The association of the K121Q polymorphism of the plasma cell glycoprotein-1 gene with type 2 diabetes and hypertension depends on size at birth

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.     

The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance.

PC-1 is a membrane glycoprotein that impairs insulin receptor function. Its K121Q polymorphism is a genetic determinant of insulin resistance. We investigated whether the PC-1 gene modulates insulin sensitivity independently of weight status (i.e. both in nonobese and obese individuals). Nondiabetic subjects [164 males, 267 females; age, 37 +/- 0.6 yr, mean +/- SEM; body mass index (BMI), 32.7 +/- 0.5 kg/m(2)], who were subdivided into 220 nonobese (BMI < or = 29.9) and 211 obese, were studied. Although subjects were nondiabetic by selection criteria, plasma insulin concentrations during oral glucose tolerance test were higher (P < 0.05) in Q allele-carrying subjects (K121Q or Q121Q genotypes), compared with K121K individuals, in both the nonobese and obese groups. Insulin sensitivity, measured by euglycemic clamp in a representative subgroup of 131 of 431 randomly selected subjects, progressively decreased (P < 0.001) from nonobese K121K [n = 61; glucose disposal (M) = 34.9 +/- 1.1 micromol/kg/min] to nonobese Q (n = 21; M = 29.9 +/- 2.0), obese K121K (n = 31, M = 18.5 +/- 1.2), and obese Q (n = 18, M = 15.5 +/- 1.2) carriers. The K121Q polymorphism was correlated with insulin sensitivity independently (P < 0.05) of BMI, gender, age, and waist circumference. In conclusion, the Q121 PC-1 variant and obesity have independent and additive effects in causing insulin resistance.     

Obesity risk associated with the K121Q polymorphism of the glycoprotein PC-1 gene

BACKGROUND: Obesity is considered to be a multifactorial trait resulting from the combined influence of genetic and environmental determinants. Insulin resistance plays an important role in the development of obesity. Plasma-cell membrane differentiation antigene-1 (PC-1) inhibits insulin receptor signalling when overexpressed and thus causes insulin resistance. PC-1 gene polymorphism might be associated with adipocyte metabolism disturbance and energy imbalance. The purpose of this study was to determine whether K121Q polymorphism in PC-1 gene is involved in obesity susceptibility in Chinese Han population. METHODS: The genotype of the polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism analysis for 338 unrelated subjects of Beijing, China. Their Body mass index (BMI), plasma glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), free fatty acid (FFA) and insulin level were measured. Chi-square analyses were applied to test the significance differences in genotypic and allelic frequencies. Association studies were undertaken using the t-test and logistic regression analyses. RESULTS: The obese had significantly higher frequency of KQ/QQ genotype or Q allele than non-obese in females (26.7% vs. 10.9%, p = 0.014 and 13.3% vs. 5.5%, p = 0.021). Significant elevation of insulin amongst the Q121 carrier women in obesity individuals and higher FFA level of Q121 carrier men in non-obese controls (BMI < or = 23 kg/m2) were observed. Binary logistic regression analysis revealed that PC-1 genotype together with higher glucose, total cholesterol, triglyceride and serum HDL were independently associated with the presence of obesity. CONCLUSIONS: The observed genotype distributions revealed a significant association of PC-1 K121Q with obesity. PC-1 Q121 carriers are more likely to be insulin-resistant or get fatter in respect to KK subjects and carriers of the Q allele are at higher risk for the development of obesity in female.     

Ethnic differences in the frequency of ENPP1/PC1 121Q genetic variant in the Dallas Heart Study cohort

Genetic susceptibility modulates the impact of obesity on the risk for type 2 diabetes. One candidate gene predisposing to type 2 diabetes is ENPP1/PC1. A common polymorphism in this protein, K121Q, is associated with insulin resistance and increased susceptibility to type 2 diabetes in Caucasian, Afro-Caribbean, and South Asian populations. The goal of this study was to evaluate differences in the prevalence of the ENPP1 121Q variant in the Caucasian, African-American, and Hispanic populations in Dallas county and to establish a population-based estimate of gene variant prevalence for future investigations. We also evaluated the association between the ENPP1 121Q variant and diabetes. The Dallas Heart Study (DHS) is a multiethnic probability-based sample of the Dallas county population in which African-Americans were systematically oversampled so that the final sample was 50% African-Americans. We performed ENPP1/PC1 genotyping in 1038 non-Hispanic Whites (544 women, 494 men), 1815 African-Americans (1052 women and 763 men), and 597 Hispanics (347 women, 250 men). The frequency of ENPP1/PC1 K121Q was higher in both African-Americans (78.5%) and Hispanics (21.9%) than in the non-Hispanic White group (13.2%). The former two groups also have a higher prevalence of type 2 diabetes (African-Americans, 14.1%, and Hispanics, 11.7%) compared to non-Hispanic Whites (6.8%). Logistic regression analysis revealed significant interactions between the ENPP1 genotype, age, and body mass index within each ethnic group. After adjustment for these variables and their interactions, ENPP1 Q allele predicted diabetes when a recessive model was tested. Ethnic differences in ENPP1 121Q allele frequency may contribute to the increased susceptibility to type 2 diabetes observed in US minority groups.     

The Arg972 variant in insulin receptor substrate-1 is associated with an atherogenic profile in offspring of type 2 diabetic patients

The insulin receptor substrate-1 (IRS-1) gene has been considered a candidate for insulin resistance, type 2 diabetes, and coronary artery disease. To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities.     

The Gly-->Arg972 amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells

Molecular scanning of insulin receptor substrate-1 (IRS-1) revealed several amino acid substitutions. The most common IRS-1 variant, a Gly to Arg972 change, is more prevalent among type 2 diabetic patients. In this study we overexpressed wild-type and Arg972IRS-1 variant in L6 skeletal muscle cells and examined the functional consequences of this polymorphism on insulin metabolic signaling. L6 cells expressing Arg972-IRS-1 (L6-Arg972) showed a decrease in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity compared with L6 cells expressing wild-type IRS-1 (L6-WT) as a consequence of decreased binding of p85 subunit of PI 3-kinase to IRS-1. L6-Arg972 exhibited a decrease in both basal and insulin-stimulated glucose transport due to a reduction in the amount of both GLUT1 and GLUT4 translocated to the plasma membrane. Both basal and insulin-stimulated Akt phosphorylations were decreased in L6-Arg972 compared with L6-WT. Basal glycogen synthase kinase-3 (GSK-3) activity was increased in L6-Arg972 compared with L6-WT, and insulin-induced inactivation of GSK-3 was also reduced in L6-Arg972. This change was associated with a significant decrease in insulin-stimulated glucose incorporation into glycogen and glycogen synthase activity in L6-Arg972 compared with L6-WT. These results indicate that the Arg972-IRS-1 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI 3-kinase/Akt/GSK-3 signaling pathway. The present data indicate that the polymorphism at codon 972 of IRS-1 may contribute to the in vivo insulin resistance observed in carriers of this variant.     

Impaired endothelial function in never-treated hypertensive subjects carrying the Arg972 polymorphism in the insulin receptor substrate-1 gene

Some cardiovascular risk factors, such as hypertension and insulin resistance, are associated with endothelial dysfunction. Insulin regulates both in vitro and in vivo expression of endothelial nitric oxide synthase (eNOS) via a pathway involving insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3 kinase. Recently, we found that human endothelial cells obtained from carriers of the Arg(972) IRS-1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between Arg(972) IRS-1 polymorphism and endothelial dysfunction in vivo, we enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. IRS-1 polymorphism was detected by PCR. The allelic frequency of the Arg(972) IRS-1 variant was 8.0%. Stratifying subjects according to IRS-1 genotype, we observed that acetylcholine-stimulated forearm blood flow was significantly (P < 0.0001) lower in Gly/Arg heterozygous carriers than in Gly/Gly carriers (11.3 +/- 4.4 vs. 14.7 +/- 5.9 ml/100 ml(-1) of tissue per min(-1)). Sodium nitroprusside caused comparable increments in forearm blood flow in both groups (12.9 +/- 2.4 vs. 13.3 +/- 3.5 ml/100 ml(-1) of tissue per min(-1)). Our data strongly suggest that, by inducing endothelial dysfunction, the Arg(972) IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.     

The G972R variant of the insulin receptor substrate-1 (IRS-1) gene is associated with insulin resistance in "uncomplicated" obese subjects evaluated by hyperinsulinemic-euglycemic clamp

Several association studies have indicated the insulin receptor substrate-1 (IRS-1) gene G972R variant as a genetic risk factor for insulin resistance, particularly in presence of obesity. A few studies have also suggested a possible effect of the G972R variant on insulin secretion. The aim of this study was to evaluate the role of the IRS-1 gene G972R variant in 61 subjects with "uncomplicated" obesity [i.e. without diabetes, hypertension, dyslipidemia, coronary artery disease (CAD)], studied by hyperinsulinemic-euglycemic clamp. The presence of the G972R variant, detected in real-time with LightCycler hybridisation probes, was related to the indexes of insulin sensitivity. Furthermore, the possible role of this variant on insulin secretion was studied by means of insulin release indexes derived from oral tolerance test (OGTT). Twenty-four point five percent (24.5%) (no.=15) of the obese subjects proved to be carriers of the G972R variant. M index (p<0.05), non-oxidative glucose (p<0.01), insulin clearance (p<0.03) and insulin sensitivity index (ISI) (p<0.005) were all significantly reduced in G972R carriers compared to non-carriers, indicating a significant reduction in insulin sensitivity in carriers of the variant. A logistic regression analysis confirmed the independent association between the G972R variant and reduced insulin sensitivity (p<0.03). The interaction between obesity and the G972R variant was also independently associated with a reduced insulin sensitivity (p<0.005), suggesting that obesity and G972R variant were more than additive in predicting insulin resistance. The analysis of insulin release indexes did not show any significant differences. Our results demonstrate the association of the G972R variant of the IRS-1 gene with reduced insulin sensitivity in obese subjects, and indicate a possible interaction between the IRS-1 variant and obesity in worsening of insulin sensitivity.     

The PC-1 Q121 allele is exceptionally prevalent in the Dominican Republic and is associated with type 2 diabetes

The human glycoprotein PC-1 codon Q121 allele has been correlated with insulin resistance, but not with type 2 diabetes or obesity. We investigated the prevalence of PC-1 Q121 in the Dominican Republic population (755 subjects studied) and whether this variant is associated with insulin resistance, obesity, or type 2 diabetes. The prevalence of PC-1 Q121 was high compared with that in other populations. The proportions of genotypes detected were: KK, 21.6%; KQ, 48.3%; and QQ, 30.1%. This compares to approximately 74%, 24%, and 2% in other populations. Among nonobese, nondiabetic subjects, the insulin response of KQ (P = 0.027) and QQ (P = 0.031) subjects was greater during the oral glucose tolerance test than that of KK subjects, whereas plasma glucose profiles were comparable. The Q allele was more prevalent in obese type 2 diabetics than in controls (P = 0.026; odds ratio = 1.56). Multiple regression analysis, after adjusting for age, gender, and body mass index, showed the QQ genotype to be associated with type 2 diabetes (P = 0.043; odds ratio = 2.74), but not obesity (P = 0.068). These results indicate that the PC-1 Q121 allele is exceptionally prevalent in the Dominican Republic, contributing to both insulin resistance and type 2 diabetes.     

The G972R variant of the insulin receptor substrate-1 gene impairs insulin signaling and cell differentiation in 3T3L1 adipocytes; treatment with a PPARgamma agonist restores normal cell signaling and differentiation

The insulin receptor substrate-1 (IRS-1) plays a central role in insulin sensitivity, and association studies have shown that the IRS-1 G972R variant is a risk factor for insulin resistance. However, how this mutation may lead to impaired insulin sensitivity is still to be determined. Our study aimed to evaluate, after transfection of the IRS-1 G972R variant in 3T3L1 adipocytes, the effect of this mutation on insulin signaling and on cell differentiation. The 3T3L1 cells were transfected with pcDNA3 expression vector containing either the human wild-type IRS-1 or the G972R variant. After induction of differentiation, the 3T3L1 transfected with wild-type IRS-1 differentiated in 6-8 days, while the cells transfected with G972R variant did not differentiate. To determine whether the defect in IRS-1 was responsible for this, we analyzed the expression of several genes involved in the insulin signaling pathway. Results showed that PPARgamma expression was significantly reduced in cells transfected with the mutated IRS-1, together with a significant decrease in binding of phosphatidylinositol-3 kinase (PI 3-kinase) to IRS-1 G972R and in PI 3-kinase activity. In addition, we observed that the interaction between the insulin receptor (IR) and the IRS-1 G972R protein was increased and that the autophosphorylation of the IR was significantly inhibited in 3T3L1-G972R cells compared with 3T3L1-WT. Treatment of the 3T3L1-G972R cells with pioglitazone (PIO), a PPARgamma agonist, restored differentiation with higher level of PPARgamma expression and restoration of PI 3-kinase binding to IRS-1 G972R and PI 3-kinase activity. IR autophosphorylation was also increased. Withdrawal of PIO in fully differentiated 3T3L1-G972R cells determined the reappearance of the insulin signaling defect. Finally, we observed higher levels of IRS-2 expression, suggesting that IRS-2 may play a more important role in adipocyte insulin signaling. In conclusion, IRS-1 G972R variant impairs insulin signaling, and treatment with PPARgamma agonist restores the normal phenotype of 3T3L1 cells.     

Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects

Aims/hypothesis Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor α subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes.Subjects and methods The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites.Results No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 [95% CI 1.10–1.25], p=1×10⁻⁶). In case–control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m²; odds ratio 1.63 [95% CI 1.09–2.46], p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait.Conclusions/interpretation In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.     

Insulin resistance and vascular dysfunction in nondiabetic Asian Indians

Asian Indians are at higher risk for diabetes and cardiovascular disease than European Caucasians. To examine the pathophysiology of this increased risk, we measured insulin sensitivity, cardiovascular risk factors, fat distribution, and endothelium-dependent (reactive hyperemia) and -independent (nitroglycerin) vasodilation before and after a 2-h hyperinsulinemic clamp (40 mU/m(2).min) in 25 nondiabetic Asian Indians and 15 Caucasians with similar age and body mass index. Asian Indians had higher fasting insulin than Caucasians (6.7 +/- 0.8 vs. 3.7 +/- 0.3 microU/ml, P = 0.007) but similar FPG (90 +/- 2 vs. 88 +/- 2 mg/dl). Glucose uptake during the clamp was markedly reduced in Asian Indians vs. Caucasians (4.5 +/- 0.3 vs. 7.5 +/- 0.4 mg/kg x min, P < 0.0001). During the clamp, basal brachial artery diameter increased less in Asian Indians vs. Caucasians (2.6 +/- 1.0 vs. 5.7 +/- 1.0%, P = 0.04), and the reduction was correlated with the impairment in insulin sensitivity (r = 0.38, P = 0.04). In contrast, vasodilatory responses to reactive hyperemia and nitroglycerin were similar in Asian Indians and Caucasians both before and during hyperinsulinemia. Plasminogen activator inhibitor-1 and FFA were significantly elevated and adiponectin was significantly lower in Asian Indians vs. Caucasians, and there were trends toward higher low-density lipoprotein and triglycerides, lower high-density lipoprotein, and increased total, sc, and visceral fat. These risk factors were all significantly correlated with insulin sensitivity. Thus, apparently healthy Asian Indians have severe insulin resistance, dyslipidemia, elevated plasminogen activator inhibitor-1, impaired insulin-mediated vasodilation, and trends toward altered body fat distribution. These abnormalities may contribute to the increased risk of diabetes and cardiovascular disease in this population.     

The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities

Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). A number of laboratories have observed that membrane glycoprotein plasma cell antigen 1 (PC-1) [ectonucleotide pyrophosphatase phosphodiesterase 1] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, in cultured cells in vitro and in transgenic mice in vivo, PC-1 overexpression impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling. PC-1 binds to the connecting domain of the IR alpha-subunit that is located in residues 485-599. The connecting domain transmits insulin binding in the alpha-subunit to activation of tyrosine kinase activation in the beta-subunit. When PC-1 is overexpressed, it inhibits insulin-induced IR beta-subunit tyrosine kinase activity. In addition, a polymorphism of PC-1 (K121Q) in various ethnic populations is closely associated with insulin resistance, T2D, and cardio- and nephrovascular diseases. The product of this polymorphism has a 2- to 3-fold increased binding affinity for the IR and is more potent than the wild-type PC-1 protein (K121K) in inhibiting the IR. These data suggest therefore that PC-1 is a candidate protein that may play a role in human insulin resistance and T2D by its overexpression, its overactivity, or both.     

Population-specific alleles: the polymorphism (K121Q) of the human glycoprotein PC-1 gene is strongly associated with race but not with insulin resistance in black and white children

The K121Q polymorphism of the glycoprotein PC-1 gene was recently reported to associate with insulin resistance (IR) in an all-Caucasian, Sicilian population. Given black-white differences in plasma insulin and IR, we compared the prevalence of the KK, KQ, and QQ genotypes and their associations with insulin and IR in 2 large, biracial pediatric samples: 1 hospital-based (n = 301, 137 blacks and 164 whites) and 1 school-based (n = 639, 344 blacks and 295 whites). The Q allele frequencies in the hospital-based and school-based cohorts in black children were 0.80 and 0.77 and in the white children, 0.15 and 0.13. The K allele frequencies in the hospital-based and school-based cohorts in black children were 0.20 and 0.23 and in the white children, 0.85 and 0.87. Differences in allelic frequencies were highly significant (chi square test, P <.0001) for both the hospital-based cohort and the school-based cohort. Both cohorts were in Hardy-Weinberg equilibrium. Within race, after covariance adjusting for age and body mass index (BMI), there were no significant differences (P >/=.10) among the 3 PC-1 genotypes for insulin, glucose, or homeostasis model assessment (HOMA) IR. After covariance adjusting for age and BMI, black girls had higher insulin (P =.0007) and higher HOMA IR (P =.0002) than white girls. The K121Q polymorphism was not associated with insulin, glucose, or HOMA IR measures in black or white children. However, the QQ genotype was population-specific, encompassing most black children versus 1% to 3% of white children. As such, K121Q genotyping should be useful in epidemiology, population genetics, and forensic anthropology.     

The G1057D polymorphism of IRS-2 gene and its relationship with obesity in conferring susceptibility to type 2 diabetes in Asian Indians

OBJECTIVE: To investigate the association of insulin receptor substrate-2 (IRS-2) G1057D polymorphism with type 2 diabetes and obesity in Asian Indians. METHODS: The study comprised of 1193 normal glucose tolerant (NGT) subjects and 1018 subjects with type 2 diabetes, aged >/=20 years with an average body mass index of 23.7+/-4.6 and 25.3+/-4.2 kg/m(2), respectively. The subjects were unrelated and randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), a population-based study in Chennai in southern India. The G1057D polymorphism of the IRS-2 gene was genotyped using PCR-RFLP assay. RESULTS: The genotype frequency of the IRS-2 G1057D polymorphism was significantly different between the NGT and type 2 diabetic groups (P=0.0007) in the total study subjects and among the obese subjects (P=0.00007). Logistic regression analysis showed that the DD genotype showed an increased susceptibility to diabetes with an odds ratio (adjusted for age and sex) of 2.19 (95% CI: 1.34-3.57, P=0.002) when compared to the GG+GD genotype, among the obese subjects, but not in non obese subjects. In order to explore possible interaction with obesity, logistic regression analysis was performed and the coefficient corresponding to the interaction parameter (genotype x obesity) was significant (P=0.0001). CONCLUSION: In Asian Indians, the DD genotype increases susceptibility to type 2 diabetes by interacting with obesity.     

2型糖尿病家系膜糖蛋白PC-1基因多态性的研究

目的 探讨膜糖蛋白PC1基因多态性与胰岛素抵抗(IR)特征和2型糖尿病(T2DM)的关系。方法 选择T2DM家系中的T2DM患者(216例)、非DM一级亲属(133例)，运用PCR-RFLP技术进行PC-1基因编码区K121Q多态性研究，同时检测临床和生化指标，并与正常人(106名)相比较。结果 (1)T2DM患者基因型频率和等位基因频率与正常对照无明显差异。携带Q等位基因的DM患者，收缩压、甘油三酯(TG)、胆固醇(TC)、空腹胰岛素(Fins)水平等较后者明显增高。(2)非DM一级亲属的基因型频率和等位基因频率与正常对照比较差异无显著意义。携带KQ基因型者虽然其体质指数明显低于KK基因型者，但前者舒张压、TG、TC、Fins、餐后2h胰岛素(2hlns)、空腹血浆C肽(FCP)水平等显著高于后者。(3)合并高血压的DM患者(84例)和无高血压的DM患者(132例)比较，QQ基因型只见于前者。结论 (1)T2DM患者、非DM一级亲属和正常人中该多态性分布没有明显差异。(2)PC-1基因Q121K基因型与家族性T2DM家系成员的IR表型相关。(3)PC1基因Q121K基因多态性与T2DM患者的高血压无关。     

Amino acid polymorphism Gly 972 Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with type 2 diabetes.

The Gly 972 Arg variant in the insulin receptor substrate-1 (IRS-1) gene may interact with the pathogenesis of common insulin-resistance disorders raising the hypothesis that the mutation may predispose to type 2 diabetes. We examined the codon 972 variant in 144 non-diabetic first degree relatives of patients with type 2 diabetes (FDR), who underwent extensive phenotyping: Glucose tolerance was determined by an oral glucose load, insulin sensitivity by euglycaemic-hyperinsulinaemic glucose clamp (glucose metabolic clearance rate, MCR) and body composition by bioelectrical impedance. 20 (14%) of the FDR showed the Gly 972 Arg variant in heterozygous form, 2 (1.3%) probands were homozygous. Carriers of the polymorphism did not differ in MCR independent of body weight and total body fat. The polymorphism does not seem to determine clamp-derived insulin sensitivity. Despite identical fasting plasma glucose, carriers of the polymorphism showed a slightly lower fasting serum insulin and lower insulin response to an oral glucose load but higher glucose concentrations. In an obese subgroup (BMI > 25) the polymorphism did not show a higher frequency and was not associated with lower insulin sensitivity. In the investigated group of young, healthy relatives of type 2 diabetes patients, the frequency of the mutation corresponded to that of a diabetic population. In summary our data show that the polymorphism is not suitable to predict insulin resistance.     

Hyperhomocysteinemia in Asian Indians living in the United States

Hyperhomocysteinemia has been reported in Asian Indians (people from Indian subcontinent) to be related to relatively low plasma levels of folate and vitamin B-12. However, a true ethnic-related characteristic has not been excluded. This study was done to determine whether Asian Indians have high plasma homocysteine compared with Caucasians in the United States in the era of folate fortification, and whether low vitamin B-12 or insulin resistance may account for possible interethnic differences in plasma homocysteine. A total of 227 Asian Indians (131 males and 96 females) and 155 Caucasians (66 males and 89 females) completed a questionnaire for medical, family, and personal history. They had height, weight, and blood pressure measured and fasting blood drawn for routine chemistry, TSH, plasma homocysteine, vitamin B-12, and folate. Oral glucose tolerance test and vitamin B-6 was measured in a subgroup of 66 Asian Indians (47 males and 19 females) and 63 Caucasians (33 males and 30 females). Asian Indians were found to have significantly higher plasma homocysteine than Caucasians (median of 12.6 and 8.0 micro mol/liter, P < 0.0001, respectively) and lower plasma concentrations of B-6 (median 49 vs. 70 nmol/liter; P = 0.05, respectively). Plasma folate was relatively high and similar in both ethnic groups. Plasma vitamin B-12 was significantly lower in Asian Indians than Caucasians (median of 204 vs. 320 pmol/liter, P < 0.0001, respectively). Vitamin B-12 correlated significantly with plasma homocysteine. When vitamin B-12 was between 150 and 379 pmol/liter, the regression curve between vitamin B-12 and homocysteine had significantly different slope in the two ethnic groups (P value < 0.05) and Asian Indians had significantly higher homocysteine for any level of vitamin B-12. Although insulin resistance, measured as insulin area under the curve by oral glucose tolerance test was higher in Asian Indians and correlated significantly with homocysteine, it did not explain inter-ethnic differences in plasma homocysteine in a multivariate analysis. We conclude that Asian Indians living in the United States have significant elevation of plasma homocysteine concentrations despite normal plasma folate. Lower plasma concentrations of vitamin B-12 and lower insulin sensitivity may contribute to this finding but only partially explained the ethnic-related hyperhomocysteinemia of the Asian Indians.     

Association of a genetic polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 with hepatitis C virus infection and hepatitis C virus core antigen levels in subjects in a hyperendemic area of Japan

Background  The clinical course of chronic hepatitis C virus (HCV) infection is strongly associated with insulin resistance and obesity. The K121Q polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP)-1 gene and the rs7566605 genotype located near insulin-induced gene 2 have been shown to be associated with insulin resistance and obesity. This study examined whether the K121Q polymorphism in ENPP1 or the rs7566605 genotype is associated with the clinical course of HCV infection. Methods  The relationships between the clinical characteristics of 469 anti-HCV antibody-seropositive subjects (353 were positive for HCV core antigen or RNA, whereas 116 were negative for HCV RNA) and the polymorphisms were analyzed. Results  No significant differences in body mass index, plasma glucose level, serum insulin level, and other biochemical markers were observed between subgroups of subjects with different genotypes at the K121Q polymorphism or rs7566605. The frequency of the homozygous wild-type genotype at K121Q in HCV carriers, however, was significantly higher than that in subjects who were negative for HCV RNA (84.5% vs. 75.9%; P < 0.05). Moreover, in HCV carriers, HCV core antigen levels in subjects homozygous for the wild-type genotype at K121Q were significantly higher than in heterozygous carriers of K121Q (5358 fmol/l vs. 4002 fmol/l; P = 0.04). In contrast, the rs7566605 genotype was not associated with hepatitis C viremia or with the HCV core antigen level. Conclusions  The K121Q variant of ENPP1 may be associated with hepatitis C viremia and core antigen levels in HCV carriers.     

Polymorphisms of insulin receptor substrate 1 and beta3-adrenergic receptor genes in gestational diabetes and normal pregnancy

Gestational diabetes mellitus (GDM) is considered an important risk factor for the development of type 2 diabetes mellitus. We studied possible relations between GDM and both insulin receptor substrate 1 (IRS-1) (Gly972Arg) and beta3-adrenergic receptor (ADRB3 Trp64Arg, beta3-AR) gene mutations, considered potential modifying factors in the etiology of type 2 diabetes mellitus. We evaluated the 2 gene mutations in late gestation in 627 pregnant women, all studied using the glucose challenge test, followed (in positive tests) by the oral glucose tolerance test (100 g, Carpenter and Coustan [J Obstet Gynecol. 1982;144:768-773] criteria) We diagnosed 309 women with GDM, 41 with gestational impaired glucose tolerance and 277 normal pregnant women. Age, family history of diabetes, prepregnancy body mass index, weight gain during pregnancy, plasma glucose levels, hemoglobin A1c, islet autoantibody levels, and insulin treatment during pregnancy were all evaluated. All pregnant women were genotyped for IRS-1 (Gly972Arg) and beta3-AR (ADRB3 Trp64Arg) polymorphisms. The frequency of IRS-1 gene polymorphism was significantly higher in women with GDM than in women with a normal glucose tolerance (NGT) (P = .039), and there was a significant trend (P = .032) in the increasing frequency of mutant allele Arg from NGT > gestational impaired glucose tolerance > GDM. The search for beta3-AR gene polymorphism showed no significant differences between women with GDM and women with NGT. The X-Arg genotype of IRS-1 was significantly associated with a positive family history of diabetes in NGT (P = .006) and neared significance in GDM (P = .057). Moreover, we found that NGT carriers of both polymorphisms had a higher prepregnancy body mass index than carriers of the IRS-1 variant alone (P = .0034), the beta3-AR variant alone (P = .039), or neither (P = .048), suggesting a possible synergistic effect of the 2 gene polymorphisms. These results suggest that the IRS-1 genetic polymorphism is involved in the occurrence of gestational diabetes, as well as type 2 diabetes mellitus.