Abstract:
OBJECTIVE:We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes-associated variants in the JAZF1 (rs864745), CDC123/CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), ADAMTS9 (rs4607103), and NOTCH2 (rs10923931) loci, which were recently identified by meta-analysis of genome-wide association data. RESEARCH DESIGN AND METHODS:We genotyped the six variants in 4,516 middle-aged glucose-tolerant individuals of the population-based Inter99 cohort who were all characterized by an oral glucose tolerance test (OGTT). RESULTS:Homozygous carriers of the minor diabetes risk G-allele of the CDC123/CAMK1D rs12779790 showed an 18% decrease in insulinogenic index (95% CI 10-27%; P = 4 x 10(-5)), an 18% decrease in corrected insulin response (CIR) (8.1-29%; P = 4 x 10(-4)), and a 13% decrease in the ratio of area under the serum-insulin and plasma-glucose curves during an OGTT (AUC-insulin/AUC-glucose) (5.8-20%; P = 4 x 10(-4)). Carriers of the diabetes-associated T-allele of JAZF1 rs864745 had an allele-dependent 3% decrease in BIGTT-AIR (0.9-4.3%; P = 0.003). Furthermore, the diabetes-associated C-allele of TSPAN8 rs7961581 associated with decreased levels of CIR (4.5% [0.5-8.4]; P = 0.03), of AUC-insulin/AUC-glucose ratio (3.9% [1.2-6.7]; P = 0.005), and of the insulinogenic index (5.2% [1.9-8.6]; P = 0.002). No association with traits of insulin release or insulin action was observed for the THADA, ADAMTS9, or NOTCH2 variants. CONCLUSIONS:If replicated, our data suggest that type 2 diabetes at-risk alleles in the JAZF1, CDC123/CAMK1D, and TSPAN8 loci associate with various OGTT-based surrogate measures of insulin release, emphasizing the contribution of abnormal pancreatic beta-cell function in the pathogenesis of type 2 diabetes.
journal_name
Diabetesjournal_title
Diabetesauthors
Grarup N,Andersen G,Krarup NT,Albrechtsen A,Schmitz O,Jørgensen T,Borch-Johnsen K,Hansen T,Pedersen Odoi
10.2337/db08-0436subject
Has Abstractpub_date
2008-09-01 00:00:00pages
2534-40issue
9eissn
0012-1797issn
1939-327Xpii
db08-0436journal_volume
57pub_type
杂志文章相关文献
DIABETES文献大全abstract::Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulatin...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db13-0095
更新日期:2013-11-01 00:00:00
abstract::We explored the role of reactive oxygen species (ROS) in the pathogenesis of muscle insulin resistance. We assessed insulin action in vivo with a hyperinsulinemic-euglycemic clamp in mice expressing a mitochondrial-targeted catalase (MCAT) that were fed regular chow (RC) or a high-fat diet (HFD) or underwent an acute ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-1334
更新日期:2017-08-01 00:00:00
abstract::Diabetes is generally diagnosed too late. Therefore, biomarkers indicating early stages of β-cell dysfunction and mass reduction would facilitate timely counteraction. Transgenic pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) reveal progressive deterioration of glu...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db11-1133
更新日期:2012-08-01 00:00:00
abstract::We previously showed that pancreatic beta-cells express a neuronal isoform of nitric oxide synthase (nNOS) that controls insulin secretion by exerting two enzymatic activities: nitric oxide (NO) production and cytochrome c reductase activity. We now bring evidence that two inhibitors of nNOS, N-omega-nitro-l-arginine ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.6.1467
更新日期:2004-06-01 00:00:00
abstract::IA-2 and IA-2beta are members of the transmembrane protein tyrosine phosphatase family located in dense core vesicles of neuroendocrine cells, including the beta-cells of pancreatic islets. In the present study, by mating C57BL/6Nci IA-2(+/-) with IA-2beta(+/-) mice, we generated double knockout mice (IA-2(-/-)/IA-2be...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.54.suppl_2.s46
更新日期:2005-12-01 00:00:00
abstract:OBJECTIVE:The presence of autoantibodies to islet antigens GAD and/or tyrosine phosphatase 2 (IA-2) in type 2 diabetic patients (latent autoimmune diabetes in adults [LADA]) identifies subjects at high risk to develop insulin dependency. The aim of this study was to dissect humoral anti-IA-2 immune response in Caucasia...
journal_title:Diabetes
pub_type: 杂志文章,多中心研究
doi:10.2337/db07-0874
更新日期:2008-05-01 00:00:00
abstract::We previously described a prosthetic group methodology for incorporating 18F into peptides and showed that 18F-labeled insulin (18F-insulin) binds to insulin receptors on human cells (IM-9 lymphoblastoid cells) with affinity equal to that of native insulin (1). We now report studies using 18F-insulin with positron emi...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.41.7.855
更新日期:1992-07-01 00:00:00
abstract::Adiponectin, one of the most abundant gene transcript proteins in human fat cells, has been shown to improve insulin action and is also suggested to exert antiatherogenic effects. We measured circulating adiponectin levels and risk factors for atherosclerosis in 45 healthy first-degree relatives of type 2 diabetic sub...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.5.1182
更新日期:2003-05-01 00:00:00
abstract::Changes in tissue levels of sorbitol, myo-inositol, and Na+-K+-ATPase enzyme activity have been implicated in the development of diabetic complications in animal models of the disease and in humans. The ability of the aldose reductase inhibitor sorbinil to reverse the hyperglycemia-induced changes in these lenticular ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.36.12.1414
更新日期:1987-12-01 00:00:00
abstract::OKT3 has emerged as a highly effective antirejection therapy, but its efficacy in pancreas transplantation remains to be determined. During a 26-mo period, 46 vascularized pancreas transplants were performed with pancreaticoduodenocystostomy. Twenty-one patients (45.7%) were treated with OKT3. Indications for OKT3 use...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.38.1.s74
更新日期:1989-01-01 00:00:00
abstract::Recent work suggests that insulin may exert both positive and negative feedback directly on pancreatic beta-cells. To investigate the hypothesis that insulin modulates beta-cell metabolism, mouse islets and beta-cell clusters were loaded with rhodamine 123 to dynamically monitor mitochondrial membrane potential (Delta...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.7.1765
更新日期:2004-07-01 00:00:00
abstract::Beiging of white adipose tissue has potential antiobesity and antidiabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1), protects mice from high-fat diet-i...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-0886
更新日期:2017-05-01 00:00:00
abstract::T-1095A and T-1095 are synthetic agents derived from phlorizin, a specific inhibitor of Na+-glucose cotransporters (SGLTs). Unlike phlorizin, T-1095 is absorbed into the circulation via oral administration, is metabolized to the active form, T-1095A, and suppresses the activity of SGLTs in the kidney. Orally administe...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.48.9.1794
更新日期:1999-09-01 00:00:00
abstract::Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, most people with diabetic nephropathy will never develop ESRD but will instead die of cardiovascular (CV) disease (CVD). The first evidence of kidney injury in diabetes is often microalbuminuria, itself also an independent risk mar...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db13-0795
更新日期:2013-11-01 00:00:00
abstract::Hyperglycemia-triggered vascular abnormalities are the most serious complications of diabetes mellitus (DM). The major cause of vascular dysfunction in DM is endothelial injury and dysfunction associated with the reduced number and dysfunction of endothelial progenitor cells (EPCs). A major challenge is to identify ke...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db18-1178
更新日期:2019-08-01 00:00:00
abstract::A total of 32 pairs of obese fathers or mothers and their obese offsprings, aged 20 yr or younger, from 25 families with established hyperinsulinemic obesity aged 11-20 yr equally showed an insulin hyperresponse to glucose, the offspring 10 yr or younger revealed a rather normal insulin response, despite the presence ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.30.1.14
更新日期:1981-01-01 00:00:00
abstract::Little is known about the molecular mechanisms underlying age-dependent deterioration in β-cell function. We now demonstrate that age-dependent impairment in insulin release, and thereby glucose homeostasis, is associated with subtle changes in Ca(2+) dynamics in mouse β-cells. We show that these changes are likely to...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db13-1855
更新日期:2014-12-01 00:00:00
abstract::This article seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to type 1 diabetes (T1D) risk among autoantibody-positive children in The Environmental Determinants of Diabetes in the Young (T...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db17-0261
更新日期:2017-12-01 00:00:00
abstract::The association of type 1 diabetes with the insulin gene (IDDM2 locus) has been mapped to a short haplotype encompassing two single nucleotide polymorphisms (SNPs) in perfect linkage disequilibrium (r(2) = 1) with each other and with the two allele classes at the variable number of tandem repeats (VNTR) polymorphism u...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-0402
更新日期:2007-03-01 00:00:00
abstract:OBJECTIVE:The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic beta-cell function was recently observed in the mouse model, we assessed the association of this ...
journal_title:Diabetes
pub_type: 杂志文章,多中心研究
doi:10.2337/db07-0484
更新日期:2008-02-01 00:00:00
abstract::The fa-gene was transferred from the Zucker rat (13 M strain) to the Wistar Kyoto (WKY) rat. The survey, performed at the 10th generation of backcrossing, showed that Wistar fatty rats (fa/fa), a congenic strain of WKY, developed obesity and obesity-related features, such as hyperinsulinemia and hyperlipemia, in the s...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.30.12.1045
更新日期:1981-12-01 00:00:00
abstract::Diabetes-induced alterations in heme and hemoproteins, as well as its relationship to drug-mediated induction of ALA Synthase (ALA-S), were examined in female Sprague-Dawley rats. Animals were rendered diabetic by a single i.v. injection of streptozotocin (STZ, 65 mg/kg) and measurements were made at various times aft...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.33.1.37
更新日期:1984-01-01 00:00:00
abstract::To identify mitochondrial haplogroups that confer resistance against or susceptibility to metabolic syndrome, we performed a large-scale association study on 1,337 unrelated Japanese individuals, including 871 subjects with metabolic syndrome and 466 control subjects. Metabolic syndrome was diagnosed according to modi...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-1105
更新日期:2007-02-01 00:00:00
abstract::Type 2 diabetes (T2D) is hallmarked by insulin resistance, impaired insulin secretion, and increased hepatic glucose production. The worldwide increasing prevalence of T2D calls for efforts to understand its pathogenesis in order to improve disease prevention and management. Recent genome-wide association studies have...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db13-1921
更新日期:2014-10-01 00:00:00
abstract:OBJECTIVE:Polymerase I and transcript release factor (PTRF) is a protein highly expressed in adipose tissue and is an integral structural component of caveolae. Here, we report on a novel role of PTRF in lipid mobilization. RESEARCH DESIGN AND METHODS:PTRF expression was examined in different adipose depots of mice du...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db10-0744
更新日期:2011-03-01 00:00:00
abstract::Diurnal variation in insulin sensitivity in patients with NIDDM has long been suspected but has been difficult to document mainly because of the interdependence of changes in glucose and insulin. Stable serum insulin levels during hyperglycemic clamping in patients with NIDDM in the present study provided the opportun...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.45.8.1044
更新日期:1996-08-01 00:00:00
abstract::We have attempted to define the nature of insulin secretory defect(s) in aged animals. In these studies, pancreatic islets were isolated from 2- and 18-mo-old Fischer 344 rats. Margination of secretion vesicles during exocytosis was assessed by measuring the recruitment of somatostatin (SRIF) receptors to the surface ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.34.11.1168
更新日期:1985-11-01 00:00:00
abstract::The early renal growth in streptozotocin (STZ)-induced diabetic rats is preceded by a transient rise in renal tissue insulin-like growth factor (IGF)-I concentration. Administration of the long-acting somatostatin analog octreotide to STZ diabetic rats inhibits the early increase in kidney IGF-I and the increase in ki...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.47.6.924
更新日期:1998-06-01 00:00:00
abstract::The gene for insulin-degrading enzyme (IDE) represents a strong positional and biological candidate for type 2 diabetes susceptibility. IDE maps to chromosome 10q23.3, a region linked to diabetes in several populations; the rat homolog has been directly implicated in diabetes susceptibility; and known functions of IDE...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.5.1300
更新日期:2003-05-01 00:00:00
abstract::It is accepted for insulin-secreting cells in culture that the closure of ATP-sensitive K+ channels causes the glucose-dependent depolarization of pancreatic beta-cells seen at subthreshold levels (less than 100 mg/dl) of glucose. The question remains for the more thoroughly studied beta-cells in freshly dissected int...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.38.4.416
更新日期:1989-04-01 00:00:00