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Selection from: Small for Gestational Age: Issues in 2008

Assessing the Risk of Insulin Resistance and Metabolic Syndrome (Slides With Transcript)  CME

Disclosures

Slide 1.

Claire Lévy-Marchal, MD: Thank you for the invitation of being here and explaining thoroughly to you the relation between born SGA, developing later in life type 2 diabetes, and also the metabolic syndrome.

Slide 2.

I will first show you the epidemiological evidence that relates being born small for gestational age and the further risk of type 2 diabetes.

Slide 3.

The very first observation actually published by David Barker related the birth weight here plotted on the X axis. Actually, it is the weight at 1 year of age experienced in British pounds. The weight at 1 year of age was taken as a surrogate of birth weight, which, in turn, was taken as a surrogate of fetal growth. You can see here that there is an inverse relationship between the mortality by cardiovascular accident and the birth -- and the weight at 1 year. Meaning that an increased cardiovascular mortality was associated with poor fetal growth.

From cardiovascular mortality you can go down to that type 2 diabetes, and you are here expressed the relative risk for developing type 2 diabetes by the age of 64 with respect of birth weight here. You cannot see anything, but here at the birth weight below 2.5 kg, and here above 3.5 kg, and you can see that there is one more time an inverse relationship between the risk of developing type 2 diabetes and birth weight.

The first of these observations was made on the Hertfordshire cohort, made of men born at the beginning of the 20th century. The same observation was replicated in a birth cohort in Finland. When you have here the prevalence of type 2 diabetes in adults, according to birth weight, here once more the cutoff point of 2.5 kg. Here, in a different population, you also observe an inverse relationship between birth weight and the prevalence of type 2 diabetes.

Slide 4.

In the last example, we show that the association that is indeed broadest between type 2 diabetes and low birth weight is one taken from the Pima Indians. The Pima Indians, who develop type 2 diabetes quite frequently when they are adults, you can see here the relation with the birth weight. It is a U-shaped relationship with an increased risk whether you have a high birth weight related to obesity and diabetes in the mother, but you have also an increase with the low birth weight, even in a population like the Pima, where the genetic background is very, very strong. But in this population, being born SGA or with a low birth weight can explain as much as 6% of the cases of diabetes in adults.

Slide 5.

This association is robust and in many populations, you can identify a U-shaped relationship between birth weight and the risk of type 2 diabetes. These observations here, you have the example in India and here in the US. This is just to show that once more the association is robust. But the difficulty starts here, because they can see that the inflection point on the two lines is quite different, 2.9 kg vs 3.4 kg. That points to the real difficult task of defining what is real, a low birth weight or SGA? We will come back to that point later.

Slide 6.

If we are talking about type 2 diabetes, you might ask whether it comes from a defect in insulin secretion or a defect in insulin sensitivity, so to say insulin resistance.

Slide 7.

Let's go to insulin secretion. The insulin secretion, as we measured in children at the age of 9 years, measuring the first phase insulin release and the glucose stimulation, and also the sustained insulin release under glucose stimulation. The results here from one of the Dutch groups show that there is no difference between the yellow and the orange color. That means there is no difference in insulin secretion between children born either SGA or adapted for gestational age, AGA. In our group, we also show exactly the same data in young adults, born either SGA in yellow, or AGA. At the age of 22, there was still no difference whatsoever in insulin secretion at least the way we can measure it.

Slide 8.

If it is not a primary defect in insulin secretion, it can be something related to insulin sensitivity or the other way, insulin resistance.

Slide 9.

Insulin sensitivity has been measured using the minimal model technique under glucose intravenous infusion, and you have here the result according to a quartile of birth weight. The lowest quartile is below 3 kg. You can see that the lower insulin sensitivity is observed in this lower quartile, and there is quite a continuous relation between insulin sensitivity and birth weight. That was measured in young men, and the same kind of relation was observed in young children, prepubertal children, either born SGA or in comparison with short stature children, but not born SGA.

You have here the birth weight expressed in this score, so the lower birth weight on your left hand side; and you have here the insulin sensitivity measured with the same minimal model. You can see that the lower insulin sensitivity was observed in the ones who were born SGA with lowest birth weight.

Slide 10.

That is two examples that insulin sensitivity is reduced in individuals born SGA, meaning insulin resistance. We in France have been working with a cohort of young adults. This cohort was taken more than 10 years ago from a Maternity Registry, meaning that the cohort is a population-based cohort, and not a clinically referred cohort. We compare 2 groups, the SGA in yellow were born below the tenth percentile for gender gestational age, compared with the AGA, born between the 25th and the 75th percentiles. The two groups are quite different in terms of birth weight, not in terms of gestational age. They were all full-term. They are also shorter, the SGA, and the AGA are also lighter at birth.

Slide 11.

When they are under observation at the age of 22, you can already see differences in glucose tolerance. The number of the proportion of individuals with impaired glucose tolerance at the age of 22 was two times higher in the SGA in comparison with the AGA. Point number one, there is indeed already impaired glucose tolerance.

Point number two, if you look at the rest of the individuals with normal tolerance to glucose, you can see here that the fasting insulin taken as a surrogate for insulin resistance in this cohort is significantly higher compared with the AGA by about 20%.

If you measure the insulin sensitivity, using euglycemic hyperinsulemic clamp technique, and measuring the peripheral glucose uptake, you can confirm that indeed insulin sensitivity as measured by this peripheral glucose uptake is reduced in the SGA-born individuals. When you look at the individual data here, the point I want to make in this graph, that there is mostly a reduced proportion of the individuals being born SGA were highly insulin resistant with a very low glucose uptake. But some of them are normal. That is one message that is important here, that not all the individuals born SGA will later in life develop insulin resistance and type 2 diabetes.

Slide 12.

In the same cohort, if you compare and measure all the different parameters that are associated or encompassed with the metabolic syndrome, you can see that when you compare SGA to AGA in orange, you have a difference in fat mass, in the waist-to-hip ratio, circumference ratio, in fasting insulin taken for insulin resistance, and systolic blood pressure and in lipid profile. The differences are modest, but they are statistically significant and all pointing to the same direction of the metabolic syndrome.

Slide 13.

Actually, when you look at the definition of the metabolic syndrome, as given by the ATP 3 panel, the proportion of the individuals being affected by the full metabolic syndrome is sixfold higher in the SGA group in comparison with the AGA. They are supposed to be healthy but already some of them have some indication for the disease.

Slide 14.

We will go now over the role of the catch-up growth or the inference of the catch-up growth on the metabolic risk in SGA. You may know, and you will see later that most of the children born SGA will catch up, and will do so during the first year of life.

Slide 15.

In the Haguenau cohort, which is a natural-history, under-observation cohort with no treatment at all, by the adult age, 10% of the individuals remain with short stature below -2 standard deviations. If you compare those two groups of SGA-born individuals, according to the adult stature, you can see that there is no difference in the QUICKI index that measures insulin sensitivity. The catch-up in height, that is not inference, the later metabolic risk for insulin resistance.

Slide 16.

If it is not the catch-up in height, it may be the catch-up in body size and adiposity. The way we have looked through the point in the Haguenau cohort is to look first at the body size at birth. You have here the BMI expressed in three tertiles. The lower tertile is in the, let's say, dark yellow, and the higher tertiles are in almost white. You have here insulin resistance as on the Y axis.

You can see that the normal one -- I mean, we are not skinny, but around the mean, and the BMI expressed in this cohort goes from -0.9 to 1.5. They are normal in term of body size. They are short, but they are not skinny.

They have the lowest insulin resistance. But the ones who were more skinny at birth, they are more insulin resistant. A way to evaluate the degree of catch-up is to compare the body size by BMI at birth, and in the adult age at 22 years of age. The difference between those two BMIs is taken as a surrogate for catch-up in body size. You can see here that the higher -- this marker for catch-up, the higher the insulin resistance. If you have a higher catch-up, you are more insulin resistant. If you put the two sets of results together, you have here the BMI expressed in tertiles, expressed in z score. So the mean is here at 0, and you have birth and adult. The more skinny the experience in the dark yellow line, the experience is stronger catch-up, and they end up around 0 and around the mean.

The ones who were not skinny at birth, they almost experience no catch-up at all, and they end up with BMI similar to the other two tertiles. You may notice that all those BMIs when adults are just around the mean and there is a widespread of their individual value. But still, it does mean obesity, there is a catch-up, but toward the mean. So it has nothing to do with obesity itself, but it has been shown that it has to do with relatively more adiposity, even though the body size does impede for obesity. So the more the catch -- the more skinny, the more the catch up, and the more insulin resistant you are.

Slide 17.

The role of the catch-up has been pointed out by different groups. You have here an observation in British children with a body size expressed at 5 years of age, and with the birth weight expressed on the X axis. You can see the relationship with the lower birth weight, the higher insulin, fasting insulin, indicating insulin resistance. You can see that the effect is also potentialized by your higher body size at 5 years of age in the orange line.

This observation was also made in a different ethnic group. This graph is taken from the Indian group. You have three tertiles of birth weight in the X axis, and you have the three tertiles of weight by the age of 8 years. You can see an effect or an influence of weight at 8 years of age on insulin resistance, which has been known for a long time. But you can see also this interaction with the birth weight. Eventually, the more insulin resistant, the ones who were born with the lowest birth weight but also who showed the highest weight were body size by the age of 8.

Slide 18.

The same thing was also observed already at 1 year of age, indicating that most of the catch-up and most of the, let's say, metabolic effect of the catch-up can be seen by the age of 1 year, when here, SGA-born babies with catch-up are more insulin resistant than the SGA with no catch-up at all.

Slide 19.

What about catch-up growth? You have here a natural observation of a cohort of SGA-born babies, and you have the time course of weight expressed in this curve, and the time course in height expressed in this curve. What you can see here, that most of the catch-up has been done by the age of 3 months, continues very, very slightly over the first year. You have to keep that in mind. The very first months are the most important with respect to catch-up, but what you can see also, if you want catch-up in height, you need catch-up in weight. That means you need calories and to put on weight first in order to grow in height, which follows more regularly and more smoothly along the first 2 years of life, so to say.

Slide 20.

Here I have taken indication of the role of weight gain during the first year of life, and the later occurrence of the metabolic syndrome. It is a Swedish birth cohort observed at the age of 17 years, and here you have the events between birth and 6 months of life, and what it is indicated in orange here, that the weight gain during infancy influenced the risk of developing a metabolic syndrome by the age of 17. By contrast, the weight gain observed between 3 and 6 years of age has no statistical effect on the risk of developing the metabolic syndrome by the age of 17. One more time, this study on the Swedish cohort points to the very important role of the very first month of life.

Slide 21.

There have not been many, many examples of intervention, and I have taken two, which are actually indirect evidence for that.

Slide 22.

This paper appeared in Circulation about a year ago. It has been performed by the British group of Cole and Lucas, and the intervention was on SGA, fed either a standard formula or an enriched formula for 9 months. What they have looked at here is at the blood pressure by the age between 6 and 8 years. There is a statistical difference, either on the diastolic blood pressure or at the mean arterial blood pressure at the age of 6, according to the group they were assigned. When you look at the group as a whole, there was a correlation between the mean arterial blood pressure and the delta in weight between the intervention period. For one standard deviation gained in weight, you would gain 1.5 mg Hg in mean arterial blood pressure.

Slide 23.

Actually, the purpose of the intervention was not about the metabolic consequences, but it is the observation now. Here you may be familiar with this paper by Singhal with just an intervention on low birth weight and premature babies, with a very specific population. The premies were assigned a preterm formula, breast milk, or standard formula, or in hashed here that the comparison combined between the two groups. What this complicated graph shows is that at the time of discharge, there is an effect in the weight gain on both the formula and the breast-fed. If you combine the two, you have a very low significant difference in weight gain. Then when you look at the pro-insulin concentration, when those preemies were adolescents, there is an increased concentration of pro-insulin, indicative of insulin resistance with the weight gain during the intervention strategy. So one more time, the very first here weeks of life seem very important in the determining the later metabolic complications.

Slide 24.

The other contributing factors on nutrition could be, as Ken alluded to, the genes.

Slide 25.

According to the Thrifty genotype hypothesis, some genes that can promote survival of the fittest and their deleterious environment can also promote insulin resistance later in life. The first candidate gene with this aspect would be the insulin gene. We have been told that there is a common variant at the insulin gene level, and this common variant was tested for the association between birth weight and the risk of later type 2 diabetes or insulin resistance. You have here different examples and different cohorts where the association was looked for.

Actually, you can see that the results are not really robust or strong consistent of other cohorts. This best candidate gene appears not to be a very good candidate gene at the end of the day.

Slide 26.

We have tested in the Haguenau cohort a series of candidate genes, ones some related to growth, some related to the adipose tissue, and here the TCF7L2. We could not find any robust or strong association between birth weight and insulin resistance. It is either one, but not two. So it does not work with the hypothesis of the Thrifty genotype.

Slide 27.

If you think what is SGA? We can debate on that for quite a long time.

Slide 28.

SGA is mostly an epidemiological definition according to birth weight most of the time. There has been a consensus statement a year ago on recommending the definition of -2 standard deviations for the definition of SGA. But even though we can agree on the definition, it reflects a number of clinical conditions with respect to the mother, to the fetus, or difference. Right now about a third of the cases are not really explained.

Slide 29.

Here is a plot for fetal growth according to gestational age. According to the method developed by Jason Gardosi, you can estimate the fetal weight measured by the different parameters from the ultrasound, and you can plot the growth velocity of the fetus according to maternal characteristic like the ethnicity, the parity, the birth of the mother, different parameters that can explain to you. Here you have a baby who is definitely a small individual, but normal growth pattern, a low one, but the normal growth velocity. By contrast, you have here individual who was not supposed to be, let's say, genetically really small. But when the fetal growth restriction, and the two of them will be called SGA at least by the definition of birth weight. This one is really SGA; this one is really IUGR, intrauterine growth restriction.

Slide 30.

The current hypothesis now is to explain the association between SGA or low birth weight and the risk of type 2 diabetes. You have seen that it goes through insulin resistance, but because this SGA is on the epidemiological definition related to birth weight, it does not tell you very much how it works.

Slide 31.

Now if you look at the pattern of the fetal growth, you have here this regular and also to say normal pattern of fetal growth with a small individual. Probably you see in terms of metabolic complications, nothing will happen to this baby. It may happen in terms of stature, but nothing in terms of metabolic complications. By contrast, the one who experiences a real fetal growth restriction, they will be born thin with a low birth weight. during the first year of the first months of life, they will experience catch-up growth. While catching up, they will put relatively more fat mass than lean mass, promoting the beginning of insulin resistance, which in turn will lead later in life to the development of metabolic syndrome and maybe type 2 diabetes in some individuals.

Slide 32.

What are the mechanisms? What I want to determine is whether we facing a real specific programming. That means that the fetal period is definitely unique and very important? Or is it only a matter of wasting and so losing weight and catching up with a relatively higher fat mass? What is the trigger? It can be hypoxia, like in the example of preeclampsia. It can be, let's say, quantitative undernutrition, which actually does not happen very often nowadays, but with the example of the Dutch famine in Rotterdam, with many publications related to that. Very recently, it has been shown that it could be a qualitative undernutrition, in that the defect of zinc or B12 vitamin during pregnancy can explain a large amount of the risk of type 2 diabetes in the people born SGA, at least in India.

The critical window, there are at least three. The association of diabetes with in vitro fertilization has been reported. Then with prematurity, pointing to the role of the second trimester of life, and also the association with SGA. Definitely there can be different windows, different triggers, making the mechanisms altogether quite complex.

Slide 33.

Currently, the most favored hypothesis has been proposed as the developmental mismatch by Peter Gluckman. Stating that the fetus is able to adapt to an unfavorable environment, and it will adapt to, let's say, poor nutrition or poor environment, but later what is important is actually the mismatch of the environment that when the fetus will face more favorable environment, then the complications start. But if it were to be adapted to a low or poor environment, it will work with no complications. This stipulation remains to be, let's say, maybe confirmed under prospective observation. I have shown you some data with respect to catch-up growth, with the risk of SGA and type 2 diabetes, even though the mechanisms, or the cellular mechanisms of this association remain to be elucidated. I thank you for your attention.

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Contents of: Small for Gestational Age: Issues in 2008
All sections of this activity are required for credit.

Genetic Determinants of Size at BirthKen K. Ong, MD, PhD, MRCPCHAvailable As: Slides/Audio | Slides/Transcript
Assessing the Risk of Insulin Resistance and Metabolic SyndromeClaire Lévy-Marchal, MDAvailable As: Slides/Audio | Slides/Transcript
The Treatment of Growth Failure in SGA ChildrenAnita Hokken-Koelega, MDAvailable As: Slides/Audio | Slides/Transcript
Panel DiscussionAnita Hokken-Koelega, MD; Ken K. Ong, MD, PhD, MRCPCH; Claire Lévy-Marchal, MDAvailable As: Slides/Audio | Slides/Transcript

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Copyright © 2008 Scherer Clinical Communications.

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