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Diabetes Care 29:1052-1057, 2006
DOI: 10.2337/dc05-1993
© 2006 by the American Diabetes Association
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Pathophysiology/Complications
Original Article

The Effects of the Pro12Ala Polymorphism of the Peroxisome Proliferator–Activated Receptor-{gamma}2 Gene on Glucose/Insulin Metabolism Interact With Prenatal Exposure to Famine

Susanne R. de Rooij, MSC1, Rebecca C. Painter, MD, MSC1, David I.W. Phillips, PHD, FRCP2, Clive Osmond, PHD2, Michael W.T. Tanck, PHD1, Joep C. Defesche, PHD3, Patrick M.M. Bossuyt, PHD1, Robert P.J. Michels, MD, PHD4, Otto P. Bleker, MD, PHD, FRCOG5 and Tessa J. Roseboom, PHD1

1 Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
2 Medical Research Council Epidemiology Resource Centre at the University of Southampton, Southampton, U.K
3 Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
4 Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
5 Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands

Address correspondence and reprint requests to Susanne de Rooij, MSc, Academic Medical Centre, Department of Clinical Epidemiology and Biostatistics, Room nr J1B-210-1, Meibergdreef 9, P.O. Box 22660, 1100 DD, Amsterdam, Netherlands. E-mail: s.r.derooij{at}amc.uva.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator–activated receptor (PPAR)-{gamma}2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism.

RESEARCH DESIGN AND METHODS—We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-{gamma}2 genotype among 675 term singletons born around the time of the 1944–1945 Dutch famine.

RESULTS—A significant interaction effect between exposure to famine during midgestation and the PPAR-{gamma}2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-{gamma}2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation.

CONCLUSIONS—The effects of the PPAR-{gamma}2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic ß-cell maldevelopment and carrier type of the Ala allele in the PPAR-{gamma}2 gene.

Abbreviations: AUC, area under the curve • HOMA-IR, homeostasis model assessment of insulin resistance • OGTT, oral glucose tolerance test • PPAR, peroxisome proliferator–activated receptor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
The fetal origins hypothesis proposes that metabolic and cardiovascular disease originates through adaptations made by the fetus in response to an adverse fetal environment (1). An adverse fetal environment may alter gene expression and lead to physiological or morphological phenotypes associated with disease (2). Based on this hypothesis, one can expect the effects of polymorphisms associated with specific diseases to depend on the type of fetal environment. Size at birth, a marker of the fetal environment, has been shown to modulate the effects of a number of genetic polymorphisms (3–6). In particular, there is accumulating evidence for an interaction between size at birth and the effects of the Pro12Ala polymorphism of the peroxisome proliferator–activated receptor (PPAR)-{gamma}2 gene.

PPAR-{gamma}2 is one of three PPAR-{gamma} isoforms and is a member of the nuclear hormone receptor subfamily of transcription factors, which regulate transcription of various genes (7). PPAR-{gamma} is implicated in adipocyte differentiation, regulating glucose, and lipid homeostasis (7). The PPAR-{gamma} gene contains nine exons and spans >100 kb of genomic DNA on chromosome 3p25 (8,9). Of several mutations identified on the PPAR-{gamma}2 gene, the proline-to-alanine change in codon 12 of exon B is one (10). The Ala allele reduces the transcriptional activity of PPAR-{gamma} and may protect against type 2 diabetes compared with the more common Pro/Pro genotype (11,12). In people with low birth weight, the Pro/Pro genotype has been shown to be associated with raised systolic blood pressure, increased insulin resistance, and elevated plasma insulin concentrations (13,14). Because this association was not observed in people with normal birth weights, it may be concluded that the fetal environment interacts with the effects of the PPAR-{gamma}2 Pro12Ala polymorphism. Birth weight is, however, a summary measure of the fetal environment. The Dutch famine birth cohort study provides the opportunity to study the direct effects of a specific adverse fetal environment, namely maternal undernutrition. The Dutch famine birth cohort consists of people born as term singletons in the Wilhelmina Gasthuis in Amsterdam around the time of the Dutch famine. People who were exposed to famine during gestation had higher 120-min plasma glucose and insulin concentrations at age 50 years compared with people prenatally unexposed to famine (15). The purpose of the current study was to determine whether famine exposure during gestation interacts with the effects of the PPAR-{gamma}2 Pro12Ala polymorphism on glucose and insulin metabolism.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
Selection procedures The Dutch famine birth cohort consists of 2,414 men and women born as term singletons in the Wilhelmina Gasthuis in Amsterdam between 1 November 1943 and 28 February 1947 (15). All 1,423 members of the cohort who lived in the Netherlands on 1 September 2002 and whose current address was available were invited to the hospital. Of the cohort of 1,423 eligible people, a total of 810 people agreed to participate in the study. The local medical ethics committee had approved the study, which was also carried out in accordance with the Declaration of Helsinki. All participants gave written informed consent.

Exposure to famine
Exposure to famine was defined according to the official daily food rations for the general population aged ≥21 years (16). An individual was considered to be prenatally exposed to famine if the average daily food ration of the mother during any 13-week period of gestation contained <1,000 calories. Based on this definition, babies born between 7 January 1945 and 8 December 1945 were exposed in utero. We delineated periods of 16 weeks each to differentiate between those who were exposed in late gestation (born between 7 January and 28 April 1945), in midgestation (born between 29 April and 18 August 1945), and in early gestation (born between 19 August and 8 December 1945). People born before 7 January 1945 and conceived and born after 8 December 1945 were considered as unexposed to famine in utero.

Study parameters
The medical birth records provided information about the mother, the course of the pregnancy, and the size of the baby at birth (15). Trained nurses took all measurements and conducted a standardized interview. We measured height using a fixed or portable stadiometer and weight with Seca and portable Tefal scales. Information about socioeconomic status, medical history, lifestyle, and use of medication was obtained in a standardized interview. We defined current socioeconomic status according to International Socioeconomic Index of Occupational Status 92, which is based on the participant’s, or their partner’s, occupation, whichever status was highest (17). After an overnight fast, we performed an oral glucose tolerance test (OGTT) with a standard load of 75 g. Venepuncture was performed at 0, 30, 60, and 120 min after the administration of the oral glucose load to assess plasma glucose and insulin concentrations. DNA material was extracted from the fasting blood sample. Participants with preexistent diabetes, defined as taking oral or injected antidiabetic medication, were excluded from the OGTT. Plasma glucose concentrations were measured by standardized enzymatic photometric assay on a Modular P analyzer (Roche, Basel, Switzerland) and plasma insulin concentrations by an immunoluminometric assay on an Immulite 2000 analyzer (Diagnostic Product, Los Angeles, CA). The insulin assay sensitivity was 15 pmol/l. The Pro12Ala polymorphism of the PPAR-{gamma}2 gene was determined by the PCR restriction fragment–length polymorphism method. The following primers were used: forward primer 5'-CAAGCCCAGTCCTTTCTGTG-3' and reverse primer 5'-AGTGAAGGAATCGCTTTCCG-3'.

Statistical methods
Impaired glucose tolerance was defined as a 120-min glucose level between 7.8 and 11.0 mmol/l. Type 2 diabetes was defined as a 120-min glucose level of >11.0 mmol/l (18). The ratio of the 30-min increment in insulin to 30-min increment in glucose concentrations was used as an index of insulin secretion (19). Insulin resistance was estimated by homeostasis model assessment (HOMA-IR) (20). The area under the curve (AUC) was calculated for insulin according to the following formula: [15*log (ins0min)] + [30*log (ins30min)] + [45*log (ins60min)] + [30*log (ins120min)]/120. Logarithmic transformations were applied to glucose, insulin, insulin increment ratio, HOMA-IR, and BMI values because they had skewed distributions. Allele frequencies were estimated by gene counting, and departure from Hardy-Weinberg equilibrium was tested using a {chi}2 test with one degree of freedom. Genotypes were treated as categorical variables. We used linear regression analysis to compare glucose and insulin concentrations and logistic regression to compare the prevalence of impaired glucose tolerance and type 2 diabetes between genotype groups and exposure groups. Possible interactions between the effects of prenatal famine exposure and the Pro12Ala polymorphism of the PPAR-{gamma}2 gene on glucose/insulin metabolism were assessed by adding an interaction term (genotype*exposure) to the regression equation. We adjusted for sex and BMI in all analyses. Additional adjustment was done for maternal and birth characteristics, smoking, and current socioeconomic status. We considered differences to be statistically significant if P values were ≤0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
Genotypes of the PPAR-{gamma}2 Pro12Ala polymorphism were available for 772 of 810 participants. Sixty-two of 772 participants had to be excluded from participating in the OGTT because they had preexisting diabetes. The test was not performed on another 35 participants due to the fact that they had not adhered to fasting instructions (n = 7) or due to difficulties in venepuncture (n = 28). Of 675 participants who underwent an OGTT and for whom a genotype was available, 280 (42%) had been exposed to famine in utero (Table 1). People with type 2 diabetes and people with impaired glucose tolerance were grouped together for analysis because of the relatively small number of people with type 2 diabetes based on the OGTT (31 cases).


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  		Table 1— Maternal and birth and adult characteristics according to timing of prenatal exposure to the Dutch famine

 
The prevalences of the Pro/Ala and the Ala/Ala genotypes were 25 and 2%, respectively (Table 1). The frequency of the Ala allele was 0.148. The observed genotype frequencies were in Hardy-Weinberg equilibrium for all study groups. The Ala carriers were grouped together for analysis because of the low frequency of the Ala/Ala genotype. Excluding participants with the Ala/Ala genotype from analyses did not change the results (data not shown). The proportions of Ala carriers did not significantly differ between the unexposed group (27%) and the groups exposed in late (29%), mid (28%)-, and early gestation (23%). Table 2 shows that there were no significant differences between participants carrying the Pro/Pro genotype and those carrying the Ala allele in terms of BMI, plasma glucose and insulin concentrations, the prevalence of impaired glucose tolerance and type 2 diabetes, AUC for insulin, insulin increment ratio, and insulin resistance.


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  		Table 2— Geometric means ± SD for BMI, plasma glucose and insulin concentrations, and prevalence of impaired glucose tolerance and type 2 diabetes according to PPAR-{gamma}2 gene polymorphism

 
Participants who were prenatally exposed to famine had 120-min glucose concentrations that were 0.4 mmol/l (95% CI 0.1–0.7) higher and 120-min insulin concentrations that were 27 pmol/l (0–57) higher than the glucose and insulin concentrations of unexposed participants. The prevalence of impaired glucose tolerance and type 2 diabetes, AUC for insulin, insulin increment ratio, and HOMA-IR did not differ between participants exposed and participants unexposed to famine in utero.

Table 3 shows that carriers of the Ala allele in the group exposed to famine during midgestation had a higher prevalence of impaired glucose tolerance and type 2 diabetes than carriers of the Pro/Pro genotype (odds ratio adjusted for sex and BMI 2.7 [95% CI 0.9–7.8]). Conversely, in the group unexposed to famine during gestation, carriers of the Ala allele had a lower prevalence of impaired glucose tolerance and type 2 diabetes compared with carriers of the Pro/Pro genotype (0.6 [0.3–1.2]). The interaction between famine exposure in midgestation and carrying the Ala allele on the prevalence of impaired glucose tolerance and type 2 diabetes was statistically significant (P = 0.03, Fig. 1). Inclusion of the 62 participants with known type 2 diabetes who were excluded from the OGTT yielded the same results (P = 0.02 for interaction, data not shown).


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  		Table 3— Prevalence of impaired glucose tolerance and type 2 diabetes and geometric means for insulin-associated variables according to timing of prenatal exposure to the Dutch famine and Pro12Ala polymorphism

 

Figure 1
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  		Figure 1— Prevalence of impaired glucose tolerance and type 2 diabetes (±SE) for participants carrying either the Pro/Pro genotype or the Ala allele according to timing of prenatal exposure to the Dutch famine. *Indicates a statistically significant interaction between genotype and famine exposure during midgestation.

 
Carriers of the Ala allele exposed in midgestation had a lower AUC for insulin (–54 pmol/l [95% CI –117 to –2]) and a lower insulin increment ratio (–22 [–42 to 7]) than midexposed participants with the Pro/Pro genotype. Carriers of the Ala allele unexposed to famine, on the other hand, had a higher AUC for insulin (12 pmol/l [–15 to 44]) and a higher insulin increment ratio (14 [–3 to 35]) than unexposed participants with the Pro/Pro genotype. The interactions between famine exposure in midgestation and carriership of the Ala allele were both significant on AUC for insulin and insulin increment ratio (P = 0.03 and 0.05, respectively). The participants exposed to famine in midgestation who carried the Ala allele also had a lower HOMA-IR compared with carriers of the Pro/Pro genotype, but this interaction was not statistically significant. Additional adjustment for confounding variables other than sex and BMI (including maternal characteristics, birth weight, gestational age, current smoking, and current socioeconomic status) did not significantly alter the results. There were no significant interactions between the Pro12Ala polymorphism and birth weight in terms of plasma glucose and insulin concentrations, prevalence of impaired glucose tolerance and type 2 diabetes, AUC for insulin, insulin increment ratio, and insulin resistance.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
Our findings show that prenatal exposure to famine during midgestation interacts with the Pro12Ala polymorphism of the PPAR-{gamma}2 gene in influencing the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-{gamma}2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. The Ala allele was also associated with lower insulin concentrations but, again, only in participants who had been exposed to famine during midgestation.

Although this study is the first to demonstrate that genetic influences can be modified by prenatal nutrition, gene-nutrient interaction regarding the Pro12Ala polymorphism has been shown before. Women who carried the Ala allele and who were given a hypocaloric diet for 6 months had a greater increase in insulin sensitivity and fasting carbohydrate oxidation and a greater decrease in fasting lipid oxidation compared with women on the diet who carried the Pro/Pro genotype (21).

Our findings differ from the study of Eriksson et al. (13), who reported that the effects of low birth weight on raised fasting insulin concentrations and insulin resistance were confined to carriers of the Pro/Pro genotype. We did not find evidence that the effect of the Pro/Pro genotype on fasting insulin concentrations or insulin resistance is modified by famine exposure or size at birth. Rather, we found the highest prevalence of impaired glucose tolerance and type 2 diabetes in carriers of the Ala allele who were exposed to famine during midgestation. The fact that our results diverge from the results of the study of Eriksson et al. may lie in the difference between the use of size at birth and maternal undernutrition as markers of fetal environment. Size at birth is a summary measure of fetal growth and a result of a wide range of maternal, placental, and fetal factors, of which maternal nutrition is just one. It has been shown in animals as well as in humans that restricted maternal nutrition can produce permanent effects on adult health without affecting size at birth (22–24). Our inability to show associations with birth weight may have resulted from differences in population characteristics such as the older age and the surplus of women in the Helsinki cohort used in Eriksson et al.’s study and the interference of famine exposure in our cohort. Alternatively, the fact that, compared with Eriksson et al.’s study, in our study maternal nutrition may have had a relatively large contribution to birth weight compared with placental, fetal, and other maternal characteristics may have contributed to the discrepancy.

The combination of carrying the Ala allele and prenatal exposure to famine during midgestation did not only affect the prevalence of impaired glucose tolerance and type 2 diabetes but also resulted in lower insulin concentrations and a lower insulin increment ratio. These findings suggest that this group of people is insulin deficient. There is evidence that carrying the Ala allele leads to impaired insulin secretion of the pancreatic ß-cell (25). On the other hand, the Ala allele exhibits a reduced ability for transcriptional activity of PPAR-{gamma}, leading to improved insulin sensitivity because lower levels of adipose tissue mass are accumulated (11). Fetal undernutrition has been shown to decrease the number and function of ß-cells in rats as well as in humans (26,27). In humans, ß-cells are found at ~10–11 weeks of gestation and develop for the most part during midgestation (28). It is possible that prenatal famine exposure in midgestation impairs the development of the ß-cells, leading to impaired insulin secretion. Carrying the Ala allele may further reduce insulin secretion. We speculate that the combination of impaired ß-cell development and Ala allele carriership produces a degree of insulin deficiency that can no longer be compensated for by improved insulin sensitivity related to carrying the Ala allele.

The interaction between effects of the Pro12Ala polymorphism and prenatal exposure to famine seemed to involve exposure to famine during midgestation only. Although participants who were exposed to famine during late and early gestation also had higher 120-min glucose concentrations predisposing to type 2 diabetes, we did not find interactions with the Pro12Ala polymorphism for these groups. This might indicate that depending on trimester of exposure to famine, different mechanisms relating to impaired glucose tolerance may be affected. As mentioned above, the Pro12Ala polymorphism may have interacted with famine during midgestation because midgestation is an important period for the development of the ß-cells (28).

A limitation of the study is the relatively small sample size. In our cohort, only 29 participants who carried the Ala allele had been exposed to famine during midgestation. Our findings should therefore be confirmed by future studies. Another limitation is that our finding is a post hoc finding. We aimed to look for an interaction between prenatal exposure to famine and the Pro12Ala polymorphism on glucose/insulin metabolism but did not have clear hypotheses about the direction of the interaction and investigated several glucose/insulin-associated variables.

In conclusion, our study provides the first evidence that genetic influences can be modified by nutrition of the human fetus in utero. The effects of the PPAR-{gamma}2 Pro12Ala polymorphism on the glucose/insulin metabolism are modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic ß-cell maldevelopment and carrier type of the Ala allele in the PPAR-{gamma}2 gene.


   Acknowledgments
 
Funded by the Netherlands Heart Foundation (grant nos. 2001B087 and 2003B165), the Academic Medical Centre (Amsterdam, the Netherlands), and the Medical Research Council (U.K.).

We thank the participants for their willing cooperation.


   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 October 18, 2005. Accepted for publication February 8, 2006.


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 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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