bluuebunny/crossref_metadata_2025 huggingface dataset:
Glyphosate and Multiple Herbicide Resistance in Common Waterhemp (Amaranthus rudis)Populations from Missouri
Authors: Legleiter Travis R. , Bradley Kevin W.
Published: July 2008

Field and greenhouse experiments were conducted to determine the level of glyphosate resistance in common waterhemp populations from Platte County (MO1) and Holt County, Missouri (MO2), and to determine the level and distribution of resistance to glyphosate, acetolactate synthase (ALS)–inhibiting herbicides, and protoporophyrinogen oxidase (PPO)–inhibiting herbicides across the MO1 site. Results from greenhouse experiments revealed that the MO1 and MO2 waterhemp populations were 19 and 9 times more resistant to glyphosate, respectively, than a susceptible waterhemp population. In field experiments, greater than 54% of waterhemp at the MO1 site survived 1.7 kg glyphosate ae ha−1(twice the labeled rate) 6 wk after treatment. Tank-mix combinations of ALS- and PPO-inhibiting herbicides with glyphosate also failed to provide complete control of the waterhemp population at the MO1 site. Collection and screening of seed from individual female waterhemp accessions revealed multiple resistance to glyphosate, ALS-, and PPO-inhibiting herbicides across the MO1 site. All 14 waterhemp accessions collected across the MO1 site exhibited greater than 65% survival to 2× rates of glyphosate and thifensulfuron, and these accessions were spread across a 5-km2(503-ha) area. Four waterhemp accessions collected across a 0.9-km2(87-ha) area also exhibited 26 to 38% survival to 2× rates of lactofen. The results from these experiments provide evidence and confirmation of the first glyphosate-resistant waterhemp population in the United States and reveal that multiple resistance to glyphosate, ALS-, and PPO-inhibiting herbicides can occur in waterhemp.
Use of Wild Radish (Raphanus raphanistrum) and Rye Cover Crops for Weed Suppression in Sweet Corn
Authors: Malik Mayank S. , Norsworthy Jason K. , Culpepper A. Stanley , Riley Melissa B. , Bridges William
Published: July 2008

Field experiments were conducted near Blackville, SC, and Tifton, GA, in 2004 and 2005, to evaluate the effect of wild radish and rye cover crops on weed control and sweet corn yield when used in conjunction with lower-than-recommended herbicide rates. Cover crop treatments included wild radish, rye, and no cover crop, alone and in conjunction with half and full rates of atrazine (0.84 and 1.68 kg ai ha−1) plusS-metolachlor (0.44 and 0.87 kg ai ha−1) applied before sweet corn emergence. Florida pusley, large crabgrass, spreading dayflower, ivyleaf morningglory, and wild radish infested the test sites. Wild radish and rye cover crops without herbicides reduced total weed density by 35 and 50%, respectively, at 4 wk after planting (WAP). Wild radish in conjunction with the full rate of atrazine plusS-metolachlor controlled Florida pusley, large crabgrass, and ivyleaf morningglory better than rye or no cover crop treated with a full herbicide rate in 2004 at Blackville. In 2005, at Blackville, weed control in sweet corn following wild radish cover crop plots alone was not different from that following rye. Wild radish or rye in conjunction with a half or full rate of atrazine andS-metolachlor controlled > 95% Florida pusley, wild radish, and large crabgrass in sweet corn at Tifton during both years. Ten glucosinolates, potential allelopathic compounds, were identified in wild radish, including glucoiberin, progoitrin, glucoraphanin, glucoraphenin, glucosinalbin, gluconapin, glucotropaeolin, glucoerucin, glucobrassicin, and gluconasturtin. Sweet corn yields at Blackville and Tifton following wild radish or rye cover crops were similar between the half and full rates of atrazine plusS-metolachlor. Sweet corn in wild radish or rye cover crop plots without herbicides produced less-marketable ears than herbicide-treated plots, indicating that a combination of cover crops and herbicides are required to optimize yields and to obtain desirable weed control.
Glyphosate-Resistant Italian Ryegrass (Lolium multiflorum) in California: Distribution, Response to Glyphosate, and Molecular Evidence for an Altered Target Enzyme
Authors: Jasieniuk Marie , Ahmad Riaz , Sherwood Anna M. , Firestone Jeffrey L. , Perez-Jones Alejandro , Lanini W. Thomas , Mallory-Smith Carol , Stednick Zachary
Published: July 2008

Selection by herbicides has resulted in widespread evolution of herbicide resistance in agricultural weeds. In California, resistance to glyphosate was first confirmed in rigid ryegrass in 1998. Objectives of this study were to determine the current distribution and level of glyphosate resistance in Italian ryegrass, and to assess whether resistance could be due to an altered target site. Seeds were sampled from 118 populations and seedlings were treated with glyphosate at 866 g ae ha−1. Percentage of survivors ranged from 5 to 95% in 54 populations. All plants from 64 populations died. One susceptible (S) population, four putatively resistant (R) populations, and one S accession from Oregon were used for pot dose–response experiments, shikimic acid analyses, and DNA sequencing. Seedlings were treated with glyphosate at eight rates, ranging from 108 to 13,856 g ae ha−1. Shoot biomass was evaluated 3 wk after treatment and fit to a log-logistic regression equation. On the basis of GR50(herbicide rate required to reduce growth by 50%) values, seedlings from putatively R populations were roughly two to 15 times more resistant to glyphosate than S plants. Shikimic acid accumulation was similar in all plants before glyphosate treatment, but at 4 and 7 DAT, S plants from California and Oregon accumulated approximately two and three times more shikimic acid, respectively, than R plants. Sequencing of a cDNA fragment of the EPSPS coding region revealed two different codons, both of which encode proline at amino acid position 106 in S individuals. In contrast, all R plants sequenced exhibited missense mutations at site 106. Plants from one population revealed a mutation resulting in a proline to serine substitution. Plants from three R populations exhibited a mutation corresponding to replacement of proline with alanine. Our results indicate that glyphosate resistance is widespread in Italian ryegrass populations of California, and that resistance is likely due to an altered target enzyme.
Developmental programming of adult hyperinsulinemia, increased proinflammatory cytokine production, and altered skeletal muscle expression of SLC2A4 (GLUT4) and uncoupling protein 3
Authors: Wyrwoll Caitlin S , Mark Peter J , Mori Trevor A , Waddell Brendan J
Published: July 2008

Fetal glucocorticoid excess programs detrimental effects in the adult phenotype including hyperleptinemia and aberrant glycemic control. In this study, we determined the interactive effects of maternal dexamethasone (Dex) treatment and postnatal dietary ω-3 (n-3) fatty acids on adult proinflammatory cytokine production and skeletal muscle expression of genes central to glucose handling and fatty acid metabolism. Dex acetate was administered to pregnant rats (0.75 μg/ml drinking water) from day 13 to term. Offspring of treated and control mothers were cross-fostered to mothers on either a standard (Std) or high n-3 (Hn3) diet, and remained on these diets postweaning. Adult offspring exposed to Dex in utero exhibited fasting hyperinsulinemia when raised on the Std diet but not when raised on the Hn3 diet. Dex also programmed increased plasma tumour necrosis factorα and interleukin 1β (IL-1β), but the increase in IL-1β was also prevented by the Hn3 diet. In skeletal muscle, expression of insulin regulated Slc2a4 (formerly known as GLUT4) was elevated (up to 15-fold) after Dex in utero, and this resulted in elevated intracellular, but not membrane-associated, SLC2A4 protein. Fetal glucocorticoid excess also reduced adult skeletal muscle Ucp3 expression in all offspring, whereas skeletal muscle expression of both Ppard and Ppargc1a were increased in females but not males. In conclusion, our data show that fetal glucocorticoid excess programs adult hyperinsulinemia and increased proinflammatory cytokine production. Related changes in the skeletal muscle Slc2a4, Ucp3, and Ppard indicate that fetal glucocorticoid excess disturbs adult glucose/fatty acid transport and metabolism.
Toxicity of perfluorooctane sulfonic acid and perfluorooctanoic acid on freshwater macroinvertebrates (Daphnia magna and Moina macrocopa) and fish (Oryzias latipes)
Authors: Ji Kyunghee , Kim Younghee , Oh Sorin , Ahn Byeongwoo , Jo Hyunye , Choi Kyungho
Published: July 2008

Because of their global distribution, persistence, and tendency to bioaccumulate, concerns about perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are growing. We determined the toxicity of PFOS and PFOA in several freshwater organisms, including two cladocerans, Daphnia magna and Moina macrocopa, and the teleost Oryzias latipes. In general, PFOS is approximately 10 times more toxic than PFOA in these organisms. In M. macrocopa, the median lethal concentration (LC50) was 17.95 mg/L for PFOS and 199.51 mg/L for PFOA. Moina macrocopa exhibited greater sensitivity than D. magna to both perfluorinated compounds in both acute and chronic exposures. In the 48-h acute toxicity test, M. macrocopa was approximately two times more sensitive than D. magna. In the 7-d chronic toxicity test, M. macrocopa showed significant reproductive changes at 0.31 mg/L for PFOS, which was approximately seven times lower than the effect concentrations observed over the 21-d exposure in D. magna. Two-generation fish toxicity tests showed that parental exposure to both compounds affected the performance of offspring. Unexposed progeny-generation (F1) fish exhibited elevated mortality and histopathological changes that were correlated with exposure in the parental generation (F0). Continuous exposure from F0 through F1 generations increased the extent of adverse effects. Considering the persistent nature of PFOS and PFOA, more research is required to determine potential consequences of long-term exposure to these compounds in aquatic ecosystems.
Ecological risk assessment in the United States environmental protection agency: A historical overview
Authors: Suter Glenn W
Published: July 2008

Risk assessment originated with the insurance industry and spread to the estimation of risks to people and property in other contexts, including the regulation of environmental contamination. Ecological assessment became an important component of environmental management in the United States with the legal mandate for environmental impact assessment in 1970. Risk assessment and ecological assessment merged in the 1980s to form ecological risk assessment (ERA). Since then, ERA has been institutionalized with the development of the US Environmental Protection Agency's (hereafter, USEPA or Agency) framework and guidance documents. Ecological risk assessment has been adapted by the Agency's program offices to fit their legal and policy contexts. The future of ERA will inevitably include the incorporation of more complex and demanding methods. However, the biggest challenge for future risk assessors will be to make ecological risks more compelling to decision makers.
The strengths of the ecological risk assessment process: linking science to decision making
Authors: Barnthouse Lawrence
Published: July 2008

Twenty-five years ago, ecological assessments were being performed by different organizations, using different principles and methods, with little or no communication between different groups and no means for reconciling conflicts and inconsistencies between assessment methodologies. The recognition by practitioners of environmental assessment of the need for a unifying conceptual framework stimulated the development of today's Framework and Guidelines for Ecological Risk Assessment (ERA). This paper discusses the success of ERA as a process for linking environmental science to decision making, using 3 recently published case studies involving establishment of baseline ecological risks at a contaminated site, probabilistic assessment of regional risks of pesticide use, and regulation of pharmaceutical product manufacture. Some promising future directions in ERA are briefly discussed, and 3 critical challenges to future success are identified.
A theory of practice for environmental assessment
Authors: Suter Glenn W , Cormier Susan M
Published: July 2008

Environmental assessment practices have not been as successful as they should be. We believe that this is in part because environmental assessors lack a clear and useful set of principles—that is, a theory of practice. We propose a theory that derives 19 principles from 3 axioms: 1) assessments inform environmental management decisions, 2) assessments are science based, and 3) management decisions accommodate multiple goals and constraints. The 1st axiom leads to principles that change the focus from good assessments to good decisions. The 2nd focuses assessments on the scientific needs of the decision maker rather than making policy judgments or consensus building. The 3rd axiom leads to integration across disciplines, scales, and types of evidence. This theory of assessment practice implies the need for a new framework for environmental assessment that is more integrative than existing frameworks and more focused on making decisions that resolve environmental problems. We believe that this theory of environmental assessment can lead to clear assessment practices that compel beneficial and confident environmental management.
Using artificial burrows to evaluate inhalation risks to burrowing mammals
Authors: Markwiese James T , Tiller Brett , Ryti Randall T , Bauer Roy
Published: July 2008

Since the onset of plutonium production at the US Department of Energy's Hanford Site, several hundred cubic meters of carbon tetrachloride (CCl4) has been discharged to the soil column, resulting in a dispersed CCl4 vapor plume in the subsurface. Inhalation of volatile organic chemicals could be an important exposure pathway for burrowing animals there. Historical levels of CCl4 in soil pore gas exceeded the inhalation ecological screening level for CCl4. Thus, the inhalation exposure pathway was evaluated with the use of artificial burrows deployed at locations that had elevated levels of CCl4 in soil gas. Artificial burrows were designed on the basis of information available for Hanford Site fossorial wildlife. After installation, the artificial burrow atmosphere was sampled and analyzed for CCl4 and its degradation products: chloroform, methylene chloride, and chloromethane. Sampling was repeated on 3 occasions to capture varying atmospheric conditions affecting exposure concentrations. CCl4 was detected in the artificial burrows, and maximum exposures were observed during relatively low barometric conditions. The highest CCl4 detections were still well below the inhalation-based ecological screening level and CCl4 degradation products were never detected. This study shows that artificial burrows are an efficient method for obtaining relevant exposure data and illustrates the utility of directly measuring the medium for exposure under ecologically realistic conditions.
What is meant by risk-based environmental quality criteria?
Authors: Suter Glenn W , Cormier Susan M
Published: July 2008

Criteria for the quality of water and other media are often said to be risk based. However, the relationship between the process of criterion setting and risk assessment has not been clear. This article shows that the conventional framework for risk assessment may be easily modified to represent criterion development. The critical difference is that conventional risk assessments solve an exposure-response model for an expected exposure to estimate an effect, but criterion assessments solve the same model for a benchmark effect to estimate an upper limit to acceptable exposures. Hence, the critical step in criterion setting is the determination of an effect metric that can be modeled and that represents the environmental goal. The same process applies to equivalent assessments, such as deriving screening benchmarks and remedial goals.
Pour Une Évaluation Normative De La Compétence De Traduction
Authors: Anckaert Philippe , Eyckmans June , Segers Winibert
Published: July 2008

Après un bref aperçu des risques d’infidélité d’une évaluation critériée de la compétence de traduction, liés principalement à la subjectivité du correcteur, nous mettons en évidence les limites des tentatives d’objectivation du processus d’évaluation au moyen de grilles de correction ou d’évaluation de la qualité telles qu’utilisées dans les écoles de traduction et le monde professionnel. Pour pallier le manque de fidélité des épreuves de traduction traditionnelles, nous proposons une méthode d’évaluation normative qui permet de neutraliser complètement la subjectivité du correcteur. Dans cet article, nous décrivons et illustrons par un exemple concret les différentes étapes de la confection d’une épreuve standardisée. De cette description, il ressort que notre méthode naît du mariage des principes de la docimologie, qui fournit les instruments de contrôle de la fidélité, et des acquis de la traductologie, indispensables pour se prononcer sur la validité des épreuves.
Automated User-Centred Task Selection and Input Modification in Language Learning
Authors: van der Werf Rintse , Hootsen Geke , Vermeer Anne
Published: July 2008

This article presents the results of a CALL-experiment in which reading material is selected dynamically, based on the “fit” between the vocabulary proficiency of individual students and the relative difficulty of texts. The texts were analysed, selected and presented online, together with a personalized electronic dictionary with words that were assumed to be unknown. In a pre-test – treatment – post-test design in which 32 Dutch L2-students took part, the vocabulary learned implicitly while reading the texts was measured. The relation between user-initiated noticing and word retention was also examined.

We found an average word-learning improvement of 10.8%. On the basis of the non-significant differences between various proficiency groups, we concluded that the method we propose for the automated adaptive selection of reading texts ensures that learners of different proficiency levels receive linguistic input that is best fitted to their abilities. Using frequency information for both automated analysis of texts and the compilation of a personalized dictionary has great potential for more user-centred task selection and guidance. We also found a relation between user-initiated dictionary use and word retention, which was strong for the lowest proficiency level. With respect to the words looked up in the dictionary, a strong correlation was found between noticing and retention.
‘I me Mine’ The Acquisition of Dutch Pronominal Possessives by L1 Children, L2 Children and L2 Adults
Authors: Nap-Kolhoff Elma , Broeder Peter
Published: July 2008

This study compares pronominal possessive constructions in Dutch first language (L1) acquisition, second language (L2) acquisition by young children, and untutored L2 acquisition by adults. The L2 learners all have Turkish as L1. In longitudinal spontaneous speech data for four L1 learners, seven child L2 learners, and two adult learners, remarkable differences and similarities between the three learner groups were found. In some respects, the child L2 learners develop in a way that is similar to child L1 learners, for instance in the kind of overgeneralisations that they make. However, the child L2 learners also behave like adult L2 learners; i.e., in the pace of the acquisition process, the frequency and persistence of non-target constructions, and the difficulty in acquiring reduced pronouns. The similarities between the child and adult L2 learners are remarkable, because the child L2 learners were only two years old when they started learning Dutch. L2 acquisition before the age of three is often considered to be similar to L1 acquisition. The findings might be attributable to the relatively small amount of Dutch language input the L2 children received.
Reduction of Ptf1a Gene Dosage Causes Pancreatic Hypoplasia and Diabetes in Mice
Authors: Fukuda Akihisa , Kawaguchi Yoshiya , Furuyama Kenichiro , Kodama Sota , Horiguchi Masashi , Kuhara Takeshi , Kawaguchi Michiya , Terao Mami , Doi Ryuichiro , Wright Christopher V.E. , Hoshino Mikio , Chiba Tsutomu , Uemoto Shinji
Published: July 2008

OBJECTIVE—Most pancreatic endocrine cells derive from Ptf1a-expressing progenitor cells. In humans, nonsense mutations in Ptf1a have recently been identified as a cause of permanent neonatal diabetes associated with pancreatic agenesis. The death of Ptf1a-null mice soon after birth has not allowed further insight into the pathogenesis of the disease; it is therefore unclear how much pancreatic endocrine function is dependent on Ptf1a in mammals. This study aims to investigate gene-dosage effects of Ptf1a on pancreas development and function in mice.

RESEARCH DESIGN AND METHODS—Combining hypomorphic and null alleles of Ptf1a and Cre-mediated lineage tracing, we followed the cell fate of reduced Ptf1a-expressing progenitors and analyzed pancreas development and function in mice.

RESULTS—Reduced Ptf1a dosage resulted in pancreatic hypoplasia and glucose intolerance with insufficient insulin secretion in a dosage-dependent manner. In hypomorphic mutant mice, pancreatic bud size was small and substantial proportions of pancreatic progenitors were misspecified to the common bile duct and duodenal cells. Growth with branching morphogenesis and subsequent exocrine cytodifferentiation was reduced and delayed. Total β-cell number was decreased, proportion of non-β islet cells was increased, and α-cells were abnormally intermingled with β-cells. Interestingly, Pdx1 expression was decreased in early pancreatic progenitors but elevated to normal level at the mid-to-late stages of pancreatogenesis.

CONCLUSIONS—The dosage of Ptf1a is crucial for pancreas specification, growth, total β-cell number, islet morphogenesis, and endocrine function. Some neonatal diabetes may be caused by mutation or single nucleotide polymorphisms in the Ptf1a gene that reduce gene expression levels.
Physical Activity and Insulin Sensitivity
Authors: Balkau Beverley , Mhamdi Leila , Oppert Jean-Michel , Nolan John , Golay Alain , Porcellati Francesca , Laakso Markku , Ferrannini Ele ,   on behalf of the EGIR-RISC Study Group
Published: July 2008

OBJECTIVE— Physical activity is a modifiable risk factor for type 2 diabetes, partly through its action on insulin sensitivity. We report the relation between insulin sensitivity and physical activity measured by accelerometry.

RESEARCH DESIGN AND METHODS— This is a cross-sectional study of 346 men and 455 women, aged 30–60 years, without cardiovascular disease and not treated by drugs for diabetes, hypertension, dyslipidemia, or obesity. Participants were recruited in 18 clinical centers from 13 European countries. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Physical activity was recorded by accelerometry for a median of 6 days. We studied the relationship of insulin sensitivity with total activity (in counts per minute), percent of time spent sedentary, percent of time in light activity, and activity intensity (whether the participant recorded some vigorous or some moderate activity).

RESULTS— In both men and women, total activity was associated with insulin sensitivity (P < 0.0001). Time spent sedentary, in light activity, and activity intensity was also associated with insulin sensitivity (P < 0.0004/0.01, 0.002/0.03, and 0.02/0.004, respectively, for men/women) but lost significance once adjusted for total activity. Adjustment for confounders such as adiposity attenuated the relationship with total activity; there were no interactions with confounders. Even in the 25% most sedentary individuals, total activity was significantly associated with better insulin sensitivity (P < 0.0001).

CONCLUSIONS— Accumulated daily physical activity is a major determinant of insulin sensitivity. Time spent sedentary, time spent in light-activity, and bouts of moderate or vigorous activity did not impact insulin sensitivity independently of total activity.
miR-375 Targets 3′-Phosphoinositide–Dependent Protein Kinase-1 and Regulates Glucose-Induced Biological Responses in Pancreatic β-Cells
Authors: El Ouaamari Abdelfattah , Baroukh Nadine , Martens Geert A. , Lebrun Patricia , Pipeleers Daniel , van Obberghen Emmanuel
Published: July 2008

OBJECTIVE—MicroRNAs are short, noncoding RNAs that regulate gene expression. We hypothesized that the phosphatidylinositol 3-kinase (PI 3-kinase) cascade known to be important in β-cell physiology could be regulated by microRNAs. Here, we focused on the pancreas-specific miR-375 as a potential regulator of its predicted target 3′-phosphoinositide–dependent protein kinase-1 (PDK1), and we analyzed its implication in the response of insulin-producing cells to elevation of glucose levels.

RESEARCH DESIGN AND METHODS—We used insulinoma-1E cells to analyze the effects of miR-375 on PDK1 protein level and downstream signaling using Western blotting, glucose-induced insulin gene expression using quantitative RT-PCR, and DNA synthesis by measuring thymidine incorporation. Moreover, we analyzed the effect of glucose on miR-375 expression in both INS-1E cells and primary rat islets. Finally, miR-375 expression in isolated islets was analyzed in diabetic Goto-Kakizaki (GK) rats.

RESULTS—We found that miR-375 directly targets PDK1 and reduces its protein level, resulting in decreased glucose-stimulatory action on insulin gene expression and DNA synthesis. Furthermore, glucose leads to a decrease in miR-375 precursor level and a concomitant increase in PDK1 protein. Importantly, regulation of miR-375 expression by glucose occurs in primary rat islets as well. Finally, miR-375 expression was found to be decreased in fed diabetic GK rat islets.

CONCLUSIONS—Our findings provide evidence for a role of a pancreatic-specific microRNA, miR-375, in the regulation of PDK1, a key molecule in PI 3-kinase signaling in pancreatic β-cells. The effects of glucose on miR-375 are compatible with the idea that miR-375 is involved in glucose regulation of insulin gene expression and β-cell growth.
Neuronatin: A New Inflammation Gene Expressed on the Aortic Endothelium of Diabetic Mice
Authors: Mzhavia Nino , Yu Shuiqing , Ikeda Shota , Chu Tehua T. , Goldberg Ira , Dansky Hayes M.
Published: July 2008

OBJECTIVE—Identification of arterial genes and pathways altered in obesity and diabetes.

RESEARCH DESIGN AND METHODS—Aortic gene expression profiles of obese and diabetic db/db, high-fat diet–fed C57BL/6J, and control mice were obtained using mouse Affymetrix arrays. Neuronatin (Nnat) was selected for further analysis. To determine the function of Nnat, a recombinant adenovirus (Ad-Nnat) was used to overexpress the Nnat gene in primary endothelial cells and in the mouse aorta in vivo.

RESULTS— Nnat, a gene of unknown vascular function, was upregulated in the aortas of db/db and high-fat diet–fed mice. Nnat gene expression was increased in db/db mouse aorta endothelial cells. Nnat protein was localized to aortic endothelium and was selectively increased in the endothelium of db/db mice. Infection of primary human aortic endothelial cells (HAECs) with Ad-Nnat increased expression of a panel of nuclear factor-κB (NF-κB)-regulated genes, including inflammatory cytokines, chemokines, and cell adhesion molecules. Infection of mouse carotid arteries in vivo with the Ad-Nnat increased expression of vascular cell adhesion molecule 1 protein. Nnat activation of NF-κB and inflammatory gene expression in HAECs was mediated through pathways distinct from tumor necrosis factor-α. Nnat expression stimulated p38, Jun NH2-terminal kinase, extracellular signal–related kinase, and AKT kinase phosphorylation. Phosphatidylinositol 3-kinase and p38 inhibitors prevented Nnat-mediated activation of NF-κB–induced gene expression.

CONCLUSIONS—Nnat expression is increased in endothelial cells of obese and diabetic mouse blood vessels. The effects of Nnat on inflammatory pathways in vitro and in vivo suggest a pathophysiological role of this new gene in diabetic vascular diseases.
Cytokine-Induced β-Cell Death Is Independent of Endoplasmic Reticulum Stress Signaling
Authors: Åkerfeldt Mia C. , Howes Jennifer , Chan Jeng Yie , Stevens Veronica A. , Boubenna Nacer , McGuire Helen M. , King Cecile , Biden Trevor J. , Laybutt D. Ross
Published: July 2008

OBJECTIVE—Cytokines contribute to β-cell destruction in type 1 diabetes. Endoplasmic reticulum (ER) stress–mediated apoptosis has been proposed as a mechanism for β-cell death. We tested whether ER stress was necessary for cytokine-induced β-cell death and also whether ER stress gene activation was present in β-cells of the NOD mouse model of type 1 diabetes.

RESEARCH DESIGN AND METHODS—INS-1 β-cells or rat islets were treated with the chemical chaperone phenyl butyric acid (PBA) and exposed or not to interleukin (IL)-1β and γ-interferon (IFN-γ). Small interfering RNA (siRNA) was used to silence C/EBP homologous protein (CHOP) expression in INS-1 β-cells. Additionally, the role of ER stress in lipid-induced cell death was assessed.

RESULTS—Cytokines and palmitate triggered ER stress in β-cells as evidenced by increased phosphorylation of PKR-like ER kinase (PERK), eukaryotic initiation factor (EIF)2α, and Jun NH2-terminal kinase (JNK) and increased expression of activating transcription factor (ATF)4 and CHOP. PBA treatment attenuated ER stress, but JNK phosphorylation was reduced only in response to palmitate, not in response to cytokines. PBA had no effect on cytokine-induced cell death but was associated with protection against palmitate-induced cell death. Similarly, siRNA-mediated reduction in CHOP expression protected against palmitate- but not against cytokine-induced cell death. In NOD islets, mRNA levels of several ER stress genes were reduced (ATF4, BiP [binding protein], GRP94 [glucose regulated protein 94], p58, and XBP-1 [X-box binding protein 1] splicing) or unchanged (CHOP and Edem1 [ER degradation enhancer, mannosidase α–like 1]).

CONCLUSIONS—While both cytokines and palmitate can induce ER stress, our results suggest that, in contrast to lipoapoptosis, the PERK-ATF4-CHOP ER stress–signaling pathway is not necessary for cytokine-induced β-cell death.
Evidence for Interindividual Heterogeneity in the Glucose Gradient Across the Human Red Blood Cell Membrane and Its Relationship to Hemoglobin Glycation
Authors: Khera Paramjit K. , Joiner Clinton H. , Carruthers Anthony , Lindsell Christopher J. , Smith Eric P. , Franco Robert S. , Holmes Yancey R. , Cohen Robert M.
Published: July 2008

OBJECTIVE—To determine whether interindividual heterogeneity in the erythrocyte (red blood cell [RBC]) transmembrane glucose gradient might explain discordances between A1C and glycemic control based on measured fructosamine.

RESEARCH DESIGN AND METHODS—We modeled the relationship between plasma glucose and RBC glucose as the concentration distribution (Ci-to-Co ratio) of a nonmetabolizable glucose analog 14C-3-O-methyl glucose (14C-3OMG) inside (Ci) and outside (Co) RBCs in vitro. We examined the relationship between that distribution and the degree of glycation of hemoglobin in comparison with glycation of serum proteins (fructosamine), the glycation gap. A1C, fructosamine, and in vitro determination of the 14C-3OMG distribution in glucose-depleted RBCs were measured in 26 fasted subjects.

RESULTS—The Ci-to-Co ratio 0.89 ± 0.07 for 3-O-methyl-d-glucopyranose (3OMG) ranged widely (0.72–1.04, n = 26). In contrast, urea Ci-to-Co (1.015 ± 0.022 [range 0.98–1.07], P < 0.0001) did not. Concerning mechanism, in a representative subset of subjects, the Ci-to-Co ratio was retained in RBC ghosts, was not dependent on ATP or external cations, and was reestablished after reversal of the glucose gradient. The 3OMG Ci-to-Co ratio was not correlated with serum fructosamine, suggesting that it was independent of mean plasma glucose. However, Ci-to-Co did correlate with A1C (R2 = 0.19) and with the glycation gap (R2 = 0.20), consistent with a model in which differences in internal glucose concentration at a given mean plasma glucose contribute to differences in A1C for given level of glycemic control.

CONCLUSIONS—The data demonstrate interindividual heterogeneity in glucose gradients across RBC membranes that may affect hemoglobin glycation and have implications for diabetes complications risk and risk assessment.
Decreased Fetal Size Is Associated With β-Cell Hyperfunction in Early Life and Failure With Age
Authors: Chakravarthy Manu V. , Zhu Yimin , Wice Mitchell B. , Coleman Trey , Pappan Kirk L. , Marshall Connie A. , McDaniel Michael L. , Semenkovich Clay F.
Published: July 2008

OBJECTIVE—Low birth weight is associated with diabetes in adult life. Accelerated or “catch-up” postnatal growth in response to small birth size is thought to presage disease years later. Whether adult disease is caused by intrauterine β-cell–specific programming or by altered metabolism associated with catch-up growth is unknown.

RESEARCH DESIGN AND METHODS—We generated a new model of intrauterine growth restriction due to fatty acid synthase (FAS) haploinsufficiency (FAS deletion [FASDEL]). Developmental programming of diabetes in these mice was assessed from in utero to 1 year of age.

RESULTS—FASDEL mice did not manifest catch-up growth or insulin resistance. β-Cell mass and insulin secretion were strikingly increased in young FASDEL mice, but β-cell failure and diabetes occurred with age. FASDEL β-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet. This sequence appeared to be developmentally entrained because β-cell mass was increased in utero in FASDEL mice and in another model of intrauterine growth restriction caused by ectopic expression of uncoupling protein-1. Increasing intrauterine growth in FASDEL mice by supplementing caloric intake of pregnant dams normalized β-cell mass in utero.

CONCLUSIONS—Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate β-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic β-cell to establish a template for hyperfunction in early life and β-cell failure with age.
Evaluating the Role of LPIN1 Variation in Insulin Resistance, Body Weight, and Human Lipodystrophy in U.K. Populations
Authors: Fawcett Katherine A. , Grimsey Neil , Loos Ruth J.F. , Wheeler Eleanor , Daly Allan , Soos Maria , Semple Robert , Syddall Holly , Cooper Cyrus , Siniossoglou Symeon , O'Rahilly Stephen , Wareham Nicholas J. , Barroso Inês
Published: July 2008

OBJECTIVE— Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of common LPIN1 variation on adiposity and insulin sensitivity in U.K. populations and to examine the role of LPIN1 mutations in insulin resistance syndromes.

RESEARCH DESIGN AND METHOD— Twenty-two single nucleotide polymorphisms tagging common LPIN1 variation were genotyped in Medical Research Council (MRC) Ely (n = 1,709) and Hertfordshire (n = 2,901) population-based cohorts. LPIN1 exons, exon/intron boundaries, and 3′ untranslated region were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients) and 48 control subjects.

RESULTS— We found no association between LPIN1 single nucleotide polymorphisms and fasting insulin but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8,504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K, and G582R) were detected in severely insulin-resistant patients. However, these did not cosegregate with disease in affected families, and Lipin1 protein expression and phosphorylation in patients with variants were indistinguishable from those in control subjects.

CONCLUSIONS— Our data do not support a major effect of common LPIN1 variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in U.K. cohorts require replication in larger cohorts.
Baseline Serum 25-Hydroxy Vitamin D Is Predictive of Future Glycemic Status and Insulin Resistance
Authors: Forouhi Nita G. , Luan Jian'an , Cooper Andrew , Boucher Barbara J. , Wareham Nicholas J.
Published: July 2008

OBJECTIVE—Accumulating epidemiological evidence suggests that hypovitaminosis D may be associated with type 2 diabetes and related metabolic risks. However, prospective data using the biomarker serum 25-hydroxyvitamin D [25(OH)D] are limited and therefore examined in the present study.

RESEARCH DESIGN AND METHODS—A total of 524 randomly selected nondiabetic men and women, aged 40–69 years at baseline, with measurements for serum 25(OH)D and IGF-1 in the population-based Ely Study, had glycemic status (oral glucose tolerance), lipids, insulin, anthropometry, and blood pressure measured and metabolic syndrome risk (metabolic syndrome z score) derived at baseline and at 10 years of follow-up.

RESULTS—Age-adjusted baseline mean serum 25(OH)D was greater in men (64.5 nmol/l [95% CI 61.2–67.9]) than women (57.2 nmol/l [54.4,60.0]) and varied with season (highest late summer). Baseline 25(OH)D was associated inversely with 10-year risk of hyperglycemia (fasting glucose: β = −0.0023, P = 0.019; 2-h glucose: β = −0.0097, P = 0.006), insulin resistance (fasting insulin β = −0.1467, P = 0.010; homeostasis model assessment of insulin resistance [HOMA-IR]: β = −0.0059, P = 0.005), and metabolic syndrome z score (β = −0.0016, P = 0.048) after adjustment for age, sex, smoking, BMI, season, and baseline value of each metabolic outcome variable. Associations with 2-h glucose, insulin, and HOMA-IR remained significant after further adjustment for IGF-1, parathyroid hormone, calcium, physical activity, and social class.

CONCLUSIONS—This prospective study reports inverse associations between baseline serum 25(OH)D and future glycemia and insulin resistance. These associations are potentially important in understanding the etiology of abnormal glucose metabolism and warrant investigation in larger, specifically designed prospective studies and randomized controlled trials of supplementation.
Insulin Resistance and Hyperinsulinemia
Authors: Kim Sun H. , Reaven Gerald M.
Published: July 2008

OBJECTIVE—Recently, it has been suggested that insulin resistance and hyperinsulinemia can exist in isolation and have differential impacts on cardiovascular disease (CVD). To evaluate this suggestion, we assessed the degree of discordance between insulin sensitivity and insulin response in a healthy, nondiabetic population.

RESEARCH DESIGN AND METHODS—Insulin sensitivity was quantified by determining the steady-state plasma glucose (SSPG) concentration during an insulin suppression test in 446 individuals. The integrated insulin response was calculated after a 75-g oral glucose challenge. We analyzed the correlation between insulin resistance and insulin response in addition to quantifying the proportion in quartiles of insulin response by quartiles of insulin sensitivity. Then we compared CVD risk factors between individuals within the same insulin sensitivity quartile but within different insulin response quartiles to evaluate the differential clinical impact of insulin resistance and hyperinsulinemia.

RESULTS—Insulin resistance and insulin response were highly correlated (r = 0.76, P < 0.001). A majority (95%) of the most insulin-resistant individuals (top SSPG quartile) were either in the highest insulin response quartile (71%) or second highest (24%). Similarly, 92% of the most insulin-sensitive individuals (lowest SSPG quartile) were in the lowest two insulin response quartiles. There were minimal differences in CVD risk factors between individuals with different insulin responses but within the same insulin sensitivity quartile.

CONCLUSIONS—Although not perfectly related, insulin resistance and hyperinsulinemia rarely exist in isolation in a nondiabetic population. It is difficult to discern an independent impact of hyperinsulinemia on CVD risk factors associated with insulin resistance.
Metabolic Syndrome and Incident Diabetes
Authors: Ford Earl S. , Li Chaoyang , Sattar Naveed
Published: July 2008

OBJECTIVE—Our objective was to perform a quantitative review of prospective studies examining the association between the metabolic syndrome and incident diabetes.

RESEARCH DESIGN AND METHODS—Using the title terms “diabetes” and “metabolic syndrome” in PubMed, we searched for articles published since 1998.

RESULTS—Based on the results from 16 cohorts, we performed a meta-analysis of estimates of relative risk (RR) and incident diabetes. The random-effects summary RRs were 5.17 (95% CI 3.99–6.69) for the 1999 World Health Organization definition (ten cohorts); 4.45 (2.41–8.22) for the 1999 European Group for the Study of Insulin Resistance definition (four cohorts); 3.53 (2.84–4.39) for the 2001 National Cholesterol Education Program definition (thirteen cohorts); 5.12 (3.26–8.05) for the 2005 American Heart Association/National Heart, Lung, and Blood Institute definition (five cohorts); and 4.42 (3.30–5.92) for the 2005 International Diabetes Federation definition (nine cohorts). The fixed-effects summary RR for the 2004 National Heart, Lung, and Blood Institute/American Heart Association definition was 5.16 (4.43–6.00) (six cohorts). Higher number of abnormal components was strongly related to incident diabetes. Compared with participants without an abnormality, estimates of RR for those with four or more abnormal components ranged from 10.88 to 24.4. Limited evidence suggests fasting glucose alone may be as good as metabolic syndrome for diabetes prediction.

CONCLUSIONS—The metabolic syndrome, however defined, has a stronger association with incident diabetes than that previously demonstrated for coronary heart disease. Its clinical value for diabetes prediction remains uncertain.
Too Much Glucagon, Too Little Insulin
Authors: Brown Rebecca J. , Sinaii Ninet , Rother Kristina I.
Published: July 2008

OBJECTIVE—To determine the time course of changes in glucagon and insulin secretion in children with recently diagnosed type 1 diabetes.

RESEARCH DESIGN AND METHODS—Glucagon and C-peptide concentrations were determined in response to standard mixed meals in 23 patients with type 1 diabetes aged 9.4 ± 4.6 years, beginning within 6 weeks of diagnosis, and every 3 months thereafter for 1 year.

RESULTS—Glucagon secretion in response to a physiologic stimulus (mixed meal) increased by 37% over 12 months, while C-peptide secretion declined by 45%. Fasting glucagon concentrations remained within the normal (nondiabetic) reference range.

CONCLUSIONS—Postprandial hyperglucagonemia worsens significantly during the first year after diagnosis of type 1 diabetes and may represent a distinct therapeutic target. Fasting glucagon values may underestimate the severity of hyperglucagonemia. The opposing directions of abnormal glucagon and C-peptide secretion over time support the link between dysregulated glucagon secretion and declining β-cell function.
Risk Prediction of Cardiovascular Disease in Type 2 Diabetes
Authors: Cederholm Jan , Eeg-Olofsson Katarina , Eliasson Björn , Zethelius Björn , Nilsson Peter M. , Gudbjörnsdottir Soffia ,   on behalf of the Swedish National Diabetes Register
Published: July 2008

OBJECTIVE—Risk prediction models obtained in samples from the general population do not perform well in type 2 diabetic patients. Recently, 5-year risk estimates were proposed as being more accurate than 10-year risk estimates. This study presents a diabetes-specific equation for estimation of the absolute 5-year risk of first incident fatal/nonfatal cardiovascular disease (CVD) in type 2 diabetic patients with use of A1C and clinical characteristics.

RESEARCH DESIGN AND METHODS—The study was based on 11,646 female and male patients, aged 18–70 years, from the Swedish National Diabetes Register with 1,482 first incident CVD events based on 58,342 person-years with mean follow-up of 5.64 years.

RESULTS—This risk equation incorporates A1C, as in the UK Prospective Diabetes Study risk engine, and several clinical characteristics: onset age of diabetes, diabetes duration, sex, BMI, smoking, systolic blood pressure, and antihypertensive and lipid-reducing drugs. All predictors included were associated with the outcome (P < 0.0001, except for BMI P = 0.0016) with Cox regression analysis. Calibration was excellent when assessed by comparing observed and predicted risk. Discrimination was sufficient, with a receiver operator curve statistic of 0.70. Mean 5-year risk of CVD in all patients was 12.0 ± 7.5%, whereas 54% of the patients had a 5-year risk ≥10%.

CONCLUSIONS—This more simplified risk equation enables 5-year risk prediction of CVD based on easily available nonlaboratory predictors in clinical practice and A1C and was elaborated in a large observational study obtained from the normal patient population aged up to 70 years.
Association of C-Reactive Protein With Reduced Forced Vital Capacity in a Nonsmoking U.S. Population With Metabolic Syndrome and Diabetes
Authors: Lee Hwa Mu , Le Truc Vy , Lopez Victor A. , Wong Nathan D.
Published: July 2008

OBJECTIVE—A relationship between inflammation, measured by C-reactive protein (CRP), and forced vital capacity (FVC) in diabetes or metabolic syndrome (MetS) has not been established. We investigated whether high CRP is related to reduced FVC in MetS and diabetes.

RESEARCH DESIGN AND METHODS—We examined the association of MetS/diabetes and CRP (normal ≤3 mg/l, high >3 mg/l) with predicted FVC in 4,272 nonsmoking U.S. adults aged 18–79 years without lung disease in the Third National Health and Nutrition Examination Survey. Logistic regression examined odds of FVC <80% by CRP and MetS/diabetes.

RESULTS—Mean FVC in individuals with MetS and high CRP (95.7%) and those with diabetes and high CRP (93.7%) was lower than in those with no MetS/diabetes and normal CRP (101.7%) (P < 0.01) and was lower in those with MetS and high CRP (95.7%) than in those with MetS and normal CRP (98.5%) (P < 0.01). The odds ratio (95% CI) of FVC <80% was highest in individuals with MetS and high CRP (odds ratio 4.26 [95% CI 2.08–8.73], P < 0.01) compared with those with no MetS/diabetes and normal CRP.

CONCLUSIONS—Elevated CRP is associated with lower FVC in people with MetS.