| Objective To investigate insulin resistance (IR) and isletβ-cell function of different glucose tolerance subjects in families with type 2 diabetes. To analyze the effect of abnormal metabolism related to type 2 diabetes on IR and isletβ-cell function. To discussion the relationship of IR and impairedβ-cell function to maintain stabilization of glucose.Methods 1768 subjects (764 male and 1004 female) from 406 Chongqing Han families with type 2 diabetes were enrolled. According to the diagnosis standard WHO in 1999, all subjects were divided into three groups as follow: normal glucose tolerance spouses of probands (NC group, 162 subjects), non-diabetic first-degree relatives of patients with type diabetes (FDR group, 729 subjects), patients with type 2 diabetes (DM group, 877 subjects). FDR group comprised two subgroups of normal glucose tolerance (NGT, 479 subjects) and impaired glucose regulation (IGR, 250 subjects). For all subjects, 75 gram oral glucose tolerance tests were conducted. Anthropometry, blood pressure, lipid-profile, plasma glucose, serum insulin, high-sensitivity C-reactive protein (hsCRP) and non-esterified fatty acid (NEFA) were assayed. Homeostasis model assessment of insulin resistance (Homa-IR) and IAI were used to estimate IR,and homeostasis model assessment ofβ-cell function (Homa-β),△I30/△G30, modified beta-cell function index (MBCI) and disposition index (DI1 = Homa-β/Homa-IR, DI2 =△I30/△G 30/Homa-IR, DI3 = MBCI*IAI) were used to evaluate isletβ-cell function.Results (1) There were 161 patients of newly diagnosed type 2 diabetes (nDM group) and 716 patients with history of type 2 diabetes (oDM group) in DM group. Compared with NC group, age, body mass index (BMI), waist to hip ratio (WHR) and waist circumferences of nDM and oDM groups increased, and the difference was significant (P﹤0.01). After adjustment of age, BMI and WHR, compared with NC group, blood pressure, triglyceride (TG), hsCRP, NEFA, Homa-IR of nDM and oDM groups increased, IAI of the two groups decreased, and the difference was significant (P﹤0.01). But these indices were no significant difference between nDM and oDM group. Homa-β,△I30/△G30, MBCI, DI1, DI2 and DI3 of NC, nDM and oDM groups decreased in turn, and the differences between every two of them were significant (P﹤0.01). (2) In IGR group, BMI, WHR and waist circumferences were higher than those in NC group (P﹤0.01). After adjustment of BMI and WHR, compared with NC group, systolic blood pressure (SBP), TG, NEFA, plasma glucose, 0min and 30min insulin during oral glucose tolerance test, Homa-IR increased and IAI, Homa-β,△I30/△G30, MBCI, DI1, DI2, DI3 decreased in IGR group, and the difference was significant (P﹤0.05). Compared with iIGT, Homa-IR increased and IAI, Homa-β, DI1 decreased in iIFG and IFG/IGT, and the difference was significant (P﹤0.05). Compared with iIFG, iIGT and IFG/IGT had lower MBCI and DI3, and the difference was significant (P﹤0.01). (3) After adjustment of age, compared with NC group, NGT group had higher TG, HDL-c, hsCRP, 30min plasma glucose during oral glucose tolerance test, Homa-IR and lower IAI, and the difference was significant (P﹤0.05). Others clinical biochemical indices and△I30/△G30, MBCI, DI1, DI2, DI3 were no significant difference between NC and NGT group. Subjects of NGT group were divided into three tertile groups with different area under the curve of OGTT glucose (AUCg). After adjustment of age, BMI and WHR, Homa-IR and IAI were no significant difference between every two of three tertile groups. Compared with NC group,△I30/△G30, MBCI, DI1, DI2 and DI3 of median and upper tertile group decreased, and the difference was significant (P﹤0.05). (4) Multiple linear regression analysis showed IAI, Homa-β,△I30/△G30 and MBCI were the independent effect factor of AUCg. In NGT, IGR and DM group,β-cell function could respectively explained 50%, 51% and 55% AUCg changes, and IR could respectively explained 18%, 26% and 32% AUCg changes.Conclusion In families with type 2 diabetes, normal glucose tolerance first-degree relatives, impaired glucose regulation first-degree relatives and patients with type 2 diabetes all presented IR and impairedβ-cell function. The characteristic of IR and impairedβ-cell function at different stages of glucose tolerance were various.β-cell function was likely more important than insulin sensitivity to maintain stabilization of glucose. Objective To study the association of single nucleotide polymerphisms (SNPs) in forkhead box O1A (FOXO1A) with type 2 diabetes mellitus (T2DM).Methods The DNA samples of 28 controls and 57 T2DM patients were selected to identify SNPs in FOXO1A gene. 15 SNPs in promoter, exons, introns and 3'-untranslated region (3'-UTR) of FOXO1A gene were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Then pairwise linkage disequilibrium (LD) test and haplotype were examined. Two SNPs of 3'-UTR and three SNPs of intron were genotyped in 290 controls and 414 T2DM patients in Chongqing area to investigate their genetic association with T2DM.Results (1) A total of 12 SNPs were identified in FOXO1A gene, including one SNPs in promoter (FX1A-2056), two SNPs in 3'-UTR (FX1A+108585 and FX1A+108802), nine SNPs in intron area (FX1A+6803, FX1A+22049, FX1A+24297, FX1A+36829, FX1A+44327, FX1A+60936, FX1A+84026, FX1A+97014 and FX1A+102930). LD analysis showed that D'values between every two of most SNPs were beyond 0.7. It suggested 12 SNPs were in a haplotype block. (2) Case-control study on FX1A+108802, FX1A+108585 of 3'-UTR and FX1A+60936, FX1A+36829, FX1A+24297 of intron showed that the SNP of FX1A+60936 was associated with T2DM. Subjects with FX1A+60936 AG/AA genotype were more susceptible to T2DM than those with GG genotype (additive modle: OR = 1.420, 95%CI = 0.783~2.577, P = 0.011; dominant modle: OR = 1.789, 95%CI = 1.024~3.125, P = 0.041; recessive modle: OR = 1.585, 95%CI = 1.149~2.188, P = 0.005). The SNP of FX1A+36829 was associated with T2DM. Subjects with FX1A+36829 CT/CC genotype were more susceptible to T2DM than those with TT genotype (additive modle: OR = 2.571, 95%CI = 1.404~4.695, P = 0.002; dominant model: OR = 2.457, 95%CI = 1.374~4.405, P = 0.002). No matter in T2DM group or in control group, there was no significant difference in age, body mass index (BMI), waist to hip ratio (WHR), waist circumferences, blood pressure, lipid-profile, plasma glucose, serum insulin, insulin resistant indices and isletβ-cell function indices among three groups with different genotypes. Among five SNPs genotyped, four common haplotypes accounted for 86.6% of the observed haplotypes. The frequency of haplotype H6 was higher in T2DM group than that in control group (23.2% vs 18.1%, P = 0.042).Conclusion FOXO1A gene was associated with T2DM and it was maybe the susceptible gene of T2DM. A allele gene of FX1A+60936 and C allele gene of FX1A+36829 could be regarded as molecular genetic maker of susceptibility to T2DM. Objective To investigate the association of single nucleotide polymorphisms (SNPs) and haplotypes of Gly1057Asp and -769C/T in insulin receptor substrate-2 (IRS2) gene with type 2 diabetes mellitus (T2DM). To discuss the effect of interactions among FOXO1A, IRS2 and environment factors on the risk of T2DM.Methods Case-control analysis was studied to investigate genetic association of SNPs in IRS2 gene with T2DM. The Gly1057Asp and -769C/T variants were genotyped in 306 controls and 474 T2DM patients by PCR-RFLP. Multifactor dimensionality reduction (MDR) was used to analyze gene to gene interaction of FOXO1A and IRS2, and gene to environment interaction between FOXO1A, IRS2 and environment factors (including age, body mass index, waist circumference and triglyceride). Results (1) Gly1057Asp of IRS2 gene was associated with T2DM.Subjects with GA/GG genotype were more susceptible to T2DM than those with AA genotype (additive model: OR=1.422, 95%CI=1.037~1.949, P=0.029; dominant model: OR=1.461, 95%CI=1.081~1.973, P=0.014). Subjects with GG genotype had higher 0min plasma glucose and serum insulin during OGTT, higher Homa-IR, lower DI than those with AA genotype. Four haplotypes were reconstructed from the two SNPs of Gly1057Asp and -769C/T. Haplotype H1 and H4 were accounted for 92.7% of all four haplotypes. The frequencies of haplotype H1 and H3 were lower in T2DM group than those in control group (32.0% vs 37.3%, P=0.033; 0.3% vs 1.2%, P=0.042, respectively). (2) There was no interaction among the seven SNPs of FOXO1A and IRS2 genes associated with T2DM. Using MDR methods, a significant four-factor interaction model was found between IRS2 gene and environment factors. This model showed a cross-validation consistency of 9 of 10 and a testing accuracy of 0.6230 (P=0.001). The interactions of Gly1057Asp variant, age, waist circumference and TG were associated with T2DM. Among non-obesity people with normal TG, subjects beyond 60 years and with Gly1057Asp GA or GG genotype had the higher risk of T2DM. Among obesity people with normal TG, subjects with Gly1057Asp GA or GG genotype of any ages had the higher risk of T2DM. Subjects of obesity and high triglyceride level, no matter age and genotype of Gly1057Asp, had the higher risk of T2DM. The odds ratio of the high-risk to low-risk group was 3.342 (95%CI=1.168~9.561, P=0.026). A significant three-factor interaction model was found between FOXO1A gene and environment factors. This model showed a cross-validation consistency of 9 of 10 and a testing accuracy of 0.6659 (P=0.011). The interactions of FX1A+60936, FX1A+24297 and waist circumference were associated with T2DM. Among non-obesity people, subjects with AA genotype of FX1A+60936 and AC or CC genotype of FX1A+24297 had the higher risk of T2DM. Among obesity people, subjects with AA genotype of FX1A+60936 or AA genotype of FX1A+24297 had the higher risk of T2DM. The odds ratio of the high-risk to low-risk group was 6.698 (95%CI=1.763~25.446, P=0.008).Conclusion Gly1057Asp of IRS2 gene was associated with insulin resistance, impairedβ-cell function and T2DM, so IRS2 was possibly the susceptible gene of T2DM. Gene-gene interaction of FOXO1A and IRS2 was not associated with T2DM. But the two genes could cooperate with age, obesity etc. environment factors to make T2DM susceptible.
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