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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2044-2047
Copyright © 2004 by The Endocrine Society

The Association of the K121Q Polymorphism of the Plasma Cell Glycoprotein-1 Gene with Type 2 Diabetes and Hypertension Depends on Size at Birth

Agata Kubaszek, Anu Markkanen, Johan G. Eriksson, Tom Forsen, Clive Osmond, David J. P. Barker and Markku Laakso

Department of Medicine (A.K., A.M., M.L.), University of Kuopio, 70210 Kuopio, Finland; National Public Health Institute (J.G.E.), Department of Epidemiology and Health Promotion, 00300 Helsinki, Finland; Department of Public Health (T.F.), University of Helsinki, 00300 Helsinki, Finland; and MRC Environmental Epidemiology Unit (C.O., D.J.P.B.), University of Southampton, Southampton General Hospital, 5016 6YD Southampton, United Kingdom

Address all correspondence and requests for reprints to: Markku Laakso, Professor and Chair, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail: markku.laakso{at}kuh.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Birth weight and length serve as indicators of the intrauterine environment, and a small body size at birth is a predictor of type 2 diabetes and hypertension. Insulin is one of the growth factors regulating fetal growth. The plasma cell glycoprotein 1 (PC-1) gene impairs insulin signaling at the insulin receptor level. Therefore, we investigated whether the K121Q polymorphism of the PC-1 gene association with insulin sensitivity, insulin levels, and the prevalence of diabetes and hypertension in adult life depends on size at birth in 489 subjects born in Helsinki during 1924–1933. We found that the effect of the PC-1 gene polymorphism on insulin levels and insulin sensitivity, measured as the homeostasis model assessment for insulin resistance, depended on birth length because fasting insulin levels and insulin resistance were highest in subjects carrying the 121Q allele who were small at birth (P for interaction = 0.04 and 0.05). Additionally, in those whose birth length was up to 49 cm, the K121Q polymorphism of the PC-1 gene was associated with a 2-fold higher incidence of type 2 diabetes. Moreover, subjects who were short at birth and who had the 121Q allele had the highest incidence (31.6%) of type 2 diabetes together with hypertension. We conclude that the interaction between the K121Q polymorphism of the PC-1 gene and birth length affects insulin sensitivity and increases susceptibility to type 2 diabetes and hypertension in adulthood.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE FETAL ORIGIN hypothesis proposes that adaptations to malnutrition during fetal development permanently change metabolism and predispose humans to metabolic and cardiovascular diseases in adult life (1). Because fetal adaptations include reduced growth, small size at birth is a marker of intrauterine environment. Low birth weight, thinness at birth, and short length have all been found to be associated with high rates of diabetes and hypertension (2, 3, 4, 5). Because insulin is one of the growth factors regulating fetal growth (6), adaptations to undernutrition can involve alteration in insulin action; as a result, insulin resistance can be initiated during intrauterine growth (7). Furthermore, gene expression can be permanently changed during fetal development, and therefore genes associated with insulin resistance could have different effects depending on size at birth. Indeed, the effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-{gamma}2 gene on insulin sensitivity is modified by size at birth (8).

Plasma cell glycoprotein 1 (PC-1, ENPP1) is a promising candidate gene for type 2 diabetes because it inhibits autophosphorylation of insulin receptor (IR) (9) and impairs insulin signaling downstream of IR (10). PC-1 has been shown to interact directly with IR (9), and the 121Q variant (Gln121) in exon 4 has a greater inhibitory action on IR than does the 121K allele variant (Lys121) (11). Additionally, PC-1 has enzymatic activity, and it plays a role in the regulation of signaling by nucleotides (12). Moreover, the K121Q genotype has been shown to be associated with insulin resistance (13) and high glucose and insulin levels (14). No data are available on the association of the PC-1 gene polymorphism with intrauterine growth. Therefore, the aim of our study was to investigate whether the impact of the K121Q polymorphism of the PC-1 gene on insulin sensitivity, and the occurrence of diabetes and hypertension, depends on size at birth.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The original epidemiological study of 7086 men and women, born as singletons at the Helsinki University Hospital during 1924–1933, has been previously described (5). A total of 647 subjects from the original cohort were invited to attend a clinical study after an overnight fast (15). DNA samples were available for 489 subjects [180 men and 309 women; mean age 70 ± 3 yr; mean body mass index (BMI) 26.5 ± 4.0 kg/m2] of the 500 participants who came to the clinic. Altogether, 94 subjects were either taking medication for type 2 diabetes or were diagnosed at the clinic, 209 were taking medication for hypertension, and 56 of them were taking medication for both.

An oral glucose tolerance test was performed with glucose and insulin measurements at baseline (0 min) and at 120 min after a 75-g glucose load. Plasma glucose was measured by a hexokinase method and insulin, proinsulin, and 32–33 split proinsulin were measured by two-site immunometric assay (16). The homeostasis model assessment for insulin resistance (HOMA-IR) was calculated using the following formula: fasting plasma glucose (mmol/liter) x fasting serum insulin (mU/liter)/22.5 (17). Serum lipid and lipoprotein concentrations were determined using standard methods.

Genotyping

Exon 4 of the PC-1 gene was amplified with PCR with a forward primer 5'-CTGTGTTCACTTTGGACATGTTG-3' and a reverse primer 5'-GACGTTGGAAGATACCAGGTTG-3' (13). The reaction was performed in a total volume of 20 µl containing 50 ng of genomic DNA, primers (0.5 µmol/µl), 0.375 U DNA polymerase (DynaZyme, Finnzymes, Espoo, Finland), and 100 µmol/liter deoxynucleotide triphosphate. PCR conditions were denaturation at 94 C for 4 min followed by 35 cycles of denaturation at 94 C for 40 sec, annealing at 62 C for 40 sec, and extension at 72 C for 40 sec with a final extension at 72 C for 4 min. The K121Q polymorphism was screened by the Eco47I restriction enzyme followed by polyacrylamide gel electrophoresis of the digested PCR products.

Statistical analysis

Data were analyzed with the SPSS/Windows program (version 10.0, SPSS Inc., Chicago, IL). Results are given as means ± SD unless differently indicated. Multiple linear regression was applied to compare the effect of the polymorphism on continuous variables after adjustment for age, sex, and current BMI. Plasma glucose, insulin, proinsulin, high-density lipoprotein cholesterol, and triglyceride values were log transformed before statistical analyses to achieve a normal distribution. Comparisons were made within length categories and within genotypes.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The frequency of the 121Q allele was 12.9% and did not differ from previous reports. The frequency distribution of the genotypes were in Hardy-Weinberg equilibrium. For all statistical analyses, the subjects with the Q121Q genotype (n = 9) were combined with the subjects with the K121Q genotype because of the small number of these subjects.

Subjects carrying the 121Q allele had lower ponderal index compared with subjects who had the K121K genotype, but there were no differences in birth weight and length (Table 1Go). BMI, systolic and diastolic blood pressures, and lipids and lipoproteins did not differ between subjects with the K121K genotype and those with the 121Q allele. Fasting glucose, 2-h glucose, insulin, and HOMA-IR did not differ between subjects with the K121K genotype and with the 121Q allele in the whole study group. The effect of the PC-1 gene polymorphism on insulin sensitivity, measured as fasting insulin levels or HOMA-IR, depended on birth length when subjects were divided into five length categories (P for interaction = 0.04 and 0.05, Table 2Go). Fasting insulin levels and HOMA-IR were highest in subjects carrying the 121Q allele who were small at birth. In subjects with normal size, there was no effect of the 121Q allele on insulin sensitivity.


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  		TABLE 1. Clinical and biochemical characteristics according to the K121Q polymorphism of the PC-1 gene

 

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  		TABLE 2. Mean fasting insulin concentration and HOMA-IR index according to the K121Q polymorphism of the PC-1 gene and birth length

 
Next, we investigated the simultaneous effects of the PC-1 gene polymorphism and birth length on the occurrence of type 2 diabetes and hypertension because both of these diseases cluster in subjects with the insulin resistance syndrome. To this aim, we divided our study group into two length categories, up to 49 cm and more than 49 cm. When we compared subjects with the 121Q allele with subjects having the K121K genotype, there was a 2-fold higher prevalence of type 2 diabetes in subjects up to 49 cm at birth (Fig. 1Go; 36.8 vs. 16.5%; P = 0.01). Subjects who were short at birth and who had the 121Q allele had the highest prevalence of type 2 diabetes and also the highest prevalence (31.6%) of type 2 diabetes combined with hypertension (P for interaction of genotype and birth length = 0.03). In subjects whose birth length was more than 49 cm, the 121Q allele was not associated with type 2 diabetes or hypertension. Subjects with the 121Q allele who were up to 49 cm at birth and who had diabetes and hypertension were most insulin resistant (HOMA-IR = 32.3 ± 7.7 mU x mmol/liter2; Fig. 2Go).



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  		FIG. 1. Prevalence (%) of type 2 diabetes, hypertension, and both conditions according to length at birth and the PC-1 gene polymorphism.

 


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  		FIG. 2. HOMA-IR index (mean ± SEM) in subjects with type 2 diabetes and concomitant hypertension according to length at birth and the PC-1 gene polymorphism.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The novel finding of our study was that the effect of the K121Q polymorphism of the PC-1 gene on insulin sensitivity and the prevalence of diabetes and hypertension depends on size at birth. Subjects who were short at birth and who had the 121Q allele were most insulin-resistant and had the highest prevalence of type 2 diabetes and hypertension. Additionally, subjects with the 121Q allele also had lower ponderal index scores, suggesting that inhibitory action of PC-1 on insulin signaling may affect intrauterine growth.

In our study, size at birth was related to markers of insulin resistance, such as 2-h plasma insulin level, fasting proinsulin, 32–33 split proinsulin, and HOMA-IR. We found an association of the 121Q allele with low ponderal index score, although there was no difference in birth length. This may suggest that PC-1 regulates intrauterine weight gain, as was previously shown for IGF-1 and glucokinase genes (18, 19). Subjects with the 121Q allele of the PC-1 gene can have altered response to insulin during fetal growth, resulting in decreased fetal weight gain. Insulin is an important growth determinant (6, 20, 21), especially in the third trimester, when fetal weight increases substantially. Thus, insulin sensitivity can be crucial for normal growth because subjects carrying risk genotypes, including the 121Q allele of the PC-1 gene, may be poorly adapted to undernutrition. PC-1 may affect insulin action also at the postreceptor site, but no influence of PC-1 on DNA synthesis has been found (10). Birth length may be also determined by other genes, which regulate fetal response to undernutrition and oxygen supply. Therefore, the interaction of the PC-1 gene with birth length may reflect interaction with environment or with other genes.

Subjects who had the 121Q allele of the PC-1 gene and who were short at birth were both hyperinsulinemic and insulin-resistant. They also had the highest prevalence of diabetes combined with hypertension. The prevalence of hypertension in patients with type 2 diabetes is around 60%, which is about 1.5–2 times higher than in the general population (22, 23). The causes for elevated blood pressure in patients with type 2 diabetes are unknown, but elevated blood pressure is often associated with hyperinsulinemia and insulin resistance (24, 25).

We found that the association of the 121Q allele with type 2 diabetes and hypertension was restricted to subjects who had impaired fetal growth, suggesting an interaction with environmental (for example, nutrition and oxygen supply) and genetic factors affecting intrauterine growth. The association of the PC-1 gene polymorphism with hypertension has not been previously reported. One possible mechanism explaining this association is insulin resistance. Indeed, the most insulin-resistant subjects in our study were subjects with the 121Q allele who were short at birth. These subjects also developed diabetes and hypertension (Fig. 2Go). Moreover, in this group, the prevalence of hypertension in subjects with diabetes was higher than in patients with diabetes in general. In hypertensive patients, insulin resistance is found mainly in skeletal muscle (26) where the PC-1 gene is expressed. However, it is also possible that the enzymatic role of PC-1 in regulating signaling by nucleotides through purinergic receptors may be important because they play a role in the development of hypertension (27, 28).

We conclude that there is an interaction between the K121Q polymorphism of the PC-1 gene and intrauterine environment. This interaction affects insulin sensitivity and increases susceptibility to type 2 diabetes and its association with hypertension.


   Footnotes
 
This work was supported by the British Heart Foundation, Finska Lakaresallskapet, the Academy of Finland, and the European Union (QLG1-CT-1999).

Abbreviations: BMI, Body mass index; HOMA-IR, homeostasis model assessment for insulin resistance; IR, insulin receptor; PC-1, plasma cell glycoprotein 1.

Received August 4, 2003.

Accepted January 23, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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