Human Molecular Genetics, 2000, Vol. 9, No. 17 2517-2521
© 2000 Oxford University Press
Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes
1Department of Oncology and Neurosciences, Section of Molecular Pathology, 2Department of Biomedical Sciences, Section of Epidemiology and Public Health and 3Department of Medicine and Aging Sciences, University ‘Gabriele D’Annunzio’, 66013 Chieti, Italy, 4Pierangeli Clinic, 65125 Pescara, Italy and 5Center for the Study of Diabetes, 66100 Chieti, Italy
Received 21 April 2000; Revised and Accepted 8 July 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The insulin receptor substrate-2 (IRS-2) is a major insulin signalling molecule. IRS-2 inactivation in mice induces a form of diabetes characterized by peripheral insulin resistance and reduced beta cell mass. We tested the hypothesis that a common non-conservative amino acid substitution of IRS-2 (G1057D) might interact with overweight in the pathogenesis of type 2 diabetes. The variant was genotyped in 193 Italian patients with type 2 diabetes and 206 control subjects. In the absence of overweight, the risk of type 2 diabetes decreased according to the dosage of the D1057 allele (odds ratio for GD genotype 0.46 [95% CI 0.25–0.86]; DD genotype 0.18 [0.04–0.68]; P for trend = 0.0012). Conversely, the interaction between overweight and genotype increased the risk of type 2 diabetes according to the dosage of the D1057 allele (odds ratio for GD genotype 2.50 [1.11–5.65]; DD genotype 5.74 [1.11–29.78]; P for trend = 0.0047). Among controls, fasting C-peptide levels, after adjustment for plasma glucose, were inversely related to the dosage of the D1057 allele (P = 0.020). This finding suggested that carriers of the D1057 allele may have higher insulin sensitivity and supported the protective effect of this allele. Conversely, among overweight patients there was a parallel increase in fasting plasma glucose (P for trend = 0.037) and fasting C-peptide according to the dosage of the D1057 allele, suggesting that higher insulin resistance and relative beta cell failure contributed to the increased risk of type 2 diabetes in overweight carriers of this allele. These data provide evidence for a strong association between type 2 diabetes and the G1057D common genetic variant of IRS-2, which appears to be protective against type 2 diabetes in a codominant fashion. Overweight appears to modify the effect of this polymorphism toward a higher risk of type 2 diabetes. Carriers of this polymorphism may represent an elective target for prevention of type 2 diabetes through preventing or treating excessive weight.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Type 2 diabetes is the most common metabolic disorder and results from the interaction between genetic and environmental factors (1). The remarkable clustering of type 2 diabetes in families and the high concordance rate between monozygotic twins support a strong genetic contribution to its etiology (1–3). Nonetheless, the identification of genetic variants responsible for the most common forms of the disease is still elusive and only defective alleles responsible for rare monogenic forms of type 2 diabetes have been identified (4,5). With the exception of these rare forms, the disease appears to be polygenic and its development would be due to the simultaneous inheritance of genetic variants at multiple loci interacting with several environmental factors, each having a small effect (1–6).
The two key pathophysiological defects of type 2 diabetes are impaired insulin signalling and failure of beta cells to compensate for the increased insulin demand (1). Accordingly, genetic variants of molecules involved in insulin signalling and beta cell function may play a role in the pathogenesis of the disease. In particular, the insulin receptor substrate-2 (IRS-2), one of the major substrates of the insulin receptor, may be an attractive candidate in the pathogenesis of type 2 diabetes, given its crucial role in insulin signalling (7) and in beta cell development and/or survival (8,9). In support of this hypothesis, inactivation of IRS-2 in mice induces a form of diabetes characterized by a marked peripheral insulin resistance and by a dramatic beta cell mass reduction (8,9).
A recent study conducted in a Danish population identified a frequent IRS-2 amino acid substitution (G1057D), but no association of this polymorphism with type 2 diabetes was noted (10). However, a 25% reduction in fasting serum insulin levels and an up to 34% reduction in serum insulin after oral glucose tolerance test was observed in glucose-tolerant homozygous carriers of the D1057 variant from a middle aged Danish population (11). The reduction in insulin levels remained significant after adjustment for fasting plasma glucose levels (11), suggesting that the variant may be associated with higher insulin sensitivity. We studied patients with type 2 diabetes and control subjects from the Italian population to test the association between the G1057D polymorphism and type 2 diabetes. Moreover, we tested the possibility that this frequent IRS-2 genetic variant might interact with overweight in the pathogenesis of type 2 diabetes.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In agreement with a previous study conducted in the Danish population, we found that the overall prevalence of the D1057 allele was virtually identical in patients with type 2 diabetes (28.5%) and control subjects (32.5%). However, after stratifying for different categories of body mass index (BMI), we found that in the BMI category <27 kg/m2, DD and to a lesser extent, GD genotypes showed a lower prevalence in patients than in control subjects (Table 1). Conversely, in the BMI category
27 kg/m2, DD, and to a lesser extent, GD genotypes showed a higher prevalence in patients compared with control subjects (Table 1). These findings suggested that DD and GD genotypes might have a negative association with type 2 diabetes in individuals with BMI < 27 kg/m2 and conversely, a positive association with the disease in the presence of overweight. These associations were confirmed and strengthened by logistic regression analysis designed to test the interaction between genotype and overweight (Table 2). In fact, in the unadjusted logistic model, DD and GD genotypes appeared protective against the development of type 2 diabetes in the absence of overweight, whereas the combination of overweight with these genotypes associated with an increased risk of type 2 diabetes (Table 2). Adjustment of the logistic model for potential confounders such as age, gender and BMI did not materially modify the results of the analysis (Table 2). These results indicated that overweight acted as a modifier of the effect of GD and DD genotypes on the risk of type 2 diabetes. To assess the robustness of these findings, we tested the consistency of the interaction (genotype–overweight) across a range of BMI. Moving the cut-point for BMI in 1 unit increments, from 25 to 30 kg/m2, confirmed that the association of DD and GD genotypes with type 2 diabetes was reversed at higher compared to lower BMI (data not shown). Incidentally, the GG genotype appeared to be over-represented in the overweight group in all subjects (P = 0.037) and particularly in controls (P = 0.019), whereas the DD and GD genotypes appeared under-represented. These findings suggest that the D1057 allele may confer resistance to obesity among control subjects, a hypothesis which is compatible with the effect of genotype upon BMI.
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Biochemical findings (Table 3) supported the above associations between the G1057D variant of IRS-2 and type 2 diabetes. Among controls, fasting C-peptide levels showed a significant trend of reduction according to the dosage of the D allele, confirmed in multiple regression analysis to adjust for age, gender, BMI and fasting plasma glucose levels (Table 3). This indicated that, among controls, fasting euglycemia was achieved at lower levels of fasting C-peptide in GD and DD carriers, suggesting that carriers of these genotypes may have higher insulin sensitivity than carriers of the GG genotype.
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The trend of fasting C-peptide in type 2 diabetes patients was different from that of control subjects. In patients with BMI < 27 kg/m2 there was no significant difference in fasting C-peptide among the GG, GD and DD genotypes (Table 3). Conversely, among patients with BMI
27 kg/m2 the levels of fasting C-peptide increased according to the dosage of the D allele, even though this trend did not reach statistical significance. In addition, among patients with BMI 27 kg/m2, the levels of fasting blood glucose increased significantly according to the dosage of the D allele (Table 3). This trend was confirmed using multiple regression analysis to adjust for age, gender, BMI and duration of diabetes. Therefore, in overweight patients carrying the D allele both fasting C-peptide and fasting blood glucose were higher when compared with GG carriers. The concomitant presence of higher fasting C-peptide and higher fasting blood glucose suggested that overweight patients carrying the D allele had a greater insulin resistance combined with a relative failure of beta cells to compensate for the increased insulin demand. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Interactions of genetic and environmental factors may complicate the task of recognizing associations between polymorphisms and type 2 diabetes (1). In fact, an association between a given polymorphism and diabetes might be missed when analyzing only the overall prevalence of the polymorphism, whereas the association may be revealed when taking into account not only confounders, but also factors acting as effect modifiers, such as overweight in our study. Accordingly, both a previous (10) and the present study found a lack of overall association between the D1057 IRS-2 variant and type 2 diabetes, but the role of the D1057 variant in the development of type 2 diabetes became evident in our study when taking into account its interaction with the overweight factor.
Our findings suggest that the D1057 variant of IRS-2 is protective against type 2 diabetes, but favours the development of the disease in overweight individuals. Therefore, obesity appears to act as an effect modifier, reverting the risk of type 2 diabetes in D1057 carriers. Intriguingly, an interaction between obesity and a genetic variant of another insulin receptor substrate has already been reported (12,13).
The protective effect of the D1057 variant against type 2 diabetes was supported by our biochemical findings. In fact, in control carriers of the GD and DD genotypes, fasting euglycemia was achieved at lower levels of fasting C-peptide, suggesting improved insulin signalling through the D1057 IRS-2 variant. In agreement with our findings, biochemical data obtained in middle-aged glucose tolerant subjects from the Danish population are suggestive of a higher insulin sensitivity associated with the D1057 IRS-2 variant (11). The association of the D allele with higher insulin sensitivity may partly explain the finding that GD and DD genotypes associate with a lower risk of type 2 diabetes (Table 2). Data from animal models further support this finding. Inactivation of IRS-2 in mice results both in peripheral insulin resistance and in reduced development and/or survival of beta cells (8,9). As a consequence, failure of beta cells to compensate for the increased insulin demand leads to the development of diabetes (8,9). Based on these models, it is conceivable that an improvement of IRS-2 mediated signal transduction may generate the opposite effect. Therefore, the D1057 variant, that appears to improve IRS-2 mediated signal transduction, may result in a protective effect against type 2 diabetes by increasing peripheral insulin sensitivity and by promoting development and/or survival of beta cells. The molecular mechanism by which the non-conservative D1057 variant of IRS-2 may improve insulin action is not clear. The D1057 variant introduces a charged amino acid (D) in place of a neutral one (G) in a domain of the IRS-2 molecule located in the proximity of two putative tyrosine phosphorylation sites (at positions 1042 and 1072) unique to IRS-2, which may mediate the interaction with downstream signalling molecules. A non-conservative amino acid substitution in this domain may result in a subtle alteration of the affinity between IRS-2 and downstream signalling elements. Intriguingly, mice carrying the disruption of the protein tyrosine phosphatase-1B (PTP-1B) show increased insulin sensitivity and obesity resistance (14), which appear to be features associated also with the D1057 variant of IRS-2. It has been reported recently that PTP-1B dephosphorylates IRS-1 acting as a negative regulator of its function (15) and it is possible that such negative regulation also takes place with IRS-2. Therefore, the phenotype associated with the D1057 amino acid substitution might derive from a defective interaction of the IRS-2 variant with a negative regulator molecule functionally related to PTP-1B. Alternately, the amino acid substitution could improve the interaction of IRS-2 with a downstream positive regulator molecule such as SH2-containing protein tyrosine phosphatase-2 (SHP-2). In line with this hypothesis, the D1057 variant is located in a domain of IRS-2 implicated in the interaction with SHP-2 (7).
An important issue raised by our findings is the switch of the effect of the D1057 variant toward a higher risk of type 2 diabetes when this variant interacts with overweight. This reversal of risk was also supported by our biochemical data. In fact, overweight patients carrying the GD and DD genotypes showed both higher fasting glucose and fasting C-peptide levels compared to GG carriers. These findings suggest the concomitant presence of greater insulin resistance and of relative beta cell failure in overweight patients carrying the D allele. Conversely, among overweight controls, GD and DD carriers showed slightly lower levels of C-peptide as compared to GG carriers, suggesting, if anything, lower insulin resistance. The contrasting biochemical trends observed in overweight patients compared to overweight controls carrying the GD and DD genotypes suggest that it is not overweight per se that modifies the effect of the D1057 allele on IRS-2 mediated insulin signalling. An intriguing possibility, that requires further investigation, is that other factor(s) leading to overweight might switch the impact of GD and DD genotypes from an improved to a defective IRS-2 function. In fact, the increased insulin resistance and the relative failure of beta cell compensation, observed in overweight patients carrying the GD and DD genotypes, could result from impaired IRS-2 signalling (8,9). This hypothesis would account for the increased risk of type 2 diabetes in overweight GD or DD carriers. Whatever causes the observed interaction between overweight and genotype, the consistent increase in the risk of type 2 diabetes among overweight D1057 allele carriers suggests that this allele may serve as a genetic marker to identify individuals more suitable to prevention of type 2 diabetes through weight control.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Patients
The study was designed as a case-control. A total of 193 patients with type 2 diabetes (male:female = 107:86) and 206 controls (male:female = 112:94) were enrolled. The age range for cases and controls was restricted to
35 and 
80 years old. Patients with type 2 diabetes were recruited at the diabetes outpatient clinic of the Chieti Health District. All unrelated consecutive patients with type 2 diabetes undergoing routine examinations and willing to participate in the study were eligible for the study. Diabetes was diagnosed according to World Health Organization Criteria (16). Controls were recruited at outpatient clinics within the same geographical area of the cases. All unrelated consecutive subjects undergoing routine examinations and willing to participate were eligible for the study. Among subjects eligible as controls, only those who had normal fasting plasma glucose according to the revised American Diabetes Association criteria (17) and reported no personal and no family history of type 2 diabetes were enrolled in the study. Cases had a mean age of 65.8 years (SD ± 8.7) at enrolment and a mean age of 51.2 years (SD ± 4.5) at diagnosis of type 2 diabetes. Controls had a mean age of 60.5 years (SD ± 11.9) at enrolment. Written informed consent from participants to the study was obtained and the study was approved by the ethical committee of the University of Chieti ‘Gabriele D’Annunzio’. Fasting plasma glucose was measured in the laboratory using the glucose oxidase method. C-peptide was measured using the C-PEP-CT2 radioimmunoassay kit (CIS Bio International, Gif-Sur-Yvette, France), characterized by negligible cross reaction (0.5%) with proinsulin.
DNA analysis
DNA was extracted from blood leucocytes using standard methods. Genotyping of the G1057D polymorphism was conducted using PCR followed by HaeII restriction enzyme digestion. Sequences of primers for PCR amplification are available from the authors upon request and were designed using the IRS-2 sequence (18) published by T. Asano (GenBank accession no. AB000732).
Statistical analysis
Based upon previously published criteria, we selected a BMI of 27 kg/m2 as the definition of overweight (19). The distribution of the G1057D polymorphism according to different categories of BMI was analyzed by 
2 analysis with Yates correction (alleles) and 2 analysis for trend (genotypes). Logistic regression was performed to test the association between type 2 diabetes and genotype. Multiple linear regression was employed to test the association between genotype and levels of fasting plasma glucose or levels of fasting serum C-peptide. Logarithmic transformation was performed to normalize distribution of fasting serum C-peptide concentrations. All analyses were performed using the SPSS version 8.0 statistical package (SPSS, Milan, Italy).
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ACKNOWLEDGEMENTS |
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The financial support of Telethon-Italy (Grant no. E.744 to A.C.) and of the Italian Ministry of University and Scientific Research is gratefully acknowledged. We thank Dr Michael Quon for critical review of the manuscript and Dr Simeon Taylor for helpful discussion. We are grateful to Mrs Anna Maria Napoleone and to the nursing staff of the Centro per lo Studio della Malattia Diabetica for assistance with collection of clinical information and specimens.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +39 0871 355 4108 or 4102; Fax: +39 0871 3554110; Email: cama@unich.it
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