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: 6.88). 09/2008; 51(11):1989-92. DOI: 10.1007/s00125-008-1124-7
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetic patients are insulin resistant as a result of obesity and a sedentary lifestyle. Nevertheless, it has been known for the past five decades that insulin response to nutrients is markedly diminished in type 2 diabetes. There is now a consensus that impaired glucose regulation cannot develop without insulin deficiency. First-phase insulin response to glucose is lost very early in the development of type 2 diabetes. Several prospective studies have shown that impaired insulin response to glucose is a predictor of future impaired glucose tolerance (IGT) and type 2 diabetes. Recently discovered type 2 diabetes-risk gene variants influence β-cell function, and might represent the molecular basis for the low insulin secretion that predicts future type 2 diabetes. We believe type 2 diabetes develops on the basis of normal but 'weak'β-cells unable to cope with excessive functional demands imposed by overnutrition and insulin resistance. Several laboratories have shown a reduction in β-cell mass in type 2 diabetes and IGT, whereas others have found modest reductions and most importantly, a large overlap between β-cell masses of diabetic and normoglycemic subjects. Therefore, at least initially, the β-cell dysfunction of type 2 diabetes seems more functional than structural. However, type 2 diabetes is a progressive disorder, and animal models of diabetes show β-cell apoptosis with prolonged hyperglycemia/hyperlipemia (glucolipotoxicity). β-Cells exposed in vitro to glucolipotoxic conditions show endoplasmic reticulum (ER) and oxidative stress. ER stress mechanisms might participate in the adaptation of β-cells to hyperglycemia, unless excessive. β-Cells are not deficient in anti-oxidant defense, thioredoxin playing a major role. Its inhibitor, thioredoxin-interacting protein (TXNIP), might be important in leading to β-cell apoptosis and type 2 diabetes. These topics are intensively investigated and might lead to novel therapeutic approaches. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00094.x, 2011).
    Journal of diabetes investigation. 04/2011; 2(2):82-91.
  • Source
    [Show abstract] [Hide abstract]
    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).
    PLoS ONE 12/2013; 8(12):e83093. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To assess the association of birth weight with incident type 2 diabetes, and the possible mediating influence of obesity, in a large cohort of U.S. black women.
    Diabetes Care 09/2014; 37(9):2572-8. · 8.57 Impact Factor


Available from