabetes. Further studies examining the health of children of mothers with diabetes in this population, and whether maternal glycemic control can impact upon this risk, are clearly critical.


   Acknowledgments
 
Funding for the study was provided by the Auckland Medical Research Foundation. Medica Pacifica provided the Precision meters used for maternal glucose monitoring. B.H.B. is supported by the Health Research Council of New Zealand.

We thank the delivery suite staff at Middlemore Hospital for collecting and processing cord blood gas samples, Alec Ekeroma for translating the consent form into Samoan, Eunice Sharma for help with neonatal examinations, and Raewyn McCort for administrative assistance. We acknowledge the help and expertise of Ian Halsall, University of Cambridge, for the insulin assays.


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication September 8, 2005. Accepted for publication February 26, 2006.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

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