bluuebunny/crossref_metadata_2025 huggingface dataset:
Di-(2-ethylhexyl)phthalate and Deep Venous Thrombosis in Children: A Clinical and Experimental Analysis
Authors: Danschutter Dirk , Braet Filip , Van Gyseghem Elke , Hachimi-Idrissi Said , Van Bruwaene Benny , Moloney-Harmon Pat , Huyghens Luc
Published: February 2007

BACKGROUND. Five children with catheter-related deep venous thrombosis were encountered in our PICU. Three types of polyvinyl chloride tubing for the administration of intravenous solutions were in use (Terumo, Codan, and Perfusend). All were di-(2-ethylhexyl)phthalate plasticized. We suspected problems with the Codan tubing.

METHODS. Different types of tubing at different time intervals in vitro were investigated. Tubing segments were assessed on structural alterations by surface electron microscopy. High-performance liquid chromatography-diode array detection and liquid chromatography-mass spectrometry-diode array detection were performed to identify and to quantify di-(2-ethylhexyl)phthalate. The hospital's minimal clinical data set (coded with the International Classification of Diseases, Ninth Revision, Clinical Modification) was investigated on catheter-related deep venous thrombosis between 2000 and 2004.

RESULTS. Surface electron microscopy demonstrated that the Codan tubing's inner surface was severely altered, showing large particles (34.5 ± 6.1 μm). High-performance liquid chromatography documented that all Codan samples showed a peak at the di-(2-ethylhexyl)phthalate retention time. The analysis of the minimal clinical data set for total catheter-related deep venous thrombosis showed an unusual high incidence in 2001 (52) compared with the expected 36 per year.

CONCLUSIONS. Such occurrence of catheter-related deep venous thrombosis led to the assumption that disintegration of intravenous tubing resulted in intravenous administration of debris. Our data suggested that the particles derived from the tubing are of such size that they might induce catheter-related deep venous thrombosis. The absence of catheter-related deep venous thrombosis caused by the introduction of submicron inline filters outlines the important pathophysiological role of di-(2-ethylhexyl)phthalate-plasticized particles in the onset of catheter-related deep venous thrombosis. Our data indicate that a considerable number of patients might have been exposed to di-(2-ethylhexyl)phthalate, and a major concern is whether this jeopardized the health of the patients at that time.
A constitutive model for soft clayey rocks that includes weathering effects
Authors: Pinyol N. , Vaunat J. , Alonso E. E.
Published: February 2007

Microstructural and mineralogical observations of clay-stones reveal the presence of clay aggregates bonded by a skeleton of inert minerals such as calcium carbonate. The behaviour of these natural materials evolves from a rock-like behaviour, when undisturbed, to clay-like soil when weathered or when subjected to straining. A model has been developed to simulate the constitutive behaviour of these transitional materials. Following the proposal made by Vaunat & Gens, the material is conceived as a composite medium made of a clay matrix and a quasi-brittle bonding microstructure. The basic model has been modified and extended to reproduce the expansive behaviour of the clay matrix, a fundamental aspect to simulate weathering effects, induced largely by drying–wetting cycles. The clay matrix reacts to stress and suction changes, whereas the bond component is not affected by suction changes. An elasto-plastic double-structure model for expansive clay soils describes the clay matrix. The bonding structure follows a damage model. The interaction between the two constitutive models derives from strain compatibility conditions and energy considerations. The model performance is first illustrated by means of a sensitive analysis that explores the effect of initial bond strength, bond damage rate, bonding concentration, and wetting–drying cycles. Simple stress paths (uniaxial deformation; triaxial compression) are used to highlight the features of the formulation and the role of significant parameters. Some published tests are also reproduced with the model. They have been selected to show some relevant features of evolving soft clay rocks: stiffness and strength degradation during loading and enhanced rebound during unloading, and the effect of drying–wetting cycles on subsequent stiffness and strength degradation.
Undrained behaviour of brecciated Upper Lias Clay at Empingham Dam
Authors: Kovacevic N. , Higgins K. G. , Potts D. M. , Vaughan P. R.
Published: February 2007

Empingham Dam was built in the early 1970s on a brecciated Upper Lias Clay foundation of fill derived from it. When the dam was designed, the undrained behaviour of intact stiff plastic clay in the field was poorly understood. Thus, a conservative bound to conventional strength tests was adopted to provide an undrained strength profile in the foundation. The shearing resistance of the foundation was also investigated by incorporating an instrumented 24 m high trial bank in the upstream berm of the main dam. As the trial bank was nearing completion, two slips occurred in temporary borrow pit slopes. It was considered that this field experience, together with undrained triaxial tests with pore pressure measurement on large diameter samples carried out in the laboratory, justified the original design assumptions. However, the end lengths of the main embankment on the undrained foundation started to spread laterally when the fill was some 2 m below the final level. This was in spite of the fact that the conventional factor of safety, calculated using the original design assumptions, was in excess of two. This paper describes the finite element (FE) back analysis of the observed behaviour. For this purpose two different constitutive models have been employed: a kinematically hardening ‘bubble’ model accounting for pre-peak plasticity, and a non-linear elastic Mohr-Coulomb plastic model accounting for strain-softening. It is demonstrated that the observed undrained behaviour of the Empingham foundation can be reproduced by FE analyses, but only if the undrained shearing resistance varies from section to section.
Pore water pressure and horizontal stress changes measured during construction of a contiguous bored pile multi-propped retaining wall in Lower Cretaceous clays
Authors: Richards D. J. , Powrie W. , Roscoe H. , Clark J.
Published: February 2007

The design and construction of a contiguous bored pile propped retained cut on the approaches to Ashford International Station raised some challenging design issues. Design problems associated with under-drainage and groundwater control (including the performance of semi-permeable propped retaining walls) and the effects of wall installation and movement on in situ stresses were compounded by the relatively limited geotechnical engineering experience of the Atherfield and Weald Clay formations. Differences in the permeabilities of these two strata were expected, but the impact of these on the design was only fully established at the start of construction. Some aspects of the engineering behaviour of the Atherfield and Weald Clays are discussed with reference to an instrumented section of the propped retained cut. The changes in total horizontal stress and pore water pressures measured during and over a six-year period following construction of the retained cut are presented, and their significance is discussed.
Evaluation of Common Variants in the Six Known Maturity-Onset Diabetes of the Young (MODY) Genes for Association With Type 2 Diabetes
Authors: Winckler Wendy , Weedon Michael N. , Graham Robert R. , McCarroll Steven A. , Purcell Shaun , Almgren Peter , Tuomi Tiinamaija , Gaudet Daniel , Boström Kristina Bengtsson , Walker Mark , Hitman Graham , Hattersley Andrew T. , McCarthy Mark I. , Ardlie Kristin G. , Hirschhorn Joel N. , Daly Mark J. , Frayling Timothy M. , Groop Leif , Altshuler David
Published: February 2007

An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4–MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value <0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values <0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value <10−6 in >15,000 samples. We combined these results with our previous studies on HNF4α and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.
Investigation of the Estrogen Receptor-α Gene With Type 2 Diabetes and/or Nephropathy in African-American and European-American Populations
Authors: Gallagher Carla J. , Keene Keith L. , Mychaleckyj Josyf C. , Langefeld Carl D. , Hirschhorn Joel N. , Henderson Brian E. , Gordon Candace J. , Freedman Barry I. , Rich Stephen S. , Bowden Donald W. , Sale Michèle M.
Published: February 2007

The estrogen receptor-α gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes–ESRD was with rs1033182 in intron 2 (P = 0.013, admixture-adjusted Pa = 0.021). Genotyping 17 SNPs across a region of ESR1 intron 1–intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P = 0.004, Pa = 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, Pa < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 European-American type 2 diabetes–ESRD case subjects and 310 European-American control subjects. Two intron 2 SNPs, rs2431260 (P = 0.015) and rs1709183 (P = 0.019), and a four-SNP haplotype containing these SNPs (P = 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk.
Antidiabetic Effects of cis-9, trans-11–Conjugated Linoleic Acid May Be Mediated via Anti-Inflammatory Effects in White Adipose Tissue
Authors: Moloney Fiona , Toomey Sinead , Noone Enda , Nugent Anne , Allan Bernard , Loscher Christine E. , Roche Helen M.
Published: February 2007

Adipose tissue may be the source of insulin desensitizing proinflammatory molecules that predispose to insulin resistance. This study investigated whether dietary fatty acids could attenuate the proinflammatory insulin-resistant state in obese adipose tissue. The potential antidiabetic effect of cis-9, trans-11–conjugated linoleic acid (c9,t11-CLA) was determined, focusing on the molecular markers of insulin sensitivity and inflammation in adipose tissue of ob/ob C57BL-6 mice. Feeding a c9,t11-CLA–enriched diet reduced fasting glucose (P < 0.05), insulin (P < 0.05), and triacylglycerol concentrations (P < 0.01) and increased adipose tissue plasma membrane GLUT4 (P < 0.05) and insulin receptor (P < 0.05) expression compared with the control linoleic acid–enriched diet. Interestingly, after the c9,t11-CLA diet, adipose tissue macrophage infiltration was less, with marked downregulation of several inflammatory markers in adipose tissue, including reduced tumor necrosis factor-α and CD68 mRNA (P < 0.05), nuclear factor-κB (NF-κB) p65 expression (P < 0.01), NF-κB DNA binding (P < 0.01), and NF-κB p65, p50, c-Rel, p52, and RelB transcriptional activity (P < 0.01). To define whether these observations were direct effects of the nutrient intervention, complimentary cell culture studies showed that c9,t11-CLA inhibited tumor necrosis factor-α–induced downregulation of insulin receptor substrate 1 and GLUT4 mRNA expression and promoted insulin-stimulated glucose transport in 3T3-L1 adipocytes compared with linoleic acid. This study suggests that altering fatty acid composition may attenuate the proinflammatory state in adipose tissue that predisposes to obesity-induced insulin resistance.
Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene With Diabetes
Authors: Marchand Luc , Polychronakos Constantin
Published: February 2007

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 (r2 = 1) with each other and with the two allele classes at the variable number of tandem repeats (VNTR) polymorphism upstream of the transcription site. Although it is believed that the genetic effect is mediated through transcriptional effects of the VNTR, an alternative mechanism has been recently proposed: In transfected cells, the common A allele at one of the SNPs (−23A→T, in relation to the translation-initiation codon) weakens the splicing of intron 1, resulting in a minor (∼15% of total RNA) transcript with a longer 5′ untranslated region and sixfold enhanced translational efficiency. The purpose of our study was to confirm these findings in RNA from normal human pancreas and thymus. We report that pancreas does contain the alternative transcript in an allele-dependent manner but at a very low proportion (<5% of total INS mRNA). We believe that this level would have a minor, if any, biological effect involved in the mechanism of the IDDM2 locus.
Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes
Authors: Thum Thomas , Fraccarollo Daniela , Schultheiss Maximilian , Froese Sabrina , Galuppo Paolo , Widder Julian D. , Tsikas Dimitrios , Ertl Georg , Bauersachs Johann
Published: February 2007

Uncoupling of the endothelial nitric oxide synthase (eNOS) resulting in superoxide anion (O2−) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction. eNOS regulates mobilization and function of endothelial progenitor cells (EPCs), key regulators of vascular repair. We postulate a role of eNOS uncoupling for reduced number and function of EPC in diabetes. EPC levels in diabetic patients were significantly reduced compared with those of control subjects. EPCs from diabetic patients produced excessive O2− and showed impaired migratory capacity compared with nondiabetic control subjects. NOS inhibition with NG-nitro-l-arginine attenuated O2− production and normalized functional capacity of EPCs from diabetic patients. Glucose-mediated EPC dysfunction was protein kinase C dependent, associated with reduced intracellular BH4 (tetrahydrobiopterin) concentrations, and reversible after exogenous BH4 treatment. Activation of NADPH oxidases played an additional but minor role in glucose-mediated EPC dysfunction. In rats with streptozotocin-induced diabetes, circulating EPCs were reduced to 39 ± 5% of controls and associated with uncoupled eNOS in bone marrow. Our results identify uncoupling of eNOS in diabetic bone marrow, glucose-treated EPCs, and EPCs from diabetic patients resulting in eNOS-mediated O2− production. Subsequent reduction of EPC levels and impairment of EPC function likely contributes to the pathogenesis of vascular disease in diabetes.
Role of Excess Glycogenolysis in Fasting Hyperglycemia Among Pre-Diabetic and Diabetic Zucker (fa/fa) Rats
Authors: Jin Eunsook S. , Park Byung-Hyun , Sherry A. Dean , Malloy Craig R.
Published: February 2007

Sources of plasma glucose and glucose turnover were investigated in 8-week-old (pre-diabetic) and 13-week-old (diabetic) Zucker (fa/fa) rats after a 24-h fast. Intraperitoneal 2H2O was administered and [3,4-13C2]glucose and [U-13C3]propionate were infused into conscious active rats. 13C nuclear magnetic resonance analysis of monoacetone glucose derived from blood glucose indicated that glucose production was increased significantly in 8- and 13-week-old fa/fa rats compared with age-matched Zucker (+/+) rats, and hepatic glycogen was dramatically higher among fa/fa animals regardless of age. Glycogenolysis, essentially 0 in +/+ rats after a 24-h fast, was significant in fa/fa rats (11 ± 6 and 17 ± 7% of glucose production in 8- and 13-week-old rats, respectively), even after a 24-h fast. Tricarboxylic acid (TCA) cycle flux and efflux of carbon skeletons from the cycle (cataplerosis) were both significantly higher in fa/fa rats compared with controls, but net gluconeogenesis from the TCA cycle was not higher because products leaving the cycle were returned to the cycle via a pyruvate cycling pathway. Thus, pyruvate cycling flux increased in proportion to TCA cycle flux, leaving net gluconeogenesis unchanged in fa/fa animals compared with control animals. The distribution of 2H in skeletal muscle glycogen suggested that at least a fraction of glucose molecules entering glycogen pass through phosphomannose isomerase.
Superiority of Small Islets in Human Islet Transplantation
Authors: Lehmann Roger , Zuellig Richard A. , Kugelmeier Patrick , Baenninger Philipp B. , Moritz Wolfgang , Perren Aurel , Clavien Pierre-Alain , Weber Markus , Spinas Giatgen A.
Published: February 2007

Many factors influence the outcome of islet transplantation. As islets in the early posttransplant setting are supplied with oxygen by diffusion only and are in a hypoxic state in the portal system, we tested whether small human islets are superior to large islets both in vitro and in vivo. We assessed insulin secretion of large and small islets and quantified cell death during hypoxic conditions simulating the intraportal transplant environment. In the clinical setting, we analyzed the influence of transplanted islet size on insulin production in patients with type 1 diabetes. Our results provide evidence that small islets are superior to large islets with regard to in vitro insulin secretion and show a higher survival rate during both normoxic and hypoxic culture. Islet volume after 48 h of hypoxic culture decreased to 25% compared with normoxic culture at 24 h due to a preferential loss of large islets. In human islet transplantation, the isolation index (islet volume as expressed in islet equivalents/islet number), or more simply the islet number, proved to be more reliable to predict stimulated C-peptide response compared with islet volume. Thus, islet size seems to be a key factor determining human islet transplantation outcome.
Patients With Chronic Pancreatitis Have Islet Progenitor Cells in Their Ducts, but Reversal of Overt Diabetes in NOD Mice by Anti-CD3 Shows No Evidence for Islet Regeneration
Authors: Phillips Jenny M. , O’Reilly Lorraine , Bland Chris , Foulis Alan K. , Cooke Anne
Published: February 2007

Monoclonal antibodies to T-cell coreceptors have been shown to tolerise autoreactive T-cells and prevent or even reverse autoimmune pathology. In type 1 diabetes, there is a loss of insulin-secreting β-cells, and a cure for type 1 diabetes would require not only tolerance induction but also recovery of the functional β-cell mass. Although we have previously shown that diabetic mice have increased numbers of ductal progenitors in the pancreas, there is no evidence of any increase of insulin-secreting cells in the ducts. In contrast, in the adult human pancreas of patients with chronic pancreatitis, we can demonstrate, in the ducts, increased numbers of insulin-containing cells, as well as cells containing other endocrine and exocrine markers. There are also significantly increased numbers of cells expressing the homeodomain protein, pancreatic duodenal homeobox-1. Anti-CD3 has been shown to reverse overt diabetes in NOD mice; thus, we have used this model to ask whether monoclonal antibody–mediated inhibition of ongoing β-cell destruction enables islet regeneration to occur. We find no evidence that such monoclonal antibody therapy results in either regeneration of insulin-secreting β-cells or of increased proliferation of islet β-cells.
Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration
Authors: Bajaj Mandeep , Medina-Navarro Rafael , Suraamornkul Swangjit , Meyer Christian , DeFronzo Ralph A. , Mandarino Lawrence J.
Published: February 2007

Lipid oversupply plays a role in developing insulin resistance in skeletal muscle, decreasing expression of nuclear-encoded mitochondrial genes, and increasing extracellular matrix remodeling. To determine if a decrease in plasma lipid content reverses these abnormalities, insulin-resistant subjects with a family history of type 2 diabetes had euglycemic clamps and muscle biopsies before and after acipimox treatment to suppress free fatty acids. Free fatty acids fell from 0.584 ± 0.041 to 0.252 ± 0.053 mmol/l (P < 0.001) and glucose disposal increased from 5.28 ± 0.46 to 6.31 ± 0.55 mg · kg−1 · min−1 (P < 0.05) after acipimox; intramuscular fatty acyl CoA decreased from 10.3 ± 1.9 to 4.54 ± 0.82 pmol/mg muscle (P < 0.01). Paradoxically, expression of PGC-1–and nuclear-encoded mitochondrial genes decreased after acipimox, and expression of collagens I and III α-subunits (82- and 21-fold increase, respectively, P < 0.05), connective tissue growth factor (2.5-fold increase, P < 0.001), and transforming growth factor-β1 increased (2.95-fold increase, P < 0.05). Therefore, a reduction in lipid supply does not completely reverse the molecular changes associated with lipid oversupply in muscle. Changes in expression of nuclear-encoded mitochondrial genes do not always correlate with changes in insulin sensitivity.
Common Variation in the LMNA Gene (Encoding Lamin A/C) and Type 2 Diabetes
Authors: Owen Katharine R. , Groves Christopher J. , Hanson Robert L. , Knowler William C. , Shuldiner Alan R. , Elbein Steven C. , Mitchell Braxton D. , Froguel Philippe , Ng Maggie C.Y. , Chan Juliana C. , Jia Weiping , Deloukas Panos , Hitman Graham A. , Walker Mark , Frayling Timothy M. , Hattersley Andrew T. , Zeggini Eleftheria , McCarthy Mark I. ,   for the International Type 2 Diabetes 1q Consortium
Published: February 2007

Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98–1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99–1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04–1.16], P = 0.001).
Relationship of Traditional and Nontraditional Cardiovascular Risk Factors to Coronary Artery Calcium in Type 2 Diabetes
Authors: Mazzone Theodore , Meyer Peter M. , Kondos George T. , Davidson Michael H. , Feinstein Steven B. , D’Agostino Ralph B. , Perez Alfonso , Haffner Steven M.
Published: February 2007

We evaluated correlates of coronary atherosclerosis, measured by coronary artery calcium, in a racially diverse group of male and female subjects with type 2 diabetes. Age, systolic blood pressure, sex, and race/ethnicity were significant determinants of coronary artery calcium. Among lipoproteins, cholesterol level contained in a particle excluded from direct measures of LDL and HDL cholesterol (designated triglyceride-rich lipoprotein cholesterol) was most strongly linked to coronary artery calcium. Neither inflammatory markers nor metabolic factors correlated with coronary artery calcium in models adjusted for age and sex, but measures of adipose distribution did. Waist-to-hip ratio and the ratio of visceral to total abdominal tissue were positively associated with coronary artery calcium. In fully adjusted multivariate models, the relationship of adiposity measures to coronary artery calcium was no longer significant after inclusion of apolipoprotein B or triglyceride-rich lipoprotein cholesterol. Traditional risk factors and race/ethnicity remain important correlates of coronary artery calcium in a cohort at elevated risk of cardiovascular disease because of type 2 diabetes. Adiposity measures are significantly associated with coronary artery calcium score, but their importance may be largely explained by apolipoprotein B or triglyceride-rich lipoprotein cholesterol.
Lamin A/C Polymorphisms, Type 2 Diabetes, and the Metabolic Syndrome
Authors: Mesa José L. , Loos Ruth J.F. , Franks Paul W. , Ong Ken K. , Luan Jian’an , O’Rahilly Stephen , Wareham Nicholas J. , Barroso Inês
Published: February 2007

Mutations in the LMNA gene, encoding the nuclear envelope protein lamin A/C, are responsible for a number of distinct disease entities including Dunnigan-type familial partial lipodystrophy. Dunningan-type lipodystrophy is characterized by loss of subcutaneous adipose tissue, insulin resistance, dyslipidemia, and type 2 diabetes and shares many of the features of the metabolic syndrome. Furthermore, several genome-wide linkage scans for type 2 diabetes have found evidence of linkage at chromosome 1q21.2, the region that harbors the LMNA gene. Therefore, LMNA is a biological and positional candidate for type 2 diabetes susceptibility. Previous studies have reported association between a common LMNA variant (1908C>T; rs4641) and adverse metabolic traits in ethnically diverse populations from Asia and North America. In the present study, we characterized the common variation across the LMNA gene (including rs4641) and tested for association with type 2 diabetes in two large case-control studies (n = 2,052) and with features of the metabolic syndrome in a separate cohort study (n = 1,572). Despite our study being sufficiently powered to detect effects similar and even smaller in magnitude than those previously reported, none of the LMNA single nucleotide polymorphisms were statistically significantly associated with type 2 diabetes or the metabolic syndrome. Thus, it appears unlikely that variation at LMNA substantially increases the risk of type 2 diabetes or related traits in U.K. Europids.
Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects With Type 2 Diabetes
Authors: Sriwijitkamol Apiradee , Coletta Dawn K. , Wajcberg Estela , Balbontin Gabriela B. , Reyna Sara M. , Barrientes John , Eagan Phyllis A. , Jenkinson Christopher P. , Cersosimo Eugenio , DeFronzo Ralph A. , Sakamoto Kei , Musi Nicolas
Published: February 2007

Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI ∼25 kg/m2) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m2), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator–activated receptor coactivator (PGC)-1α, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% Vo2max) and moderate (70% Vo2max) intensities, with a 4–6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects.
Increases in Adiponectin Predict Improved Liver, but Not Peripheral, Insulin Sensitivity in Severely Obese Women During Weight Loss
Authors: Lin Edward , Phillips Lawrence S. , Ziegler Thomas R. , Schmotzer Brian , Wu Kongjun , Gu Li H. , Khaitan Leena , Lynch Scott A. , Torres William E. , Smith C. Daniel , Gletsu-Miller Nana
Published: February 2007

Obesity-related glucose intolerance is a function of hepatic (homeostatic model assessment-insulin resistance [HOMA-IR]) and peripheral insulin resistance (Si) and β-cell dysfunction. We determined relationships between changes in these measures, visceral (VAT) and subcutaneous (SAT) adipose tissue, and systemic adipocytokine biomarkers 1 and 6 months after surgical weight loss. HOMA-IR decreased significantly (−50%) from baseline by 1 month and decreased further (−67%) by 6 months, and Si was improved by 6 months (2.3-fold) weight loss. Plasma concentrations of leptin decreased and adiponectin increased significantly by 1 month, and decreases in interleukin-6, C-reactive protein (CRP), and tumor necrosis factor-α were observed at 6 months of weight loss. Longitudinal decreases in CRP (r = −0.53, P < 0.05) were associated with increases in Si, and decreases in HOMA-IR were related to increases in adiponectin (r = −0.37, P < 0.05). Decreases in VAT were more strongly related to increases in adiponectin and decreases in CRP than were changes in general adiposity or SAT. Thus, in severely obese women, specific loss of VAT leads to acute improvements in hepatic insulin sensitivity mediated by increases in adiponectin and in peripheral insulin sensitivity mediated by decreases in CRP.
PED/PEA-15 Regulates Glucose-Induced Insulin Secretion by Restraining Potassium Channel Expression in Pancreatic β-Cells
Authors: Miele Claudia , Raciti Gregory Alexander , Cassese Angela , Romano Chiara , Giacco Ferdinando , Oriente Francesco , Paturzo Flora , Andreozzi Francesco , Zabatta Assunta , Troncone Giancarlo , Bosch Fatima , Pujol Anna , Chneiweiss Hervé , Formisano Pietro , Beguinot Francesco
Published: February 2007

The phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (ped/pea-15) gene is overexpressed in human diabetes and causes this abnormality in mice. Transgenic mice with β-cell–specific overexpression of ped/pea-15 (β-tg) exhibited decreased glucose tolerance but were not insulin resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the β-tg also exhibited little response to glucose. mRNAs encoding the Sur1 and Kir6.2 potassium channel subunits and their upstream regulator Foxa2 were specifically reduced in these islets. Overexpression of PED/PEA-15 inhibited the induction of the atypical protein kinase C (PKC)-ζ by glucose in mouse islets and in β-cells of the MIN-6 and INS-1 lines. Rescue of PKC-ζ activity elicited recovery of the expression of the Sur1, Kir6.2, and Foxa2 genes and of glucose-induced insulin secretion in PED/PEA-15–overexpressing β-cells. Islets from ped/pea-15–null mice exhibited a twofold increased activation of PKC-ζ by glucose; increased abundance of the Sur1, Kir6.2, and Foxa2 mRNAs; and enhanced glucose effect on insulin secretion. In conclusion, PED/PEA-15 is an endogenous regulator of glucose-induced insulin secretion, which restrains potassium channel expression in pancreatic β-cells. Overexpression of PED/PEA-15 dysregulates β-cell function and is sufficient to impair glucose tolerance in mice.
Polymorphisms of the Renin-Angiotensin System Genes Predict Progression of Subclinical Coronary Atherosclerosis
Authors: Kretowski Adam , McFann Kim , Hokanson John E. , Maahs David , Kinney Gregory , Snell-Bergeon Janet K. , Wadwa R. Paul , Eckel Robert H. , Ogden Lorraine , Garg Satish , Li Jia , Cheng Suzanne , Erlich Henry A. , Rewers Marian
Published: February 2007

Premature coronary artery disease (CAD) in subjects with type 1 diabetes dramatically affects quality of life and morbidity and leads to premature death, but there is still little known about the mechanisms and predictors of this complication. In the present study, we explored the role of genetic variants of angiotensinogen (AGT, M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1, A1166C) as predictors of rapid progression of subclinical coronary atherosclerosis. Five-hundred eighty-five type 1 diabetic patients and 592 similar age and sex control subjects were evaluated for progression of coronary artery calcification (CAC), a marker of subclinical CAD, before and after a 2.5-year follow-up. In logistic regression analysis, CAC progression was dramatically more likely in type 1 diabetic subjects not treated with ACE inhibitor/angiotensin receptor blocker who had the TT-ID-AA/AC genotype combination than in those with other genotypes (odds ratio 11.6 [95%CI 4.5–29.6], P < 0.0001) and was even stronger when adjusted for cardiovascular disease risk factors and the mean A1C (37.5 [3.6–388], P = 0.002). In conclusion, a combination of genotype variants of the renin-angiotensin system genes is a powerful determinant of subclinical progression of coronary artery atherosclerosis in type 1 diabetic patients and may partially explain accelerated CAD in type 1 diabetes.
Globular Adiponectin Activates Nuclear Factor-κB and Activating Protein-1 and Enhances Angiotensin II–Induced Proliferation in Cardiac Fibroblasts
Authors: Hattori Yoshiyuki , Hattori Sachiko , Akimoto Kazumi , Nishikimi Toshio , Suzuki Kunihiro , Matsuoka Hiroaki , Kasai Kikuo
Published: February 2007

Adiponectin is present in the serum as a trimer, hexamer, or high–molecular weight form. A proteolytic cleavage product of adiponectin, known as globular adiponectin (gAd), also circulates in human plasma. The biological activities of these isoforms are not well characterized. Pressure overload in adiponectin-deficient mice results in enhanced concentric cardiac hypertrophy and increased mortality, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium. Therefore, we examined whether gAd exerts the same effects on myocardium signaling. Nuclear factor-κB (NF-κB) and activating protein-1 (AP-1) activation were examined using cardiac fibroblasts prepared from the ventricles of 1- to 2-day-old Wistar rats and grown in culture. gAd activated NF-κB and enhanced tumor necrosis factor-α (TNF-α)-induced NF-κB activity. gAd also activated AP-1 and enhanced angiotensin II (Ang II)-induced AP-1 activity. gAd induced mRNA expression of c-fos and c-jun and activated extracellular signal–regulated kinase. Thus, gAd enhanced Ang II–induced DNA and collagen synthesis. Antibodies against adiponectin receptor (AdipoR)1 and AdipoR2 elicit activation of NF-κB or AP-1, two redox-sensitive transcription factors. Thus, rather than having an antihypertrophic effect, gAd might contribute to the activation of myocardium signaling, leading to myocardial hypertrophy.
Opposing Effects of Adiponectin Receptors 1 and 2 on Energy Metabolism
Authors: Bjursell Mikael , Ahnmark Andrea , Bohlooly-Y Mohammad , William-Olsson Lena , Rhedin Magdalena , Peng Xiao-Rong , Ploj Karolina , Gerdin Anna-Karin , Arnerup Gunnel , Elmgren Anders , Berg Anna-Lena , Oscarsson Jan , Lindén Daniel
Published: February 2007

The adipocyte-derived hormone adiponectin regulates glucose and lipid metabolism and influences the risk for developing obesity, type 2 diabetes, and cardiovascular disease. Adiponectin binds to two different seven-transmembrane domain receptors termed AdipoR1 and AdipoR2. To study the physiological importance of these receptors, AdipoR1 gene knockout mice (AdipoR1−/−) and AdipoR2 gene knockout mice (AdipoR2−/−) were generated. AdipoR1−/− mice showed increased adiposity associated with decreased glucose tolerance, spontaneous locomotor activity, and energy expenditure. However, AdipoR2−/− mice were lean and resistant to high-fat diet–induced obesity associated with improved glucose tolerance and higher spontaneous locomotor activity and energy expenditure and reduced plasma cholesterol levels. Thus, AdipoR1 and AdipoR2 are clearly involved in energy metabolism but have opposing effects.
Risk Factors Associated With the Onset and Progression of Posttransplantation Diabetes in Renal Allograft Recipients
Authors: Hur Kyu Yeon , Kim Myoung Soo , Kim Yu Seun , Kang Eun Seok , Nam Jae Hyun , Kim So Hun , Nam Chung Mo , Ahn Chul Woo , Cha Bong Soo , Kim Soon Il , Lee Hyun Chul
Published: February 2007

OBJECTIVE—The aim of this study was to assess the incidence of posttransplantation diabetes mellitus (PTDM) in renal allograft recipients and to investigate factors contributing to the onset and progression of PTDM and its underlying pathogenic mechanism(s).

RESEARCH DESIGN AND METHODS—A total of 77 patients with normal glucose tolerance (NGT) were enrolled in this study. An oral glucose tolerance test was performed 1 week before transplantation and repeated at 1 and 7 years after transplantation.

RESULTS—The overall incidence of PTDM was 39% at 1 year and 35.1% at 7 years posttransplantation. The incidence for each category of PTDM was as follows: persistent PTDM (P-PTDM) (patients who developed diabetes mellitus within 1 year of transplantation and remained diabetic during 7 years), 23.4%; transient PTDM (T-PTDM) (patients who developed diabetes mellitus during the 1st year after transplantation but eventually recovered to have NGT), 15.6%; late PTDM (L-PTDM) (patients who developed diabetes mellitus later than 1 year after transplantation), 11.7%; and non-PTDM during 7 years (N-PTDM7) (patients who did not develop diabetes mellitus during 7 years), 49.3%. Older age (≥40 years) at transplantation was a higher risk factor for P-PTDM, whereas a high BMI (≥25 kg/m2) and impaired fasting glucose (IFG) at 1 year posttransplantation were higher risk factors for L-PTDM. Impaired insulin secretion rather than insulin resistance was significantly associated with the development of P- and L-PTDM.

CONCLUSIONS—Impaired insulin secretion may be the main mechanism for the development of PTDM. Older age at transplantation seems to be associated with P-PTDM, whereas a high BMI and IFG at 1 year after transplantation were associated with L-PTDM.
Diabetes and Coronary Heart Disease in Filipino-American Women
Authors: Langenberg Claudia , Araneta Maria Rosario G. , Bergstrom Jaclyn , Marmot Michael , Barrett-Connor Elizabeth
Published: February 2007

OBJECTIVE—To investigate associations between adult markers of childhood growth and the prevalence of diabetes and coronary heart disease (CHD) in Filipino-American women and to determine the role of social and educational differences, including the influence of social mobility between childhood and adulthood.

RESEARCH DESIGN AND METHODS—Socioeconomic disadvantage and poor infant growth, resulting in short leg length, may contribute to the dramatically increased risk of diabetes and CHD in Filipino-American women, but this has not been investigated. This study is a cross-sectional study of 389 Filipino-American women (age 58.7 ± 9.4 years [mean ± SD]). Diabetes was defined by 1999 World Health Organization criteria and CHD by ischemic electrocardiogram changes, Rose angina, a history of myocardial infarction, or revascularization surgery. A score of social mobility (0–4) was calculated by summarizing childhood and adult financial circumstances.

RESULTS—Diabetes prevalence (31.4%) was not associated with measures of growth but was significantly lower in women with greater education, childhood and adult income, or social mobility score. Compared with Filipinas who were poorest in childhood and adulthood, respective odds ratios (95% CI) for diabetes were 0.55 (0.18–1.68), 0.19 (0.06–0.62), and 0.11 (0.03–0.42), down to 0.07 (0.01–0.51) in the most advantaged women (P < 0.0001). Family history of diabetes [5.14 (2.72–9.70)] and larger waist [1.07 per cm (1.03–1.10)] were also significant predictors in multiple adjusted models. In contrast, CHD prevalence (22.4%) was most strongly associated with leg length, but not trunk length; compared with individuals with the shortest legs, respective odds ratios (95% CI) for CHD were 0.60 (0.31–1.19), 0.53 (0.26–1.05), and 0.44 (0.22–0.91) in the tallest group, in age- (Ptrend = 0.02) and multiple-adjusted models (Ptrend = 0.01).

CONCLUSIONS—Socioeconomic disadvantage contributes to the high prevalence of diabetes in Filipinas. Factors limiting early growth of the legs may increase the risk of CHD in this comparatively short population.
Improving Diabetic Retinopathy Screening Ratios Using Telemedicine-Based Digital Retinal Imaging Technology
Authors: Taylor Cathy R. , Merin Lawrence M. , Salunga Amy M. , Hepworth Joseph T. , Crutcher Terri D. , O’Day Denis M. , Pilon Bonita A.
Published: February 2007

OBJECTIVE—To evaluate the impact of a telemedicine, digital retinal imaging strategy on diabetic retinopathy screening rates in an inner-city primary care clinic.

RESEARCH DESIGN AND METHODS—This retrospective cohort study included all diabetic patients aged ≥18 years (n = 495) seen at Vine Hill Community Clinic between 1 September 2003 and 31 August 2004. Patients were offered ophthalmology referral or digital screening. Patients choosing referral received the next available (within 3 months) appointment at the Vanderbilt Eye Clinic; patients choosing digital screening were screened during the visit.

RESULTS—Retinal screening was documented for 293 (59.2%) patients, a significant improvement compared with the 23% baseline rate. Of 293 patients screened, 92 (31.4%) were screened in ophthalmology, and 201 (68.6%) were digitally screened. Among the 201 digitally screened patients, 104 (51.7%) screened negative and were advised to rescreen in 1 year, 75 (37.3%) screened positive and were nonurgently referred to ophthalmology, and 22 (11.0%) screened positive for sight-threatening eye disease and were urgently referred for ophthalmological follow-up. Digital imaging technical failure rate was 0.5%. Referral status was associated with race/ethnicity (χ2 = 7.9, P < 0.02) with whites more likely to screen negative than non-whites (62.4 vs. 47.8%, respectively). Sight-threatening disease among non-whites (14.7%) was more than double that observed for whites (5.9%).

CONCLUSIONS—Digital imaging technology in the primary care visit can significantly improve screening rates over conventional methods, increase access to recommended diabetic eye care, and focus specialty care on medically indigent patients with greatest need.
Prediction of Diabetic Nephropathy Using Urine Proteomic Profiling 10 Years Prior to Development of Nephropathy
Authors: Otu Hasan H. , Can Handan , Spentzos Dimitrios , Nelson Robert G. , Hanson Robert L. , Looker Helen C. , Knowler William C. , Monroy Manuel , Libermann Towia A. , Karumanchi S. Ananth , Thadhani Ravi
Published: February 2007

OBJECTIVE—We examined whether proteomic technologies identify novel urine proteins associated with subsequent development of diabetic nephropathy in subjects with type 2 diabetes before evidence of microalbuminuria.

RESEACH DESIGN AND METHODS—In a nested case-control study of Pima Indians with type 2 diabetes, baseline (serum creatinine <1.2 mg/dl and urine albumin excretion <30 mg/g) and 10-year urine samples were examined. Case subjects (n = 31) developed diabetic nephropathy (urinary albumin–to–creatinine ratio >300 mg/g) over 10 years. Control subjects (n = 31) were matched to case subjects (1:1) according to diabetes duration, age, sex, and BMI but remained normoalbuminuric (albumin–to–creatinine ratio <30 mg/g) over the same 10 years. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was performed on baseline urine samples, and training (14 cases:14 controls) and validation (17:17) sets were tested.

RESULTS—At baseline, A1C levels differed between case and control subjects. SELDI-TOF MS detected 714 unique urine protein peaks. Of these, a 12-peak proteomic signature correctly predicted 89% of cases of diabetic nepropathy (93% sensitivity, 86% specificity) in the training set. Applying this same signature to the independent validation set yielded an accuracy rate of 74% (71% sensitivity, 76% specificity). In multivariate analyses, the 12-peak signature was independently associated with subsequent diabetic nephropathy when applied to the validation set (odds ratio [OR] 7.9 [95% CI 1.5–43.5], P = 0.017) and the entire dataset (14.5 [3.7–55.6], P = 0.001), and A1C levels were no longer significant.

CONCLUSIONS—Urine proteomic profiling identifies normoalbuminuric subjects with type 2 diabetes who subsequently develop diabetic nephropathy. Further studies are needed to characterize the specific proteins involved in this early prediction.