| Type 2 diabetes is a choronic metabolic disorder, which is caused by the interaction of both genetic and environmental factors, the major hazard of diabetes are various acute or chronic complications. At the same time, type 2 diabetes also usually accompanies with a number of other metabolic disorders, such as obesity, hyperlipidemia, hyperuricemia and so on. Exploring the association between susceptibility loci of type 2 diabetes and risk factors of this disease(obesity, acute or chronic complications etc.) may shed new light on the mechanism underlyingthe pathophsiology of type 2 diabetes. Therefore, our study focused on irisin, a novel beneficial myokine that may ameliorate insulin sensitivity but also an anti-inflammatory hormone, to investigate the relationship between irisin and type 2 diabetes, obesity and related chronic complications. The contents and main findings are as follows:1. Circulating irisin levels is associated with lipid and uric acid metabolism in a Chinese populationWe totally recruited a total of 203 subjects, Of which, 68 subjects with NGT, 63 subjects with IGR and 72 subjects with new-onset T2 DM. Three tagging single nucleotide polymorphisms within the region of the FNDC5 gene were selected and genotyped. Circulating irisin levels were measured by ELISA. Detailed clinical investigations and biochemistry measurements were carried out in all of the subjects. Multivariate linear regression analysis was performed to assess the association between irisin levels and related metabolic characteristics. All subjects were classified into normal weight and overweight/obese subgroups according to body mass index(BMI). No significant differences of circulating irisin levels were identified among the three groups(p=0.9741). Multiple linear regression analysis after adjusting for covariates revealed that serum irisin level was independently and significantly associated with total cholesterol(p=0.0005), low-density lipoprotein cholesterol(p=0.0014), fasting fatty acids(p=0.0402) and uric acid(p=0.0062). By dividing the serum irisin levels into three tertile group, the values of total cholesterol, low-density lipoprotein cholesterol, fasting fatty acids and uric acid were all increased significantly with the increase of irisin(p<0.05). Moreover, serum irisin levels remain closely related with total cholesterol in both normal weight and overweight/obese subgroups. Our study suggest that circulating irisin concentrations is significantly associated with lipid and uric acid metabolism in a Chinese population.2. Association of FNDC5 variants with type 2 diabetes and obesity in a Chinese Han populationWe explored the association between the gene enconding irisin- FNDC5 and type 2 diabetes, obesity in Han Chinese. We recruited 6822 diabetic and non-diabetic samples from Shanghai. Three tagging single nucleotide polymorphisms within the region of the FNDC5 gene were selected and genotyped. Detailed clinical investigations and biochemistry measurements were carried out in all of the participants. Subjects without diabetes were classified into normal weight and overweight/obese subgroups according to body mass index(BMI). None of the SNPs were associated with either the risk of type 2 diabetes in all of the participants or with any of the clinical quantitative traits in the controls with normal glucose regulation. Subgroup analysis showed that in controls with normal weight(BMI<25kg/m2), the rs16835198 major allele G was significantly associated with fasting insulin levels, and that each additional copy of the allele resulted in a 1.042 m U/L increment of the values(p=0.046). Moreover, after adjusting for confounding variables, there were trends towards correlation of rs16835198 with HOMA-insulin resistance(HOMA-IR)(p=0.057) and low-density lipoprotein cholesterol(LDL-C) levels(p=0.083). In overweight/obese subjects(BMI≥25Kg/m2), we noted rs16835198 showed trends towards association with fasting insulin(p=0.057) and HOMA-IR levels(p=0.091), both of which declined with additional copies of the major allele G. Moreover, rs16835198 was significantly associated with high-density lipoprotein cholesterol(HDL-C) levels(p=0.013), and HOMA-β cell function(p=0.028) in the overweight/obese subjects. Finally, we observed a significant interaction between BMI-rs16835198 and fasting insulin levels in the control group(p=0.003). Our data indicate that the effect of the common FNDC5 SNP rs16835198 on fasting insulin was significantly modified by BMI in the Chinese Han population.3. Association between FNDC5 genetic variants and proliferative diabetic retinopathy in a Chinese populationWe performed two-stage analysis to investigate the association between FNDC5 genetic variants and microvascular complications in Han Chinese. In the first stage, three tagging single nucleotide polymorphisms within the region of the FNDC5 gene were selected and genotyped in 1555 patients with type 2 diabetes. Detailed clinical investigations and biochemical measurements were performed in all of the participants. In the second stage, the single nucleotide polymorphism that showed significant association or a trend towards an association with diabetic kidney disease or retinopathy was additionally genotyped in 352 patients for replication. In stage 1 analysis, rs1570569 showed a trend towards an association with diabetic retinopathy(OR=1.177, 95%CI 0.983-1.409, p=0.077). In addition, it was also marginally associated with proliferative diabetic retinopathy(OR=1.645, 95%CI 0.981-2.757, p=0.057). In stage 2 analysis, a similar effect size of rs1570569 on proliferative diabetic retinopathy was observed(OR=1.647, 95%CI 0.662-4.100, p=0.277). After combining stage 1 and stage 2, rs1570569 exhibited a significant association with proliferative diabetic retinopathy(OR=1.642, 95%CI 1.048-2.573, p=0.029). In addition, this SNP was also associated with the severity of diabetic retinopathy in all samples(p=0.036 for trend). Our data indicate that rs1570569 of FNDC5 is associated with diabetic retinopathy, especially proliferative diabetic retinopathy in Chinese patients with T2 DM. |
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