Fetal growth and the physiological control of glucose tolerance in adults: a minimal model analysis

Daniel E. Flanagan1, Vivienne M. Moore2, Ian F. Godsland3, Richard A. Cockington4, Jeffrey S. Robinson2, and David I. W. Phillips1

1 Medical Research Council Metabolic Programming Group, University of Southampton, Southampton General Hospital, Southampton SO16 6YD; 3 Wynn Department of Metabolic Medicine, Imperial College School of Medicine, London NW8 9SQ, United Kingdom; 2 Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide 5005; and 4 Child Development Unit, Women's and Children's Hospital, Adelaide 5006, South Australia


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Although there is now substantial evidence linking low birthweight with impaired glucose tolerance and type 2 diabetes in adult life, the extent to which reduced fetal growth is associated with impaired insulin sensitivity, defective insulin secretion, or a combination of both factors is not clear. We have therefore examined the relationships between birth size and both insulin sensitivity and insulin secretion as assessed by an intravenous glucose tolerance test with minimal model analysis in 163 men and women, aged 20 yr, born at term in Adelaide, South Australia. Birth size did not correlate with body mass index or fat distribution in men or women. Men who were lighter or shorter as babies were less insulin sensitive (P = 0.03 and P = 0.01, respectively), independently of their body mass index or body fat distribution. They also had higher insulin secretion (P = 0.007 and P = 0.006) and increased glucose effectiveness (P = 0.003 and P = 0.003). Overall glucose tolerance, however, did not correlate with birth size, suggesting that the reduced insulin sensitivity was being compensated for by an increase in insulin secretion and insulin-independent glucose disposal. There were no relationships between birth size and insulin sensitivity or insulin secretion in women. These results show that small size at birth is associated with increased insulin resistance and hyperinsulinemia in young adult life but that these relationships are restricted to the male gender in this age group.

birthweight; intravenous glucose tolerance test; insulin sensitivity; insulin secretion; glucose effectiveness


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

LOW BIRTH WEIGHT, or suboptimal fetal growth as indicated by thinness or stunting in term babies, is linked with a higher prevalence of impaired glucose tolerance or type 2, non-insulin-dependent diabetes mellitus (NIDDM) in adult life (27). These observations have led to the hypothesis that NIDDM may arise as a result of programming, a term used to describe persistent changes in structure and function caused by malnutrition or exposure to other adverse influences restricting growth during critical periods of development (15). Although both impaired insulin action and reduced insulin secretion are important in the pathogenesis of NIDDM, it is not clear whether the association between early growth and diabetes is mediated by alterations in insulin sensitivity, insulin secretion, or a combination of both factors. It was originally suggested that growth restriction in utero might adversely affect the development of the endocrine pancreas, an idea encouraged by animal experiments showing that exposure of rats to a low protein diet during gestation resulted in impaired pancreatic function in the offspring (11, 15, 23). However, most human studies show that low birth weight is associated with impaired insulin action (9, 25, 28) and a raised prevalence of the metabolic or insulin resistance syndrome (4, 35). Whether low birth weight is also linked with a defect in insulin secretion is not clear. Some studies have not shown any association between birth weight and beta -cell function (2, 9, 22, 29), others suggest that insulin secretion is reduced in low-birth-weight subjects (10), and others suggest that secretion is increased (18). Many of these studies have been carried out in later adult life, when aging, obesity, or the development of abnormal glucose tolerance may have modified the relationships between early growth and carbohydrate metabolism. Furthermore, few of the studies report simultaneous measurements of insulin sensitivity and insulin secretion in the same subjects. The objective of the present study was to determine the interrelationships between fetal growth and both insulin resistance and insulin secretion. We studied men and women in young adult life, when the prevalence of abnormal glucose tolerance would be very low. The frequently sampled intravenous glucose tolerance test with minimal model analysis was used to measure simultaneously insulin sensitivity and insulin secretion in a population-based sample of young men and women aged 20 yr whose birth measurements had been recorded in detail.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. The study sample was drawn from an existing cohort of young adults known as the Adelaide Children's Hospital Family Heart Study (7). As previously described (26), the obstetric records of births between 1975 and 1976, maintained at the Queen Victoria Hospital, Adelaide, were used to trace 764 individuals currently living in Adelaide who were singletons and had been born after 37 completed weeks of gestation. Computer-generated random samples were drawn for each sex to obtain a birth weight-stratified subset of ~150 subjects, which a priori power calculations indicated would be sufficient for the present analyses. Letters of invitation were sent to all subjects selected by this process. When a subject did not wish to participate, he or she was replaced by a randomly selected individual from the same birth weight and sex stratum. The final sample comprised 163 subjects. Information available on the subjects included length of gestation, based on the date of the mother's last menstrual period, birth weight, and crown-heel and crown-rump length.

Protocol and measurements. The study was approved by the Human Ethics Committee of the Adelaide Women's and Children's Hospital. Informed written consent was obtained from each of the subjects. Subjects were requested to consume >200 g/day of carbohydrate for 3 days. They were asked to fast overnight and to refrain from smoking and alcohol overnight before attending the department between 0800 and 0900. Medical history, smoking habits, alcohol consumption, and social class were recorded. Alcohol consumption was converted into the total number of units each week (1 unit = 8 g ethanol). Occupation of the father (determined when the subjects were 8 yr of age) was used to indicate social class at birth. Area of residence was used to define current social class. Subjects were categorized as either not doing exercise, or doing less than three sessions of aerobic exercise or three or more sessions per week. Measurements of the subject's weight, made using an electronic scale (AND weighing equipment, Adelaide, Australia), and height, with a stadiometer (Holtain, Crymych, Dyfed, Wales, UK), were used to calculate the body mass index (BMI), defined as weight divided by the height squared. Measurement of sitting height was used to estimate adult leg length. Waist and hip circumferences were measured using a steel tape measure. Waist circumference was measured at the level of the umbilicus and hip circumference at the level of the greater trochanters. The ratio of the waist-to-hip measurements was used as an index of central obesity. Skin-fold thicknesses were measured by a single observer with Harpenden skin-fold calipers at the biceps and triceps sites.

Subjects then underwent a fifteen point frequently sampled intravenous glucose tolerance test (IVGTT). Each subject received a glucose dose of 0.5 g/kg body wt as 50% wt/vol dextrose via an antecubital vein over 3 min. Blood was sampled from the opposite arm at the following time points: -30, -5, 3, 5, 7, 10, 15, 20, 30, 45, 60, 75, 90, 120, and 180 min. Plasma samples were analyzed for glucose by the hexokinase method and insulin by two-site immunometric assays with alkaline phosphatase as label (1). The within-assay coefficient of variation of the insulin measurements was <10%.

Calculations. Basal insulin and basal glucose were each calculated as the mean of the two fasting samples taken before the IVGTT. The areas under the glucose and insulin concentration profiles were analyzed using the trapezoidal rule. The first-phase insulin response to glucose (AIRGlc) was calculated as the increment above the fasting insulin level in area under the IVGTT insulin concentration profile from 0 to 10 min. Similarly, the second-phase incremental insulin area was calculated as increment in area under the IVGTT insulin concentration profile from 10 to 180 min. The intravenous glucose tolerance index (Kg) was used as the measure of overall glucose tolerance. This is a measure of the rate of decay of glucose after the glucose bolus. Kg was determined as the least square slope of the log of the glucose concentrations between 20 and 60 min after the glucose bolus. Insulin sensitivity (Si) and glucose effectiveness (Sg) were determined from the IVGTT glucose and insulin profiles by use of the minimal model of glucose disappearance (6) with programs written in Fortran 77, run on a PDP-11/83 microcomputer. Briefly, the minimal model of glucose disappearance provides a measure of the sensitivity of glucose elimination to insulin (Si, inversely proportional to insulin resistance) and glucose-dependent glucose elimination (Sg). In the minimal model analysis, the insulin sensitivity index represents the increase in fractional clearance rate of glucose per unit change in plasma insulin concentration. Glucose effectiveness (Sg) represents the fraction of the glucose distribution space (a single compartment of glucose distribution is assumed) cleared per minute solely as a result of the ability of elevated glucose levels to stimulate their own normalization. This depends on inhibiting hepatic glucose output or enhancing peripheral glucose uptake.

The IVGTT protocol employed in the present study differs in two respects from that traditionally used with mathematical modeling analysis. First, after glucose injection, a reduced sample schedule of 15 rather than 26 samples is followed, the reduced schedule being more useful for relatively large studies (33). Second, a glucose load of 0.5 g/kg, rather than 0.3 g/kg, is employed, which provides for a sufficient endogenous insulin response in nondiabetic volunteers without recourse to additional augmentation of pancreatic insulin secretion. The validity and effectiveness of the IVGTT protocol employed in the present study, with regard to measurement of insulin sensitivity (Si), are apparent in the high rate of model identification and good correlation with measures of insulin sensitivity derived from the euglycemic clamp (r = 0.92) that it provides (34, 36). Net insulin-dependent glucose elimination depends both on insulin sensitivity and the accompanying plasma insulin concentration, the latter being largely dependent on beta -cell function. The relationship between these variables is hyperbolic and may be expressed as Si × AIRGlc = a constant (5, 20) that provides an index of insulin-dependent glucose elimination.

Statistical methods. Because the metabolic variables had a skewed distribution, the data were transformed to normality using logarithms (insulin and glucose measurements) or square root transformations (Si and Sg) before analysis. We analyzed the data by using multiple linear regression. Data are presented in Tables 1-5 by use of categories that best approximate to quartiles, although because of the rounding of birth measurements the numbers of subjects in each of the groups are unequal. However, all analyses were undertaken using continuous variables. P values presented in Tables 1-5 are therefore derived from the relevant correlation or regression equations.


    RESULTS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The characteristics of the sample of subjects studied (85 men and 78 women) are shown in Table 1. Their mean birth weight was 3.6 ± 0.5 kg for men and 3.4 ± 0.4 kg for women. This did not differ from the birth weight of the individuals eligible but not studied (3.5 ± 0.5 kg for men and 3.4 ± 0.4 kg for women). Birth weight did not correlate with current BMI or the skin-fold thicknesses. Although both genders were of similar age and BMI, the women had significantly greater biceps and triceps skin-fold thicknesses. They also had higher fasting insulin levels and, after intravenous glucose, had lower Si and higher AIRGlc. The gender difference in Si and insulin secretion was abolished after the data were adjusted for the biceps or triceps skin-fold thicknesses.

                              
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Table 1.   Clinical characteristics of the subjects

Si correlated inversely with the current BMI (for men, r = -0.445, P = 0.001; for women, r = -0.629, P = 0.001) and waist-to-hip ratio (for men, r = -0.391, P = 0.001; for women, r = -0.397, P = 0.001) but not with height or sitting height in either men or women. Si correlated positively with alcohol consumption (r = 0.185, P = 0.020) but not with current smoking habits, level of exercise, or current socioeconomic status. Forty-four of the women were using hormonal contraception, but neither their glucose tolerance nor their insulin sensitivity was found to differ from that of women who were not. There was a strong and significant hyperbolic relationship between AIRGlc and Si (P < 0.001). Because of the gender differences in Si, we analyzed the data for men and women separately. Data are presented as values unadjusted and adjusted for BMI.

Figure 1 shows plasma glucose and insulin concentrations during the IVGTT in men. Plasma glucose concentrations were unrelated to birth weight, but plasma insulin concentrations were higher in subjects who were smaller at birth, particularly during the first phase of insulin secretion (0-10 min). There was no trend in fasting glucose and insulin concentrations with birth weight (Table 2). After the intravenous glucose load, overall glucose tolerance, as indicated by the IVGTT, integrated glucose area, and the glucose tolerance index, Kg, were also unrelated to birth weight. However, mechanisms for glucose disposal differed markedly according to the pattern of early growth. Si was reduced in subjects who were light at birth (P = 0.03). In contrast, the ability of glucose to promote its own disposal, Sg, was increased (P = 0.003). Lightness at birth was associated with increased AIRGlc. There was a weak but nonsignificant increase in second-phase insulin secretion (data not shown). These trends were similar but more pronounced in relation to birth length (Table 2). Shortness at birth was associated with insulin resistance (P = 0.01), increased Sg (P = 0.003), and increased AIRGlc (P = 0.006). These associations persisted after adjustment for current BMI (Table 2), the waist-to-hip ratio, or triceps or biceps skin-fold thicknesses. Although both Si and AIRGlc were independently related to birth size, the product of these variables was not, suggesting that the increased insulin secretion in men who were small at birth was appropriate for their level of insulin resistance. Because the anthropometric measurements available at birth included the crown-rump as well as the crown-heel length of the baby, we were able to analyze further the relationships between the size of the baby and insulin sensitivity in adult life. There were no significant trends with trunk length. Short leg length at birth, however, was significantly associated with lower Si (P = 0.04), increased AIRGlc (P = 0.04), and increased Sg (P = 0.02). There were no relationships between Si, AIRGlc, or the other measurements of carbohydrate metabolism and either gestational age or ponderal index at birth.


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Fig. 1.   Plasma insulin (A) and plasma glucose concentrations (B) during intravenous glucose tolerance test in 85 men aged 20-21 yr who were born in Adelaide (birth weight <3,195 g, ; 3,195-3,540 g, open circle ; 3,540-3,885 g, black-down-triangle ; and >3,885 g, triangle ).


                              
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Table 2.   Glucose and insulin variables according to birth weight and birth length in 85 men aged 20-21 yr

Table 3 shows how the effects of birth weight and adult BMI combine to affect Si in the men. At each level of birth weight, Si fell with increasing BMI, whereas at each level of BMI, Si tended to rise with increasing birth weight. The lowest Si was seen in men who were of low birth weight but were most obese in adult life (Si = 3.02), whereas the highest Si was seen in men who had been heavy at birth but who had a low BMI in adult life (Si = 8.76). In the same way, birth weight and adult BMI combine to determine insulin secretion (AIRGlc) in the men (Table 3).

                              
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Table 3.   Si and AIRGlc according to birth size and current body mass index in 85 men aged 20-21 yr

Table 4 shows the metabolic measurements according to birth weight and birth length in women. In contrast to the men, neither Si nor the other metabolic measurements were associated with birth size before or after adjustment for BMI or other indexes of obesity.

                              
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Table 4.   Glucose and insulin variables according to birth weight and birth length in 78 women aged 20-21 yr

Multiple regression analyses were carried out with Si as the dependent variable and birth weight, BMI, current smoking habit, alcohol consumption, and level of physical fitness as independent variables. These analyses, which are summarized in Table 5, showed that, in men, both birth weight and obesity significantly predicted Si (P = 0.03 and < 0.001, respectively), but not smoking (P = 0.92), alcohol consumption (P = 0.06), or the current exercise level (P = 0.42). The results in men were similar if birth length rather than birth weight was used as an independent variable in the regression model. The relative strength of the effects of birth size and adult obesity is shown by the standardized regression coefficient (Table 5), representing the standard deviation (SD) change in Si per SD change in BMI or birth size. These regression coefficients suggest that the effects of obesity on Si are twice as strong as the effects of birth size. In a further multiple regression analysis, the association between birth weight or length and Si was independent of current socioeconomic status (as assessed by area of residence) or the socioeconomic status of the parents at the time of the subject's birth. The findings in men contrast with those of the women, where only BMI significantly predicted Si.

                              
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Table 5.   Multiple linear regression models for variables predicting Si in men and women born in Adelaide


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Although there have now been numerous studies showing that small size at birth is linked with a higher prevalence of glucose intolerance or diabetes in adult life (13, 16, 22, 24, 31), almost all of these studies were based on older populations with a high prevalence of established disease. We therefore studied a population of young adults at an age when the prevalence of glucose intolerance or diabetes is low, to determine whether low birth weight is linked with decreased insulin sensitivity alone or in combination with a defect in insulin secretion. There was a marked gender difference in the results. Men aged 20 who were shorter or lighter at birth were less insulin sensitive, independently of their BMI or body fat distribution, but they also had higher insulin secretion and increased glucose effectiveness. However, overall glucose tolerance, as shown by the IVGTT integrated glucose area and glucose tolerance index (Kg), did not correlate with birth size, suggesting that the reduced insulin sensitivity in these young men was being compensated for by an increase in glucose effectiveness as well as insulin secretion. These findings therefore differ somewhat from previous studies in older subjects, which show strong inverse associations between low birth weight and overall glucose tolerance. This difference is likely to be explained by the relatively young age of the subjects and suggests that the declining glucose tolerance in low-birth-weight subjects with increasing age may be due to failure of these compensatory mechanisms. Nevertheless, our data add to the increasing evidence suggesting that the association between birth size and glucose intolerance is mediated through an effect of size at birth on insulin resistance, rather than through effects on beta -cell function. Although the effect of adult obesity is more potent than that of low birth weight (Table 5), obesity added to the effects of low birth weight or shortness at birth in determining the level of insulin sensitivity (Table 3). In contrast, birth size was unrelated to the same metabolic measurements in women, and obesity appeared to be the major factor determining insulin sensitivity.

The men and women we studied were born at term (37 wk of completed gestation or more), and within this group we found no relationships between duration of gestation and insulin sensitivity or insulin secretion. The relationships we have observed are therefore likely to be due to growth retardation in utero rather than prematurity. As in previous studies, we found that more detailed measurements at birth were more predictive of the metabolic abnormalities in adult life than birth weight alone. However, in contrast to previous studies, which suggested a link between thinness at birth and insulin resistance or diabetes (25, 28), it was shortness but not thinness that was associated with reduced insulin sensitivity and hyperinsulinemia in our study. Shortness or stunting at birth is known to be associated with glucose intolerance in some populations (14). The reasons for these differences in birth phenotypes and the differences in their associations with adult insulin resistance and glucose intolerance are not known. Although it is not proven that intrauterine undernutrition is responsible for these birth phenotypes, it has been suggested that thinness at birth results from undernutrition in mid- to late gestation, when linear growth continues at the expense of growth of muscle and subcutaneous tissue (3). In contrast, shortness at birth is due to a failure of linear (skeletal) growth, possibly as part of a "brain-sparing" mechanism.

A novel finding in this population, not reported in previous studies employing the IVGTT technique (9, 18), is that lightness or shortness at birth in men was associated with increased glucose effectiveness (a measure of the rate of insulin-independent glucose disposal). Glucose effectiveness is known to be an important factor contributing to acute glucose disappearance and is increased in subjects with NIDDM and in their normoglycemic but insulin-resistant relatives (17). It could be argued that the link between fetal growth and reduced insulin sensitivity and increased glucose effectiveness might have resulted from one of the assumptions inherent in the minimal model. This is that glucose, once injected, distributes into a single distribution space, an assumption which is made to provide the necessary simplicity for model identification based solely on IVGTT glucose and insulin profile measurements. In reality, glucose distributes into at least two compartments, and it has been argued that the undermodeling inherent in the single-compartment assumption results in overestimation of glucose effectiveness and underestimation of insulin sensitivity (8). It is conceivable that reduced fetal growth leads to altered exchange kinetics between the different glucose pools and that it is this that leads to the increasing glucose effectiveness and decreasing insulin sensitivity with decreasing birth weight. The increased glucose effectiveness and decreased insulin sensitivity associated with low birth weight would then be an artifact of the modeling process. It seems likely, however, that the low-birth-weight men in the present study are genuinely insulin resistant, because they had higher IVGTT insulin concentrations but identical glucose profiles to those of higher birth weight. Alterations in glucose exchange kinetics would have been expected to lead to differences in the glucose concentration profile. There is also the evidence from earlier studies consistent with there being insulin resistance in low-birth-weight individuals (25, 28). If this is the case, then the increase in glucose effectiveness in low-birth-weight subjects (which was not seen in obese subjects) could represent a compensatory mechanism to maintain normal glucose tolerance. Recent animal studies have suggested that intrauterine growth retardation induced by uterine artery ligation is associated with an increased hepatic (21) and skeletal muscle (32) expression of GLUT-1 in the neonatal period. Because GLUT-1 is largely a non-insulin-dependent glucose transporter, these experiments suggested that the changes in glucose transporter were a compensatory mechanism to increase glucose uptake after intrauterine hypoglycemia. Although it is not known whether these changes persist into adulthood, a change in glucose transporter expression may underlie our findings of an increase in glucose effectiveness in men who were small at birth.

A striking feature of our study is the lack of correlation between birth size and insulin resistance or hyperinsulinemia in women. Although the women in our study had a greater upper body obesity, as indicated by their larger biceps and triceps skin-fold thicknesses, and were more insulin resistant, adjustment for obesity did not reveal any underlying association with birth size (Table 4). Our observations of gender differences in the strength of the associations between fetal growth and adult outcomes are consistent with some but not all previous studies (13, 16, 30). Gender differences are also reported in animal studies. Desai et al. (12) studied glucose tolerance in the offspring of protein-restricted female rats. Although the male offspring were less glucose tolerant than the non-protein-restricted controls, there was no significant difference for the females (12). These gender differences remain unexplained.

The mechanisms linking reduced fetal growth with insulin resistance and glucose intolerance in adult life are not understood. Animal studies suggest that early nutritional restriction augments the development of insulin resistance and impaired glucoregulation after high-fat feeding (19). Although human studies have not yet studied the interaction between birth size and adult diet, the present study (Table 3) and previous studies show that the effects of adult obesity add to (28) or even interact with (22) low birth weight to determine the level of insulin resistance or glucose tolerance in adult life. These observations emphasize the importance of further studies to determine the mechanisms by which low birth weight leads to insulin resistance and how the early environment interacts with obesity or other aspects of adult lifestyle to increase the risk of glucose intolerance or diabetes.


    ACKNOWLEDGEMENTS

We gratefully acknowledge the work of those who have contributed to the Adelaide Children's Hospital Family Heart Study, especially Prof. J. Bolton and Dr. A. Margery. Professor N. Hales and Dr. P. Wood performed the assays. We also thank Sister M. Logan, Dr. S. Flanagan, M. Rourke, L. Raggett, and J. Flanagan for assistance with the fieldwork.


    FOOTNOTES

This study was generously supported by the Medical Research Council, the British Diabetic Association, the Wessex Medical Trust, and the Women's and Children's Hospital Foundation. Dr. V. Moore was supported by the Public Health Research and Development Committee, National Health and Medical Research Council of Australia.

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

Address for reprint requests and other correspondence: D. Phillips, MRC Environmental Epidemiology Unit, Southampton General Hospital, Southampton SO16 6YD, UK (E-mail: diwp{at}mrc.soton.ac.uk).

Received 20 July 1999; accepted in final form 1 November 1999.


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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Endocrinol Metab 278(4):E700-E706
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