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CSS-Mendel Institute (S.P., V.T.), 00198 Rome, Italy; Research Laboratory of Diabetes and Endocrine Diseases (S.P., V.T.), CSS Scientific Institute, 71013 San Giovanni Rotondo, Italy; and Department of Clinical Sciences (V.T.), University of Rome "La Sapienza," 00161 Rome, Italy
Address all correspondence and requests for reprints to: Vincenzo Trischitta, M.D., Istituto CSS-Mendel, Viale Regina Margherita 261, 00198 Rome, Italy. E-mail: vincenzo.trischitta{at}uniroma1.it.
The worldwide increasing prevalence of insulin resistance, obesity, and type 2 diabetes is alarming. These metabolic diseases are mainly due to an abnormal lifestyle, which may be particularly deleterious for a subgroup of genetically predisposed individuals. Unraveling the molecular causes of this predisposition is an essential prerequisite to set up predicting and preventive strategies, which are urgently needed in consideration of the recent emergence of insulin-resistance-related abnormalities also in children (1). Among several genes described as modulators of susceptibility to insulin resistance is ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1, also known as PC-1). ENPP1 encodes for a transmembrane glycoprotein, which interacts with the insulin receptor, inhibits subsequent insulin signaling (2), and, when overexpressed in peripheral insulin target tissues, is associated with human insulin resistance (3, 4, 5). Several (6, 7, 8, 9), although not all (10), studies have reported that a missense ENPP1 variation, K121Q (where a lysine, K, is substituted by a glutamine, Q, at codon 121), predisposes to insulin resistance and related abnormalities. The molecular mechanism responsible for the role of the Q121 variant resides in a "gain of function" of the ENPP1 protein inhibitory activity on the insulin receptor (11). Studies in transfected cells have shown that, compared to that carrying the more frequent K121, the ENPP1 carrying the Q121 variant is a stronger inhibitor of insulin receptor function, and this effect occurs through an increased physical interaction between the two proteins at the cell membrane (11). According to the deleterious role of the Q121 variant on insulin resistance, three recent meta-analyses performed on published case-control studies (8, 9, 10) have shown that, although results are not homogeneous across all samples, individuals carrying this variant have an approximately 20% increased risk of type 2 diabetes.
In this issue of this journal, Bottcher et al. (12) report on the association of the ENPP1 Q121 variant (either alone or in haplotype combination with two functionally uncharacterized variants located in the regulatory regions) with increased risk of obesity in children from Germany. Interestingly, the same haplotype was associated with hyperglycemia; whereas, in contrast, haplotypes carrying the K121 variant were associated with improvement of both insulin sensitivity and glucose homeostasis. The latter associations were independent of body mass index (BMI), thus suggesting pleiotropic (i.e. multiple and diverse) effects of this gene on several abnormalities clustering together in insulin-resistant individuals. Data shown by Bottcher et al. (12) strongly resemble those recently published by Meyre et al. (13), who reported a deleterious effect of the Q121 variant on the risk of both morbid obesity and hyperglycemia in large samples of French children and adults. Similarly, an increased BMI has been reported in British adults (14) homozygous for the Q121 variant. At variance, the Q121 variant has been associated with reduced BMI in African-Americans (15) and in people of European descent from both the United States (15, 16) and Italy (16). So, whereas the effect of ENPP1 variants in the modulation of BMI seems to be reproducible in children (12, 13), this does not seem to be the case in adults (13, 14, 15, 16). In the study of complex disorders, discordant results in genotype-phenotype association are not uncommon. Such a frustrating event does not necessarily imply that some, or all, findings represent false results (either positive and/or negative); rather, it might depend on differences in genetic and/or environmental background as well as in recruitment procedures of the studied populations. In this context, it is worth noting that subject recruitment in most studies reporting on the association of the Q121 variant with BMI changes did not have normoglycemic status as a recruitment criterion (12, 13, 14, 15), thus making it highly possible that obese individuals with impaired glucose tolerance or frank type 2 diabetes were included in the samples analyzed. The associations with high BMI levels observed in some of these studies (12, 13, 14) might have been, therefore, confounded by the tendency of the Q121 variant to be more prevalent in hyperglycemic individuals (8, 9, 10). Given the major role of obesity in deteriorating glucose homeostasis, the different effect of the Q121 variant on BMI in different samples may be, at least partly, responsible for the nonhomogeneous results so far reported on the risk of type 2 diabetes across different studies (8, 9, 10). This possibility is reinforced by the consistently reported observation indicating that high BMI exacerbates (8), or in some cases is a prerequisite (9, 17) for, the deleterious role of the Q121 variant on insulin resistance-related phenotypes (8, 9) and type 2 diabetes (17). The mechanism through which ENPP1 modulates BMI is unknown. It may be hypothesized that the reported association with higher BMI (12, 13, 14) is due to the fact that individuals carrying the ENPP1 Q121 variant develop insulin resistance in the brain, where insulin has potent anorectic actions (18), and this, in turn, increases appetite and eventually body weight. Conversely, the reduced BMI in Q121 carriers (15, 16) might be due to the deleterious effect of this variant on peripheral insulin resistance, which, itself, has been reported in a prospective study to be a predictor of lower BMI (19), a possible consequence of impaired insulin-mediated lipid storage in adipocytes. Therefore, according to the latter hypothesis, it could be hypothesized that, in some cases, genetic determinants improving insulin sensitivity have an opposite deleterious role on body weight and vice versa. In line with this hypothesis, recent studies have shown that variants of both the PPAR
2 (20) and the adiponectin (21) genes predicting higher insulin sensitivity are, in fact, associated with increased BMI. Compatible with this scenario is the observation that the net effect of several candidate genes able to modulate insulin signaling, including ENPP1, on insulin resistance and/or the risk of type 2 diabetes is barely detectable in lean individuals, although it becomes appreciable among overweight/obese people (8, 9, 17, 22, 23), in whom the deleterious effect of insulin resistance on glucose disposal is not more counterbalanced by its positive effect on BMI.
The potential role of the ENPP1 gene in the modulation of body weight and the risk of obesity deserves further, possibly prospective, large-scale studies specifically designed to dissect the gene effect on BMI with that on insulin resistance-related phenotypes and type 2 diabetes and to provide sufficient power to investigate gene-gene and gene-environment interactions. The hypothesis that genes with pleiotropic effects might simultaneously induce insulin resistance, obesity, and type 2 diabetes with cardiovascular complications is not novel, but examples have been scarce so far. The paper published in this issue by Bottcher et al. (12), as well as several other previous reports on the ENPP1 gene (3, 4, 5, 6, 7, 8, 10, 13, 14, 15, 16, 17) clearly indicate that such a scenario is, in fact, a plausible one. The question is: does this new genetic information have any practical health implications? Not yet, and not very soon, but probably yes in the future. As a matter of fact, the great improvement of knowledge obtained in the last few years encourages us to be optimistic. Future research aimed at understanding the mechanisms regulating ENPP1 expression and function promises to yield important information for translational human investigation. This will provide a new target, in combination with other genetic and nongenetic information, for identification of individuals prone to insulin resistance, obesity, type 2 diabetes, and related cardiovascular diseases and possible novel common avenues for treatment of these devastating diseases.
Footnotes
The authors are supported by Telethon Grant E1239 (to V.T.) and by the Italian Ministry of Health Grants RF 2005 and RC 2006 (to S.P.).
Abbreviations: BMI, Body mass index; ENPP1; ectonucleotide pyrophosphatase phosphodiesterase.
Received October 10, 2006.
Accepted October 11, 2006.
References
gene expression, is associated with a reduction of both whole body insulin sensitivity and insulin receptor tyrosine-kinase activity. Diabetologia 40:282–289[CrossRef][Medline]2 gene (Pro12Ala) affects metabolic responses to weight loss and subsequent weight regain. Diabetes 9:2172–2176This article has been cited by other articles:
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  J. B. McAteer, S. Prudente, S. Bacci, H. N. Lyon, J. N. Hirschhorn, V. Trischitta, J. C. Florez, and for the ENPP1 Consortium The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations: Evidence From an Updated Meta-Analysis in 42,042 Subjects Diabetes, April 1, 2008; 57(4): 1125 - 1130. [Abstract] [Full Text] [PDF]
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