Previously Associated Type 2 Diabetes Variants May Interact With Physical Activity to Modify the Risk of Impaired Glucose Regulation and Type 2 Diabetes: A Study of 16,003 Swedish Adults

OBJECTIVE-Recent advances in type 2 diabetes genetics have culminated in the discovery and confirmation of multiple risk variants. Two important, and largely unanswered questions are whether this information can be used to identify individuals most susceptible to the adverse consequences of sedentary behavior and to predict their response to lifestyle intervention; such evidence Would be mechanistically informative and provide a rationale for targeting genetically susceptible subgroups of the population. RESEARCH DESIGN AND METHODS-Gene X physical activity interactions were assessed for 17 polymorphisms ill a prospective population-based cohort of initially nondiabetic middle-aged adults. Outcomes were 1) impaired glucose regulation (IGR) versus normal glucose regulation determined with either fasting or 2-h plasma glucose concentrations (n = 16,003), 2) glucose intolerance (in mmol/l, n = 8,860), or 3) incident, type 2 diabetes (n = 2,063 events). RESULTS-Tests of gene X physical activity interactions oil IGR risk for 3 of the 17 polymorphisms were nominally statistically significant: CDKNT2A/B rs10811661 (P-interaction = 0.015), HNF1B rs4430796 (P-interaction = 0.026), and PPARG rs1801282 (P-interaction = 0.04). Consistent interactions were observed for the CDKN2A/B (P-interaction = 0.013) and HNF1B (P-interaction = 0.0009) variants on 2-h glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed, and this was for the HNF1B rs4430796 variant, (P-interaction = 0.0004). The interaction effects for HNF1B on IGR risk and incident diabetes remained significant after correction for multiple testing (P-interaction = 0.015 and 0.0068, respectively). CONCLUSIONS-Our observations suggest that the genetic predisposition to hyperglycemia is partially dependent on a person's lifestyle. Diabetes 58:1411-1418, 200

A Variant in the KCNQ1 Gene Predicts Future Type 2 Diabetes and Mediates Impaired Insulin Secretion

Objective- Two independent genome wide association studies for type 2 diabetes in Japanese have recently identified common variants in the KCNQ1 gene to be strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI, insulin secretion and action and predict future type 2 diabetes in subjects from Sweden and Finland. Research design and methods- Risk of type 2 diabetes conferred by KCNQ1 rs2237895 was studied in 2,830 type 2 diabetes cases and 3,550 controls from Sweden (Malmö Case-Control) and prospectively in 16,061 individuals from the Malmö Preventive Project (MPP). Association between genotype and insulin secretion/action was assessed cross-sectionally in 3,298 non-diabetic subjects from the PPP-Botnia Study and longitudinally in 2,328 non-diabetic subjects from the Botnia Prospective Study (BPS). KCNQ1 expression (n=18) and glucose-stimulated insulin secretion (n=19) was measured in human islets from non-diabetic cadaver donors. Results. The C-allele of KCNQ1 rs2237895 was associated with increased risk of type 2 diabetes in both the case-control (OR 1.23 [1.12-1.34], p=5.6x10(-6)) and the prospective (OR 1.14 [1.06-1.22], p=4.8x10(-4)) studies. Furthermore, the C-allele was associated with decreased insulin secretion (CIR p=0.013; DI p=0.013) in the PPP-Botnia study and in the BPS at baseline (CIR p=3.6x10(-4); DI p=0.0058) and after follow-up (CIR p=0.0018; DI p=0.0030). C-allele carriers showed reduced glucose-stimulated insulin secretion in human islets (p=2.5x10(-6)). Conclusion. A common variant in the KCNQ1 gene is associated with increased risk of future type 2 diabetes in Scandinavians which partially can be explained by an effect on insulin secretion

Type 2 Diabetes Susceptibility Gene TCF7L2 and Its Role in β-Cell Function

Type 2 diabetes is associated with impaired insu-lin secretion. Both 1st- and 2nd-phase insulinsecretion are reduced, but the effect is particu-larly pronounced for the 1st phase. The pro-cesses culminating in impaired insulin secretion are not fully understood, but both genetic and environmental factors are thought to play a role. Over the past 2 years, genome-wide association scans have transformed the ge-netic landscape of type 2 diabetes susceptibility, with the current gene count close to 20 (1). A couple of common themes have emerged from these studies. First, the major-ity of the genes identified thus far seem to affect diabetes susceptibility through -cell dysfunction (2). Second, the risk alleles tend to be common in the population, but their effect on diabetes risk is relatively small (3,4). TCF7L2, the susceptibility gene with the largest effect on disease susceptibility discovered to date, was iden-tified pre–genome-wide association by Grant et al. i

GAD Antibody Positivity Predicts Type 2 Diabetes in an Adult Population

OBJECTIVE-To evaluate the significance of GAD antibodies (GADAs) and family history for type 1 diabetes (FHT1) or type 2 diabetes (FHT2) in nondiabetic subjects. RESEARCH DESIGN AND METHODS-GADAs were analyzed in 4,976 nondiabetic relatives of type 2 diabetic patients or control subjects from Finland. Altogether, 289 (5.9%) were GADA(+)-a total of 253 GADA(+) and 2,511 GADA(-) subjects participated in repeated oral glucose tolerance tests during a median time of 8.1 years. The risk of progression to diabetes was assessed using Cox regression analysis. RESULTS-Subjects within the highest quartile of GADA(+) (GADA(high)(+)) had more often first-degree FHT1 (29.2 vs. 7.9%, P < 0.00001) and GADA(+) type 2 diabetic (21.3 vs. 13.7%, P = 0.002) or nondiabetic (26.4 vs. 13.3%, P = 0.010) relatives than GADA(-) subjects. During the follow-up, the GADA(+) subjects developed diabetes significantly more often than the GADA(-) subjects (36/253 [14.2%] vs. 134/2,511 [5.3%], P < 0.00001). GADA(high)(+) conferred a 4.9-fold increased risk of diabetes (95% CI 2.8-8.5) compared with GADA(-)-seroconversion to positive during the follow-up was associated with 6.5-fold (2.8-15.2) and first-degree FHT1 with 2.2-fold (1.2-4.1) risk of diabetes. Only three subjects developed type 1 diabetes, and others had a non-insulin-dependent phenotype 1 year after diagnosis. GADA(+) and GADA(-) subjects did not clinically differ at baseline, but they were leaner and less insulin resistant after the diagnosis of diabetes. CONCLUSIONS-GADA positivity clusters in families with type 1 diabetes or latent autoimmune diabetes in adults. GADA positivity predicts diabetes independently of family history of diabetes, and this risk was further increased with high GADA concentrations

A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.

Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis

Effects of impurity scattering on electron-phonon resonances in semiconductor superlattice high-field transport

A non-equilibrium Green's function method is applied to model high-field quantum transport and electron-phonon resonances in semiconductor superlattices. The field-dependent density of states for elastic (impurity) scattering is found non-perturbatively in an approach which can be applied to both high and low electric fields. I-V curves, and specifically electron-phonon resonances, are calculated by treating the inelastic (LO phonon) scattering perturbatively. Calculations show how strong impurity scattering suppresses the electron-phonon resonance peaks in I-V curves, and their detailed sensitivity to the size, strength and concentration of impurities.Comment: 7 figures, 1 tabl

Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

OBJECTIVE - At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. RESEARCH DESIGN AND METHODS - A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/ 191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. RESULTS - The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 × 1

Bloch oscillations of magnetic solitons in anisotropic spin-1/2 chains

We study the quantum dynamics of soliton-like domain walls in anisotropic spin-1/2 chains in the presence of magnetic fields. In the absence of fields, domain walls form a Bloch band of delocalized quantum states while a static field applied along the easy axis localizes them into Wannier wave packets and causes them to execute Bloch oscillations, i.e. the domain walls oscillate along the chain with a finite Bloch frequency and amplitude. In the presence of the field, the Bloch band, with a continuum of extended states, breaks up into the Wannier-Zeeman ladder -- a discrete set of equally spaced energy levels. We calculate the dynamical structure factor in the one-soliton sector at finite frequency, wave vector, and temperature, and find sharp peaks at frequencies which are integer multiples of the Bloch frequency. We further calculate the uniform magnetic susceptibility and find that it too exhibits peaks at the Bloch frequency. We identify several candidate materials where these Bloch oscillations should be observable, for example, via neutron scattering measurements. For the particular compound CoCl_2.2H_2O we estimate the Bloch amplitude to be on the order of a few lattice constants, and the Bloch frequency on the order of 100 GHz for magnetic fields in the Tesla range and at temperatures of about 18 Kelvin.Comment: 31 single-spaced REVTeX pages, including 7 figures embedded with eps