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Association of a type 2 diabetes genetic risk score with insulin secretion modulated by insulin sensitivity among Chinese Hans.

ABSTRACT: Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion. The present study aimed to identify the influence of insulin sensitivity on the genetic risk of impaired insulin secretion among a Chinese Han population. For 3229 controls and 1994 treatment-naïve T2D, single nucleotide polymorphisms (SNPs) from 24 T2D-related genomic loci were genotyped and a genetic risk score (GRS) was constructed. Results showed that GRS was associated with insulin secretion and disposition indices in both controls and treatment-naïve T2Ds. Upon stratifying the participants into tertiles by the Matsuda index, we observed an inhibitory relationship between the GRS and insulin secretion in low insulin sensitive but not in high insulin sensitive controls and treatment-naïve T2Ds. Moreover, low insulin sensitive individuals exhibited more severe impairment in insulin secretion and beta cell response to insulin sensitivity with an increase in risk alleles. Our findings identified that the association of GRS with insulin secretion was strongly modulated by insulin sensitivity in both controls and T2Ds of Chinese Han. It indicates that insulin sensitization should be emphasized in prevention and treatment of T2D for beta cell protection.

SUBMITTER: Kong X

PROVIDER: S-EPMC5148717 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Association of a type 2 diabetes genetic risk score with insulin secretion modulated by insulin sensitivity among Chinese Hans.

Kong X X Xing X X Hong J J Zhang X X Yang W W

Clinical genetics 20160721 6

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion. The present study aimed to identify the influence of insulin sensitivity on the genetic risk of impaired insulin secretion among a Chinese Han population. For 3229 controls and 1994 treatment-naïve T2D, single nucleotide polymorphisms (SNPs) from 24 T2D-related genomic loci were genotyped and a genetic risk score (GRS) was constructed. Results showed that GRS was associated with insulin secretion and dis ...[more]

PMID: 27280334

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Project description:Background This study investigated whether single nucleotide polymorphisms (SNPs) reported by previous genome-wide association studies (GWAS) to be associated with impaired insulin secretion, insulin resistance, and/or type 2 diabetes are associated with disposition index, the homeostasis model assessment of insulin resistance (HOMA-IR), and/or development of diabetes following a pregnancy complicated by gestational diabetes mellitus (GDM). Methods Seventy-two SNPs were genotyped in 374 women with previous GDM from Southern Sweden. An oral glucose tolerance test was performed 1–2 years postpartum, although data on the diagnosis of diabetes were accessible up to 5 years postpartum. HOMA-IR and disposition index were used to measure insulin resistance and secretion, respectively. Results The risk A-allele in the rs11708067 polymorphism of the adenylate cyclase 5 gene (ADCY5) was associated with decreased disposition index (beta = − 0.90, SE 0.38, p = 0.019). This polymorphism was an expression quantitative trait loci (eQTL) in islets for both ADCY5 and its antisense transcript. The risk C-allele in the rs2943641 polymorphism, near the insulin receptor substrate 1 gene (IRS1), showed a trend towards association with increased HOMA-IR (beta = 0.36, SE 0.18, p = 0.050), and the T-allele of the rs4607103 polymorphism, near the ADAM metallopeptidase with thrombospondin type 1 motif 9 gene (ADAMTS9), was associated with postpartum diabetes (OR = 2.12, SE 0.22, p = 0.00055). The genetic risk score (GRS) of the top four SNPs tested for association with the disposition index using equal weights was associated with the disposition index (beta = − 0.31, SE = 0.29, p = 0.00096). In addition, the GRS of the four SNPs studied for association with HOMA-IR using equal weights showed an association with HOMA-IR (beta = 1.13, SE = 0.48, p = 9.72874e−11). All analyses were adjusted for age, body mass index, and ethnicity. Conclusions This study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity and, ultimately, to diabetes development.

Project description:BackgroundThe increase in diabetes worldwide is alarming. Decreased acute insulin response to intravenous glucose tolerance test (IVGTT) during first-phase insulin secretion (FPIS) is a characteristic of diabetes. However, knowledge of the insulin secretion characteristics identified by different time to glucose peak in subjects with different metabolic state is sparse.AimsThis study aimed to find different patterns of FPIS in subjects with normal glucose tolerance (NGT) and analyzed the relationship between insulin secretion patterns and the risk for development of type 2 diabetes mellitus (T2DM).MethodsA total of 126 subjects were divided into three groups during a 10-min IVGTT, including NGT with time to glucose peak after 3 min (G1, n = 21), NGT with time to glucose peak at 3 min (G2, n = 95), and prediabetes or diabetes with time to glucose peak at 3 min (G3, n = 10). Glucose, insulin, and C-peptide concentrations at 0, 3, 5, 7, and 10 min during the IVGTT were tested. IVGTT-based indices were calculated to evaluate the insulin secretion and insulin sensitivity.ResultsAge, body mass index (BMI), waist-to-hip ratio, triglyceride (TG), and hemoglobin A1c (HbA1c) of subjects were gradually higher, while high-density lipoprotein cholesterol (HDL-C) was gradually lower from G1 to G3 (p for linear trend <0.05), and the differences between G1 and G2 were also statistically significant (p < 0.05). Glucose peak of most participants in G1 converged at 5 min, and the curves shape of insulin and C-peptide in G2 were the sharpest among three groups. There was no significant difference in all IVGTT-based indices between G1 and G2, but AUCIns, AUCIns/AUCGlu, and △Ins3/△Glu3 in G2 were the highest, and the p-value for linear trend of those indices among three groups were statistically significant (p < 0.05).ConclusionsTwo patterns of FPIS were in subjects with NGT, while subjects with later time to glucose peak during FPIS might be less likely to develop T2DM in the future.

Project description:Aims/introductionTo investigate the differential effects of maternal versus paternal history of diabetes on the risks for diabetes and prediabetes, as well as on insulin secretion and resistance in Chinese individuals.Materials and methodsFrom the 2007 to 2008 China National Diabetes and Metabolism Disorders Study, 39,244 participants were included and divided into four categories: negative parental history, paternal history only (PH), maternal history only (MH), and both paternal and maternal history.ResultsThe age- and sex-standardized prevalence rates of diabetes in the negative parental history, PH, MH, and both paternal and maternal history groups were 8.59, 12.56, 15.86 and 29.81%, respectively. The prevalence rates of impaired glucose metabolism were 24.13, 25.41, 31.13 and 50.80%, with the prevalence in the MH group being significantly higher than that in the PH group. Compared with that in the FH0 group, the risks of diabetes in the PH, MH, and both paternal and maternal history groups were 2.01-, 2.67- and 6.37-fold greater, and the risks of impaired glucose metabolism were 1.28-, 1.65- and 3.45-fold greater. In addition, MH had a significantly greater impact on impaired glucose metabolism than PH (PMHvsPH = 0.0292). Regression analyses suggested MH was associated with homeostatic model assessment for β-cell function (β[SE] = -0.0910[0.0334], P = 0.0065), insulinogenic index (-0.1866[0.0550], P = 0.0007), homeostatic model assessment for insulin resistance (0.0662[0.0227], P = 0.0036) and Matsuda Index [-0.0716(0.0203), P = 0.0004]. PH was specifically associated with homeostatic model assessment for insulin resistance (0.1343[0.0267], P < 0.0001) and Matsuda Index (-0.1566[0.0243], P < 0.0001), but the effects were stronger than those of MH (PMHvsPH = 0.0431, 0.0054).ConclusionsMH and PH differentially influence the risks for diabetes, insulin secretion, and insulin resistance in the Chinese population, suggesting they participate in the pathogenesis of diabetes through different mechanisms.

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Association of a type 2 diabetes genetic risk score with insulin secretion modulated by insulin sensitivity among Chinese Hans.

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Association of a type 2 diabetes genetic risk score with insulin secretion modulated by insulin sensitivity among Chinese Hans.

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