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Comparison of Plasma Insulin Levels after a Mixed-Meal Challenge in Children with and without Intrauterine Exposure to Diabetes

Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch (A.D.S., C.B.C., J.K., J.C.B.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016; BHF Glasgow Cardiovascular Research Centre (R.S.L.), University of Glasgow, Glasgow G12 8TA, United Kingdom; and Sanofi-Aventis Pharmaceuticals (P.A.T.), 75601 Paris Cedex 12, France

Address all correspondence and requests for reprints to: Joy C. Bunt, M.D., Ph.D., NIH/NIDDK/Obesity and Diabetes Clinical Research Section, 4212 North 16th Street, Room 541, Phoenix, Arizona 85016. E-mail: JBunt{at}mail.nih.gov.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background: The diabetic intrauterine environment is a known risk factor for the development of diabetes in the offspring.

Objective: We compared anthropometric and metabolic characteristics of 41 nondiabetic children whose mothers developed diabetes either before (ODM, n = 19, 9.3 ± 1.1 yr) or after (OPDM, n = 22, 9.5 ± 1.3 yr) the pregnancy of interest. Maternal diabetes status was established from OGTT results before, during, and after the pregnancy of interest.

Design: After consuming a standardized diet for 2 d, a mixed-meal breakfast was given after an overnight fast. Fasting concentrations and responses of plasma glucose and insulin were evaluated using linear regression analyses to assess potential independent determinants of plasma insulin concentration at each time point.

Results: After adjustment for age and sex, there were no differences between ODM and OPDM children for maternal age at diagnosis, height, weight, body mass index, BMI z score, or percent body fat (dual energy x-ray absorptiometry). After adjusting for age, sex, percent body fat, and the corresponding glucose level at each time point, ODM had a lower plasma insulin level at the 15-min time point during the meal test than OPDM (P = 0.01).

Conclusion: A lower initial insulin response to a standard mixed-meal challenge can be detected in nondiabetic ODM compared with OPDM children as early as 9 yr of age. This response may be another indicator for an attenuated early insulin response and explain the increased risk for diabetes in these children.

	Introduction

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THE DIABETIC INTRAUTERINE environment is a known risk factor for the development of type 2 diabetes (T2DM) in the offspring (1). In Pima Indians, the observed increase in incidence and prevalence of T2DM during childhood has been attributed in part to the increased number of diabetic pregnancies (2). The profound impact of the diabetic in utero environment, in addition to that of genetic factors in this population, has been determined from studies comparing offspring of mothers who were either diabetic or normal glucose tolerant during pregnancy (1, 3), offspring of diabetic fathers vs. diabetic mothers (4, 5), and siblings born before or after their mother developed diabetes (6).

Obesity, with subsequent insulin resistance, and impaired insulin secretion have been identified as major risk factors for the development of T2DM (7). In Pima Indian children, greater levels of adiposity have been described in offspring of diabetic mothers (ODM) when compared with offspring of nondiabetic mothers or offspring whose mothers developed diabetes after the child was born (1, 6, 8). Similar observations have been reported in other populations (9, 10, 11, 12, 13).

Insulin resistance, as a consequence of obesity, cannot by itself account for the earlier onset of T2DM observed in offspring of diabetic pregnancy. Indeed, impaired insulin secretion rather than greater insulin resistance (or adiposity) has been identified as the primary defect in adult offspring of diabetic pregnancies (14, 15).

Children with a family history of T2DM (16, 17), impaired glucose regulation (16, 18, 19), or T2DM (20, 21) during childhood or adolescence have an inadequate compensatory increase in insulin secretion [acute insulin response (AIR)] during an iv glucose tolerance test (IVGTT). However, the age at which this defect is present is not clear. Although children of diabetic pregnancies might begin developing obesity and insulin resistance earlier in life than other children (1, 6, 8, 9, 10, 11, 12, 13), a defect in insulin secretion would be the critical determinant for the early development of T2DM. Earlier studies in children (and adults) have evaluated the insulin response to potent glucose challenges in oral or IVGTTs; however, whether a difference can be detected in the insulin response to the more physiological challenge of a mixed meal is not known.

We compared anthropometric and metabolic characteristics in nondiabetic children (fasting plasma glucose range, 76–106 mg/dl) whose mothers developed diabetes either before (ODM) or after (OPDM) the pregnancy of interest. This design allowed us to distinguish between the influence of genetic and intrauterine environmental factors because these children all had a similar genetic risk for T2DM. Specifically, we evaluated the insulin response to a standard mixed-meal challenge and hypothesized that independent of adiposity, children who were ODM would have a lower insulin response to a standard meal test than children who were OPDM.

	Subjects and Methods

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Subjects

During the summer months of 2001–2004, 41 Pima Indian children (20 males/21 females) aged 7–11 yr whose mothers developed diabetes either before (ODM) or after (OPDM) the pregnancy of interest were studied. No siblings were included in this study to avoid heritability as a confounding factor. History of diagnosis of diabetes and diabetes status during the pregnancy of interest were verified from medical records of the mother before, during, and after the pregnancy, and the birth medical record of the child and maternal ages at diagnosis were similar between the groups (ODM, 28.9 yr, range, 16–39 yr; OPDM, 29.0 yr, range 18–40 yr). Diabetes status in the mothers was determined by World Health Organization criteria (22).

Children and their mothers were admitted to the Clinical Research Unit of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; Phoenix, AZ) for a 1-wk stay. The health status of the children was determined by medical history and physical examination; only healthy children with fasting glucose levels less than 6.1 mmol/liter were studied. All meals were prepared in a metabolic kitchen on the Research Unit. Before participation, volunteers and their parents were fully informed of the nature and purpose of the study, and written informed consent/assent was obtained. The experimental protocol was approved by the institutional review boards of the NIDDK, the Intertribal Council of Arizona, the Phoenix Area Indian Health Service, and the Tribal Council of the Gila River Indian Community.

Anthropometrics

Height was measured without shoes. Body weight was measured while the children were wearing preweighed robes. Measures and estimations of adiposity included assessment of percent body fat using dual energy x-ray absorptiometry (23), calculation of body mass index (BMI; kilograms per square meter), and BMI z scores (24).

Experimental procedures

After consuming a standardized diet for 2 d, children were fasted overnight. An iv catheter was placed in an antecubital vein for blood sampling and kept patent with a 0.9% saline infusion. At approximately 0730 h, subjects were fed a mixed-meal breakfast (consisting of a bacon-and-egg sandwich on toast accompanied by orange juice) containing 10% of calories from protein, 45% from fat, and 45% from carbohydrates and providing approximately 20% of daily energy requirements for each child. The meal was consumed within 15 min and subjects rested quietly in bed throughout the study. Blood samples for insulin and glucose were drawn before and 15, 30, and 60 min after initiation of the meal test.

Analytical procedures

Plasma glucose concentrations were measured using the glucose oxidase method (Beckman Instruments Inc., Fullerton, CA); plasma insulin concentrations were measured with an automated RIA (ICN Biochemicals, Costa Mesa, CA). The homeostasis model assessment of insulin resistance (HOMA-IR) was used to calculate an index from the product of fasting plasma insulin (microunits per milliliter) and fasting plasma glucose (millimolar) divided by 22.5 (25).

Statistical methods

All statistical analyses were performed using SAS software (SAS version 8.2, 1999–2001, SAS Institute, Inc., Cary, NC). Data are expressed as the mean ± SD. Fasting plasma insulin concentrations were transformed (log₁₀) before statistical analysis to approximate a normal distribution. General linear regression models were used to assess differences in anthropometric and metabolic characteristics as a result of maternal diabetes status as well as to evaluate other possible determinants of insulin concentrations during the meal test. Levels of statistical significance were set at P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subject characteristics for the 41 children who completed a meal test are shown in Table 1. There were no significant differences in sex distribution (ODM, eight males/11 females vs. OPDM, 12 males/10 females, P = 0.34 by ² analysis) and age (ODM, 9.3 ± 1.1 yr vs. OPDM, 9.5 ± 1.3 yr, P = 0.48) between the groups. Variables for body size and composition (except for BMI z scores) were adjusted for sex and age before analysis. There were no significant differences in adjusted body weight (53.2 ± 15.1 vs. 47.2 ± 14.3 kg, P = 0.32), adjusted BMI (26.3 ± 6.6 vs. 23.5 ± 5.7 kg/m², P = 0.36), adjusted body fat (41 ± 9 vs. 39 ± 9%, P = 0.65), or BMI z scores (1.78 ± 1.0 vs. 1.59 ± 1.0, P = 0.56) between the ODM and OPDM groups, respectively.

View larger version (10K): [in this window] [in a new window]   FIG. 1. Glucose and insulin responses to a standard mixed meal in 19 ODM (eight males/11 females) and 22 OPDM (12 males/10 females). Although there were no significant differences in glucose concentrations between the groups at any time point (left), ODM (, solid line) had a lower plasma insulin level at 15' (*, P = 0.01) compared with OPDM (, dashed line) after adjusting for age, sex, percent body fat, and the 15' plasma glucose level.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Among Pima Indian children of similar age, weight, adiposity, fasting plasma glucose and insulin concentrations (thus, a similar level of insulin resistance estimated by HOMA-IR), and plasma glucose responses, the offspring of diabetic pregnancies had a significantly lower plasma insulin concentration at the first time point (15 min) of a standard meal test than offspring of mothers who did not develop T2DM until after the index pregnancy. This finding supports our hypothesis that intrauterine exposure to diabetes is associated with an attenuated early insulin response to a mixed-meal challenge and that this response is already present during childhood.

Although many studies describe the association of intrauterine exposure to diabetes with overweight and/or obesity in infants (3, 10, 26), children (1, 4, 8, 9), and adolescents (11, 13), obesity only partially contributes to insulin resistance and impaired glucose tolerance (IGT). More recently, Goran et al. (16) reported that among overweight Latino children with a family history of T2DM, IGT was more prevalent in those children who were exposed to gestational diabetes; this association was not influenced by obesity. Furthermore, IGT (16) and impaired fasting glucose (18) were related to poor pancreatic ß-cell function rather than insulin sensitivity. Although we did not assess the glucose tolerance status of these children, fasting plasma glucose concentrations and glucose responses during the meal test were similar. Despite these similarities, plasma insulin concentrations at each time point were adjusted for corresponding plasma glucose concentrations to account for potential differences in glucose absorption rates.

Although it is not known specifically how intrauterine exposure to diabetes can increase the risk of earlier development of T2DM, defective insulin secretion must be present along with insulin resistance. Animal studies have demonstrated that hyperglycemia in pregnant rats (27, 28) and in utero hyperinsulinism in rhesus monkeys (29) both produce short- and long-term defects in insulin secretion in the offspring.

In humans, two studies in nondiabetic ODM adults (14, 15) have described an impaired insulin secretory response to a glucose challenge. We found that the AIR during an IVGTT was lower in normoglucose-tolerant offspring whose mothers were diabetic during the index pregnancy vs. those who developed T2DM after the index pregnancy (14). Sobngwi et al. (15) reported similar results when comparing adult nondiabetic offspring of type 1 diabetic mothers vs. type 1 diabetic fathers. Specifically, ODM subjects had lower insulin responses during an oral glucose tolerance test and during a hyperglycemic clamp and a higher incidence of IGT. ODM subjects also had lower levels of pancreatic polypeptide, suggesting that a lower parasympathetic tone in the pancreas could be responsible for this attenuated insulin secretory response. In both studies (14, 15), there was no association between intrauterine exposure to diabetes and levels of adiposity or insulin sensitivity.

Other studies have described lower insulin secretory responses in other high-risk children and adolescents [based either on family history (16, 17), obesity (19), low birth weight (30), impaired glucose regulation (16, 18, 19), or even diabetes (20, 21)] during either iv or oral glucose challenges. Indeed, this metabolic characteristic appears to have a significant heritable component given that impaired insulin secretion (assessed as AIR during an IVGTT) has been documented in subjects with normal glucose tolerance and who are first- degree relatives of individuals with diabetes (14, 31, 32). In Pima Indians, AIR was found to be a highly familial trait (heritability = 0.70 at 10 min) after controlling for percent body fat and insulin action (33). To avoid the influence of heritability, no siblings participated in the present study. We believe that the data presented here represent the first description of the insulin response to a standardized mixed-meal test in children that all have similar genetic risk for T2DM but are compared based on exposure to a diabetic vs. nondiabetic intrauterine environment.

Insulin secretion can be characterized in a number of different ways and the interpretation of the physiological relevance of these various expressions of insulin secretion is complex and is in itself an intense area of ongoing investigation and debate (34). Using a mixed-meal test more closely mimics a typical physiological stimulus and reflects the influence of not only glucose but other nutrients and potentiating factors for insulin secretion such as the incretins (35). Indeed, we previously reported in a subset of the present cohort (36) that maternal diabetes status during pregnancy was a significant determinant of childhood glycosylated hemoglobin but not fasting glucose concentrations. We proposed that this might reflect chronically higher postprandial glucose levels in the ODM than the OPDM children. We also hypothesized that because this difference was independent of adiposity, differences in glycosylated hemoglobin might reflect differences in insulin secretion rather than insulin sensitivity. Although these data do not indicate higher postprandial glucose levels in ODM children, these data do show that there is at least an attenuated early insulin response to a mixed-meal challenge in ODM children.

It could be argued that the lower insulin concentration for a similar plasma glucose concentration at 15 min in the ODM children might indicate a greater degree of insulin sensitivity. This is unlikely given the similar levels of body weight and adiposity and calculated insulin sensitivity in these children after adjustment for the possible influences of sex and age. Furthermore, significant correlations for measures of insulin sensitivity using fasting indices vs. the IVGTT (37) or clamp (38) have been demonstrated in obese children and adolescents. It should also be remembered that the relationship between plasma glucose and insulin concentrations is different in an oral glucose tolerance test compared with a meal test due to different potentiation factors for insulin secretion in these two tests (35). Therefore, one cannot assume that a difference in plasma insulin responses with similar glucose concentrations during a mixed-meal test is a reflection of differences in insulin sensitivity. Finally, if differences in insulin concentration were due to differences in insulin sensitivity, it would be more likely that differences in insulin levels would be seen over more time points or in the overall area under the curve.

Although specific mechanisms for a difference in the initial insulin response to a meal cannot be determined from this study, future studies should explore possible differences in other factors besides glucose (i.e. incretins and/or neural mechanisms) for insulin secretion after an oral mixed-nutrient challenge. Indeed, at least one study in adults (39) has described lower insulin responses as early as 15 min during a meal test in obese subjects (either compared with lean controls or immediately after bariatric surgery) that correspond with lower incretin levels at the same time point. Although the physiological or clinical relevance of the initial, isolated difference of the plasma insulin concentration at 15 min during a meal test (as described in the present study) is not known, this very early difference could conceivably reflect an alteration in an unidentified neural mechanism during in utero development. Alternatively, differences in more time points might have emerged either with the use of the more potent glucose challenge provided in an IVGTT or OGTT, or if we had studied children with a greater degree of impairment in fasting glucose regulation than the present cohort.

Finally, puberty, which is normally associated with a decline in insulin sensitivity (40), could be a confounding factor. However, as we reported elsewhere, measured dehydroepiandrosterone sulfate concentrations were in the prepubertal range in most of these children and did not significantly contribute to the variability of HOMA-IR (41).

In conclusion, intrauterine exposure to diabetes is a significant determinant of a lower early insulin response to a mixed-meal challenge independent of other factors such as adiposity or a genetic predisposition to T2DM. Evidence for this association begins to emerge during childhood and may be another indicator (in addition to the responses of insulin to iv and oral glucose challenges) of an attenuated early insulin response that could account for their increased risk of diabetes at an earlier age in ODM. Although fasting glucose and insulin concentrations were not different between the groups, there may be an inherent difference in ß-cell function and/or mass or additional neural or hormonal mechanisms responsible for the attenuated early response to a meal we report here. Whether this response can predict the development of diabetes needs to be determined in future studies.

	Acknowledgments

 
The authors thank the dietary and nursing staffs of the National Institutes of Health (NIH) Clinical Unit. Most of all, we thank the children and mothers from the Gila River Indian Community for their participation in the study.

	Footnotes

 
This work was supported by the Intramural Research Program of the NIH, NIDDK.

The authors have nothing to disclose.

First Published Online December 5, 2006

Abbreviations: AIR, Acute insulin response; BMI, body mass index; HOMA-IR, homeostasis model assessment of insulin resistance; IGT, impaired glucose tolerance; IVGTT, iv glucose tolerance test; ODM, nondiabetic children whose mothers developed diabetes before the pregnancy of interest; OPDM, nondiabetic children whose mothers developed diabetes after the pregnancy of interest; T2DM, type 2 diabetes.

Received May 31, 2006.

Accepted November 21, 2006.

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This Article Abstract Full Text (PDF) All Versions of this Article: 92/2/624    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Salbe, A. D. Articles by Bunt, J. C. Search for Related Content PubMed PubMed Citation Articles by Salbe, A. D. Articles by Bunt, J. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Diabetes and Pregnancy High Risk Pregnancy Related Collections Diabetes and Insulin Metabolism Pediatric Endocrinology