Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Diabetologia (Impact Factor: 6.67). 09/2008; 51(11):1989-92. DOI: 10.1007/s00125-008-1124-7
Source: PubMed


Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals.
A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis.
The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min(-1) m(-2) (mmol/l)(-1), p = 1.51 x 10(-6)). The same was seen for the 30 min insulin response (p = 4.17 x 10(-7)). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p < 0.001 and p = 0.003, respectively).
This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals.

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Available from: Michael Weedon, Apr 16, 2015
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    • "The use of a Combined Genetic Score (by summing up the number of risk alleles of these diabetes loci; CGS) has been shown to predict T2D risk better than using each genetic loci alone [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]. Other groups have demonstrated that pathway-specific CGS, constructed by using beta-cell function-related loci, was associated with reduced beta-cell function [24], [36], [37], [38], [39]. Despite these advancements in our understanding of the T2D genetics, the discriminative power of GCS above and beyond clinical risk factors remains low. "
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    ABSTRACT: Recent genome-wide association studies (GWAS) identified more than 70 novel loci for type 2 diabetes (T2D), some of which have been widely replicated in Asian populations. In this study, we investigated their individual and combined effects on T2D in a Chinese population. We selected 14 single nucleotide polymorphisms (SNPs) in T2D genes relating to beta-cell function validated in Asian populations and genotyped them in 5882 Chinese T2D patients and 2569 healthy controls. A combined genetic score (CGS) was calculated by summing up the number of risk alleles or weighted by the effect size for each SNP under an additive genetic model. We tested for associations by either logistic or linear regression analysis for T2D and quantitative traits, respectively. The contribution of the CGS for predicting T2D risk was evaluated by receiver operating characteristic (ROC) analysis and net reclassification improvement (NRI). We observed consistent and significant associations of IGF2BP2, WFS1, CDKAL1, SLC30A8, CDKN2A/B, HHEX, TCF7L2 and KCNQ1 (8.5×10(-18)<P<8.5×10(-3)), as well as nominal associations of NOTCH2, JAZF1, KCNJ11 and HNF1B (0.05<P<0.1) with T2D risk, which yielded odds ratios ranging from 1.07 to 2.09. The 8 significant SNPs exhibited joint effect on increasing T2D risk, fasting plasma glucose and use of insulin therapy as well as reducing HOMA-β, BMI, waist circumference and younger age of diagnosis of T2D. The addition of CGS marginally increased AUC (2%) but significantly improved the predictive ability on T2D risk by 11.2% and 11.3% for unweighted and weighted CGS, respectively using the NRI approach (P<0.001). In a Chinese population, the use of a CGS of 8 SNPs modestly but significantly improved its discriminative ability to predict T2D above and beyond that attributed to clinical risk factors (sex, age and BMI).
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "Previously, several groups investigated the impact of a GRS for loci related to β-cell function and reported that the GRS was significantly associated with glucose-stimulated insulin secretion (GSIS) in nondiabetic subjects or the subjects with impaired glucose tolerance (4,26,37,38). However, the effects of the GRS on clinical features have not been evaluated in patients with type 2 diabetes. "
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    ABSTRACT: We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes. We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to β-cell function (β-GRS) and then assessing the association between each GRS and the clinical features. Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 × 10(-21)). Among the subjects with type 2 diabetes, the β-GRS was associated with individuals receiving insulin therapy (β = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = -0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = -0.032, SE = 0.0140, P = 0.022), and C-peptide index (β = -0.031, SE = 0.012, P = 0.0125). Our data suggest that the β-GRS is associated with reduced β-cell functions and may be useful for selecting patients who should receive more aggressive β-cell-preserving therapy.
    Full-text · Article · Jun 2012 · Diabetes care
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    • "The importance of beta-cell mass for T2D risk has been further highlighted by the results of recent genome-wide scans that have linked the likelihood of developing T2D to genetic defects in insulin secretion (Saxena et al., 2007; Scott et al., 2007; Zeggini et al., 2007). Importantly, among these T2D loci, two of them (CDKAL1 and HHEX-IDE) which are associated with significant impairments in beta-cell function (Pascoe et al., 2008; Groenewoud et al., 2008), have been related to low birth weight (Freathy et al., 2009). In this case, the most likely explanation for the association between low birth weight and T2D risk seems to be a genetically determined defective development of betacells leading to insufficient insulin secretion. "

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