bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Linkage of Plasma Adiponectin Reveals a Major Locus on Chromosome 3q Distinct From the Adiponectin Structural Gene
Authors: Guo Xiuqing , Saad Mohammed F. , Langefeld Carl D. , Williams Adrienne H. , Cui Jinrui , Taylor Kent D. , Norris Jill M. , Jinagouda Sujata , Darwin Christine H. , Mitchell Braxton D. , Bergman Richard N. , Sutton Beth , Chen Y.-D. Ida , Wagenknecht Lynne E. , Bowden Donald W. , Rotter Jerome I.
Published: May 2006

Adiponectin (APM1) is an adipocyte-derived peptide that contributes to glucose, lipid, and energy homeostasis. We assessed the genetic basis of plasma adiponectin in Hispanic-American and African-American families enrolled through the Insulin Resistance Atherosclerosis Study Family Study. A 10-cM genome scan was performed in two batches: an original set (set 1) consisting of 66 families (45 Hispanic American and 21 African American) and a replication set (set 2) consisting of 66 families (45 Hispanic American and 21 African American). Adiponectin levels were measured by radioimmunoassay in 1,727 individuals from 131 of 132 families. Linkage analysis was carried out in Hispanic Americans and African Americans separately in set 1, set 2, and the pooled set (set 1 plus set 2), with and without diabetic subjects. A major gene was mapped to 3q27 with a logarithm of odds (LOD) score of 8.21 in the Hispanic-American sample. Ninety-six unrelated individuals were screened for polymorphisms in the APM1 gene, and 18 single nucleotide polyporphisms (SNPs) were genotyped in the Hispanic-American sample. Plasma adiponectin level was modestly associated with two SNPs and their accompaning haplotypes. Incorporating each or both SNPs in the linkage analysis, however, did not significantly reduce the LOD score. Therefore, a quantitative trait locus at 3q27, likely distinct from the APM1 gene, contributes to the variation of plasma adiponectin levels in the Hispanic-American population.
Fasting Insulin and Obesity-Related Phenotypes Are Linked to Chromosome 2p
Authors: Diego Vincent P. , Göring Harald H.H. , Cole Shelley A. , Almasy Laura , Dyer Thomas D. , Blangero John , Duggirala Ravindranath , Laston Sandra , Wenger Charlotte , Cantu Teresa , Dyke Bennett , North Kari , Schurr Theodore , Best Lyle G. , Devereux Richard B. , Fabsitz Richard R. , Howard Barbara V. , MacCluer Jean W.
Published: May 2006

To localize quantitative trait loci for insulin metabolism and obesity, genome scans/linkage analyses were performed on >900 members of 32 extended families participating in phase 3 of the Strong Heart Study, an investigation of the genetic and environmental determinants of cardiovascular disease in American-Indian populations from Arizona, Oklahoma, and North and South Dakota. Linkage analyses of fasting insulin and two obesity-related phenotypes, BMI and percent fat mass, were performed independently in each of the three populations. For log fasting insulin, we found a genome-wide maximum, robust logarithm of odds (LOD) score of 3.42 at 51 cM on chromosome 2p in the Dakotas. Bivariate linkage analyses of log fasting insulin with both BMI and fat mass indicate a situation of incomplete pleiotropy, as well as several significant bivariate LOD scores in the Dakotas.
Glucose Regulates Foxo1 Through Insulin Receptor Signaling in the Pancreatic Islet β-cell
Authors: Martinez Sara C. , Cras-Méneur Corentin , Bernal-Mizrachi Ernesto , Permutt M. Alan
Published: May 2006

Glucose controls islet β-cell mass and function at least in part through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway downstream of insulin signaling. The Foxo proteins, transcription factors known in other tissues to be negatively regulated by Akt activation, affect proliferation and metabolism. In this study, we tested the hypothesis that glucose regulates Foxo1 activity in the β-cell via an autocrine/paracrine effect of released insulin on its receptor. Mouse insulinoma cells (MIN6) were starved overnight for glucose (5 mmol/l) then refed with glucose (25 mmol/l), resulting in rapid Foxo1 phosphorylation (30 min, P < 0.05 vs. untreated). This glucose response was demonstrated to be time (0.5–2 h) and dose (5–30 mmol/l) dependent. The use of inhibitors demonstrated that glucose-induced Foxo1 phosphorylation was dependent upon depolarization, calcium influx, and PI3K signaling. Additionally, increases in glucose concentration over a physiological range (2.5–20 mmol/l) resulted in nuclear to cytoplasmic translocation of Foxo1. Phosphorylation and translocation of Foxo1 following glucose refeeding were eliminated in an insulin receptor knockdown cell line, indicating that the glucose effects are mediated primarily through the insulin receptor. Activity of Foxo1 was observed to increase with decreased glucose concentrations, assessed by an IGF binding protein-1 promoter luciferase assay. Starvation of MIN6 cells identified a putative Foxo1 target, Chop, and a Chop-promoter luciferase assay in the presence of cotransfected Foxo1 supported this hypothesis. The importance of these observations was that nutritional alterations in the β-cell are associated with changes in Foxo1 transcriptional activity and that these changes are predominantly mediated through glucose-stimulated insulin secretion acting through its own receptor.
Time-Dependent Effects of Free Fatty Acids on Glucose Effectiveness in Type 2 Diabetes
Authors: Kishore Preeti , Tonelli Julia , Koppaka Sudha , Fratila Corina , Bose Anita , Lee Do-Eun , Reddy Kalpana , Hawkins Meredith
Published: May 2006

Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-3H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t = 0–240 min), and hyperglycemia (10 mmol/l, t = 240–360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA1c 10.9 ± 0.4%, age 50 ± 3 years, BMI 30 ± 2 kg/m2) on at least two occasions with saline (NA− group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 ± 6% suppression of EGP with hyperglycemia vs. NA− = 8 ± 7%; P < 0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 ± 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.
Combination of HLA-A24, -DQA1*03, and -DR9 Contributes to Acute-Onset and Early Complete β-Cell Destruction in Type 1 Diabetes
Authors: Nakanishi Koji , Inoko Hidetoshi
Published: May 2006

To elucidate the genetic factors contributing to heterogeneity of the rate of β-cell destruction in type 1 diabetes, we investigated the relationship between the time course of complete β-cell loss and HLA class I and II alleles. HLA allele frequencies were also examined among subgroups classified by the mode of onset. The subjects were 266 type 1 diabetic patients (among whom 196 patients were studied longitudinally) and 136 normal control subjects. Earlier complete loss of β-cell function was observed in patients who possessed both HLA-A24 and HLA-DQA1*03 and in patients who had HLA-DR9, compared with those without these HLA alleles (P = 0.0057 and 0.0093, respectively). Much earlier complete β-cell loss was observed in the patients who possessed all of HLA-A24, -DQA1*03, and -DR9 compared with the remaining patients (P = 0.0011). The combination of HLA-A24, -DQA1*03, and -DR9 showed a higher frequency in acute-onset than slow-onset type 1 diabetes (P = 0.0002). In contrast, HLA-DR2 was associated with a slower rate of progression to complete β-cell loss. These results indicate that the combination of HLA-A24, -DQA1*03, and -DR9 contributes to the acute-onset and early complete β-cell destruction, whereas HLA-DR2 has a protective effect against complete β-cell loss in type 1 diabetes.
Cognitive Performance, Psychological Well-Being, and Brain Magnetic Resonance Imaging in Older Patients With Type 1 Diabetes
Authors: Brands Augustina M.A. , Kessels Roy P.C. , Hoogma Roel P.L.M. , Henselmans Johanna M.L. , van der Beek Boter Johanna W. , Kappelle L. Jaap , de Haan Edward H.F. , Biessels Geert Jan
Published: May 2006

Modest cognitive impairment has been reported in young-adult patients with type 1 diabetes. In older patients with type 2 diabetes, cognitive impairments are more pronounced, which might be due to age but also to differential effects of type 1 diabetes and type 2 diabetes on the brain. This study therefore assessed cognitive performance and magnetic resonance imaging (MRI) of the brain in older type 1 diabetic patients. Forty type 1 diabetic patients (age >50 years) and 40 age-matched control subjects were included. Neuropsychological assessment included all major cognitive domains, and psychological well-being was assessed with questionnaires. Atrophy, white-matter abnormalities, and infarcts were rated on MRI scans. Type 1 diabetic patients performed slightly (effect sizes <0.4) worse on cognitive tasks, but only “speed of information processing” reached statistical significance. No significant between-group differences were found on any of the MRI parameters. Type 1 diabetic patients tended to report more cognitive and depressive problems than control subjects, but this did not correlate with the performance on cognitive tests. We conclude that cognition in older type 1 diabetic patients is only mildly disturbed. Chronic exposure to hyperglycemia is in itself, even at older age, apparently not sufficient to have considerable impact on the brain.
Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice
Authors: Li Xiaoyan , Chen Hainan , Epstein Paul N.
Published: May 2006

It is widely proposed that reactive oxygen species (ROS) contribute to β-cell death in type 1 diabetes. We tested this in nonobese diabetic (NOD) mice using β-cell–specific overexpression of three antioxidant proteins: metallothionein (MT), catalase (Cat), or manganese superoxide dismutase (MnSOD). Unexpectedly, the cytoplasmic antioxidants, MT and catalase, greatly accelerated diabetes after cyclophosphamide and accelerated spontaneous diabetes in male NOD mice. This occurred despite the fact that they reduced cytokine-induced ROS production and MT reduced streptozotocin diabetes in NOD mice. Accelerated diabetes onset coincided with increased β-cell death but not with increased immune attack. Islets from MTNOD mice were more sensitive to cytokine injury. In vivo and in vitro studies indicated reduced activation of the Akt/pancreatic duodenal homeobox-1 survival pathway in MTNOD and CatNOD islets. Our study indicates that cytoplasmic ROS may have an important role for protecting the β-cell from autoimmune destruction.
Functional Effects of Mutations at F35 in the NH2-terminus of Kir6.2 (KCNJ11), Causing Neonatal Diabetes, and Response to Sulfonylurea Therapy
Authors: Proks Peter , Girard Christophe , Bævre Halvor , Njølstad Pål R. , Ashcroft Frances M.
Published: May 2006

Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K+ channel (KATP channel), cause neonatal diabetes. To date, all mutations increase whole-cell KATP channel currents by reducing channel inhibition by MgATP. Here, we provide functional characterization of two mutations (F35L and F35V) at residue F35 of Kir6.2, which lies within the NH2-terminus. We further show that the F35V patient can be successfully transferred from insulin to sulfonylurea therapy. The patient has been off insulin for 24 months and shows improved metabolic control (mean HbA1c 7.58 before and 6.18% after sulfonylurea treatment; P < 0.007). Wild-type and mutant Kir6.2 were heterologously coexpressed with SUR1 in Xenopus oocytes. Whole-cell KATP channel currents through homomeric and heterozygous F35V and F35L channels were increased due to a reduced sensitivity to inhibition by MgATP. The mutation also increased the open probability (PO) of homomeric F35 mutant channels in the absence of ATP. These effects on PO and ATP sensitivity were abolished in the absence of SUR1. Our results suggest that mutations at F35 cause permanent neonatal diabetes by affecting KATP channel gating and thereby, indirectly, ATP inhibition. Heterozygous F35V channels were markedly inhibited by the sulfonylurea tolbutamide, accounting for the efficacy of sulfonylurea therapy in the patient.
Salutary Effect of Pigment Epithelium–Derived Factor in Diabetic Nephropathy
Authors: Wang Joshua J. , Zhang Sarah X. , Mott Robert , Knapp Ryan R. , Cao Wei , Lau Kai , Ma Jian-xing
Published: May 2006

Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal diseases in the U.S. Pigment epithelium–derived factor (PEDF) is a potent angiogenic inhibitor that has been extensively studied in diabetic retinopathy. Recently, we reported that PEDF is expressed at high levels in normal kidneys and that PEDF levels are decreased in kidneys of streptozotocin (STZ)-induced diabetic rats. In the present study, we injected STZ-diabetic rats with an adenovirus expressing PEDF (Ad-PEDF) to evaluate its effects in diabetes. The results showed that increased expression of PEDF in the kidney in response to Ad-PEDF delivery significantly alleviated microalbuminuria in early stages of diabetes. Administration of Ad-PEDF was found to prevent the overexpression of two major fibrogenic factors, transforming growth factor-β (TGF-β)1 and connective tissue growth factor (CTGF), and to significantly reduce the production of an extracellular matrix (ECM) protein in the diabetic kidney. Moreover, PEDF upregulated metalloproteinase-2 expression in diabetic kidney, which is responsible for ECM degradation. In cultured human mesangial cells, PEDF significantly inhibited the overexpression of TGF-β1 and fibronectin induced by angiotensin II. PEDF also blocked the fibronectin production induced by TGF-β1 through inhibition of Smad3 activation. These findings suggest that PEDF functions as an endogenous anti–TGF-β and antifibrogenic factor in the kidney. A therapeutic potential of PEDF in diabetic nephropathy is supported by its downregulation in diabetes; its prevention of the overexpression of TGF-β, CTGF, and ECM proteins in diabetic kidney; and its amelioration of proteinuria in diabetic rats following Ad-PEDF injection.
The Intrauterine Environment as Reflected by Birth Size and Twin and Zygosity Status Influences Insulin Action and Intracellular Glucose Metabolism in an Age- or Time-Dependent Manner
Authors: Poulsen Pernille , Vaag Allan
Published: May 2006

According to the “fetal origins hypothesis,” monozygotic (MZ) twins may be more prone to develop various metabolic abnormalities compared with dizygotic (DZ) twins, and twins all together may be more predisposed to metabolic defects compared with singletons. To determine the impact of twin and zygosity status as well as birth size on in vivo measures of glucose metabolism, we examined 123 young (aged 22–31 years) and 103 elderly (aged 57–66 years) MZ and DZ twins and age-matched singleton control subjects. All participants were born at term with available birth records. Peripheral and hepatic insulin action and intracellular glucose partitioning was determined by a euglycemic-hyperinsulinemic clamp using tritiated glucose combined with indirect calorimetry. In elderly subjects, zygosity status influenced nonoxidative glucose metabolism, while twin status per se was associated with elevated hepatic glucose production during both steady-state periods. Birth weight was associated with nonoxidative glucose metabolism in a nongenetic manner within twins and with a high glucose and low lipid oxidation in singletons. In younger subjects, twin status influenced glucose and lipid oxidation rates. We demonstrate a complex age- or time-dependent relationship between independent markers of fetal environment and glucose homeostasis in twins. The documented differential programming effects associated with either low birth weight and twin or zygosity status all represent known defects of glucose homeostasis in type 2 diabetes.
Lymphocytic Infiltration and Immune Activation in Metallothionein Promoter–Exendin-4 (MT-Exendin) Transgenic Mice
Authors: Baggio Laurie L. , Holland Dianne , Wither Joan , Drucker Daniel J.
Published: May 2006

Glucagon-like peptide 1 (GLP-1) exhibits considerable potential for the treatment of type 2 diabetes because of its effects on stimulation of insulin secretion and the inhibition of gastric emptying, appetite, and glucagon secretion. However, native GLP-1 undergoes rapid enzymatic inactivation, prompting development of long-acting degradation-resistant GLP-1 receptor agonists such as exendin-4 (Ex-4). To study the consequences of sustained exposure to Ex-4, we generated metallothionein promoter–exendin-4 (MT-Exendin) mice that continuously express a proexendin-4 transgene in multiple murine tissues. We now report that MT-Exendin mice develop extensive tissue lymphocytic infiltration with increased numbers of CD4+ and CD8a+ cells in the liver and/or kidney and increased numbers of B220+ cells present in the pancreas and liver. MT-Exendin mice generate antibodies directed against Ex-4, exendin NH2-terminal peptide (ENTP), and proexendin-4 as well as antibodies that cross-react with native GLP-1. Furthermore, lymphocytes isolated from MT-Exendin mice proliferate in response to proexendin-4 but not after exposure to Ex-4 or ENTP. These findings demonstrate that expression of a proexendin-4 transgene may be associated with activation of humoral and cellular immune responses in mice.
From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation
Authors: Sagen Jørn V. , Odili Stella , Bjørkhaug Lise , Zelent Dorothy , Buettger Carol , Kwagh Jae , Stanley Charles , Dahl-Jørgensen Knut , de Beaufort Carine , Bell Graeme I. , Han Yi , Grimsby Joseph , Taub Rebecca , Molven Anders , Søvik Oddmund , Njølstad Pål R. , Matschinsky Franz M.
Published: May 2006

Glucokinase functions as a glucose sensor in pancreatic β-cells and regulates hepatic glucose metabolism. A total of 83 probands were referred for a diagnostic screening of mutations in the glucokinase (GCK) gene. We found 11 different mutations (V62A, G72R, L146R, A208T, M210K, Y215X, S263P, E339G, R377C, S453L, and IVS5 + 1G>C) in 14 probands. Functional characterization of recombinant glutathionyl S-transferase–G72R glucokinase showed slightly increased activity, whereas S263P and G264S had near-normal activity. The other point mutations were inactivating. S263P showed marked thermal instability, whereas the stability of G72R and G264S differed only slightly from that of wild type. G72R and M210K did not respond to an allosteric glucokinase activator (GKA) or the hepatic glucokinase regulatory protein (GKRP). Mutation analysis of the role of glycine at position 72 by substituting E, F, K, M, S, or Q showed that G is unique since all these mutants had very low or no activity and were refractory to GKRP and GKA. Structural analysis provided plausible explanations for the drug resistance of G72R and M210K. Our study provides further evidence that protein instability in combination with loss of control by a putative endogenous activator and GKRP could be involved in the development of hyperglycemia in maturity-onset diabetes of the young, type 2. Furthermore, based on data obtained on G264S, we propose that other and still unknown mechanisms participate in the regulation of glucokinase.
Kir6.2 Mutations Associated With Neonatal Diabetes Reduce Expression of ATP-Sensitive K+ channels
Authors: Lin Chia-Wei , Lin Yu-Wen , Yan Fei-Fei , Casey Jillene , Kochhar Malini , Pratt Emily B. , Shyng Show-Ling
Published: May 2006

Heterozygous missense mutations in the pore-forming subunit Kir6.2 of ATP-sensitive K+ channels (KATP channels) have recently been shown to cause permanent neonatal diabetes mellitus (PNDM). Functional studies demonstrated that PNDM mutations reduce KATP channel sensitivity to ATP inhibition, resulting in gain of channel function. However, the impact of these mutations on channel expression has not been examined. Here, we show that PNDM mutations, including Q52R, V59G, V59M, R201C, R201H, and I296L, not only reduce channel ATP sensitivity but also impair channel expression at the cell surface to varying degrees. By tagging the PNDM Kir6.2 mutant V59G or R201H with an additional mutation, N160D, that confers voltage-dependent polyamine block of KATP channels, we demonstrate that in simulated heterozygous state, all surface channels are either wild-type or heteromeric channels containing both wild-type and mutant Kir6.2 subunits. Comparison of the various PNDM mutations in their effects on channel nucleotide sensitivity and expression, as well as disease phenotype, suggests that both channel-gating defect and expression level may play a role in determining disease severity. Interestingly, sulfonylureas significantly increase surface expression of certain PNDM mutants, suggesting that the efficacy of sulfonylurea therapy may be compromised by the effect of these drugs on channel expression.
Altered Endothelial Nitric Oxide Synthase Targeting and Conformation and Caveolin-1 Expression in the Diabetic Kidney
Authors: Komers Radko , Schutzer William E. , Reed John F. , Lindsley Jessie N. , Oyama Terry T. , Buck David C. , Mader Scott L. , Anderson Sharon
Published: May 2006

Experimental diabetes is associated with complex changes in renal nitric oxide (NO) bioavailability. We explored the effect of diabetes on renal cortical protein expression of endothelial NO synthase (eNOS) with respect to several determinants of its enzymatic function, such as eNOS expression, membrane localization, phosphorylation, and dimerization, in moderately hyperglycemic streptozotocin-induced diabetic rats compared with nondiabetic control rats and diabetic rats with intensive insulin treatment to achieve near-normal metabolic control. We studied renal cortical expression and localization of caveolin-1 (CAV-1), an endogenous modulator of eNOS function. Despite similar whole-cell eNOS expression in all groups, eNOS monomer and dimer in membrane fractions were reduced in moderately hyperglycemic diabetic rats compared with control rats; the opposite trend was apparent in the cytosol. Stimulatory phosphorylation of eNOS (Ser1177) was also reduced in moderately hyperglycemic diabetic rats. eNOS colocalized and interacted with CAV-1 in endothelial cells throughout the renal vascular tree both in control and moderately hyperglycemic diabetic rats. However, the abundance of membrane-localized CAV-1 was decreased in diabetic kidneys. Intensive insulin treatment reversed the effects of diabetes on each of these parameters. In summary, we observed diabetes-mediated alterations in eNOS and CAV-1 expression that are consistent with the view of decreased bioavailability of renal eNOS-derived NO.
Risk Factors for Renal Dysfunction in Type 2 Diabetes
Authors: Retnakaran Ravi , Cull Carole A. , Thorne Kerensa I. , Adler Amanda I. , Holman Rury R. ,   for the UKPDS Study Group
Published: May 2006

Not all patients with type 2 diabetes develop renal dysfunction. Identifying those at risk is problematic because even microalbuminuria, often used clinically as an indicator of future renal dysfunction, does not always precede worsening renal function. We sought to identify clinical risk factors at diagnosis of type 2 diabetes associated with later development of renal dysfunction. Of 5,102 U.K. Prospective Diabetes Study (UKPDS) participants, prospective analyses were undertaken in those without albuminuria (n = 4,031) or with normal plasma creatinine (n = 5,032) at diagnosis. Stepwise proportional hazards multivariate regression was used to assess association of putative baseline risk factors with subsequent development of albuminuria (microalbuminuria or macroalbuminuria) or renal impairment (Cockcroft-Gault estimated creatinine clearance <60 ml/min or doubling of plasma creatinine). Over a median of 15 years of follow-up 1,544 (38%) of 4,031 patients developed albuminuria and 1,449 (29%) of 5,032 developed renal impairment. Of 4,006 patients with the requisite data for both outcomes, 1,534 (38%) developed albuminuria and 1,132 (28%) developed renal impairment. Of the latter, 575 (51%) did not have preceding albuminuria. Development of albuminuria or renal impairment was independently associated with increased baseline systolic blood pressure, urinary albumin, plasma creatinine, and Indian-Asian ethnicity. Additional independent risk factors for albuminuria were male sex, increased waist circumference, plasma triglycerides, LDL cholesterol, HbA1c (A1C), increased white cell count, ever having smoked, and previous retinopathy. Additional independent risk factors for renal impairment were female sex, decreased waist circumference, age, increased insulin sensitivity, and previous sensory neuropathy. Over a median of 15 years from diagnosis of type 2 diabetes, nearly 40% of UKPDS patients developed albuminuria and nearly 30% developed renal impairment. Distinct sets of risk factors are associated with the development of these two outcomes, consistent with the concept that they are not linked inexorably in type 2 diabetes.
Nutritional Supplementation Withtrans-10,cis-12–Conjugated Linoleic Acid Induces Inflammation of White Adipose Tissue
Authors: Poirier Hélène , Shapiro Jennifer S. , Kim Roy J. , Lazar Mitchell A.
Published: May 2006

Conjugated linoleic acids (CLAs) are conjugated dienoic isomers of linoleic acid. Many people supplement their diets with CLAs to attempt weight loss, and the trans-10,cis-12 isomer (t10,c12-CLA) of CLA reduces adiposity in animal models and humans. However, CLA treatment in mice causes insulin resistance that has been attributed to the lipoatrophic state, which is associated with hyperinsulinemia and hepatic steatosis. Here, we investigated the effect of t10,c12-CLA on adipose tissue inflammation, another factor promoting insulin resistance. We confirmed that t10,c12-CLA daily gavage performed in mice reduces white adipose tissue (WAT) mass and adiponectin and leptin serum levels and provokes hyperinsulinemia. In parallel, we demonstrated that this CLA isomer led to a rapid induction of inflammatory factors such as tumor necrosis factor-α and interleukin-6 gene expression in WAT without affecting their serum levels. In vitro, t10,c12-CLA directly induced IL-6 secretion in 3T3-L1 adipocytes by an nuclear factor-κB–dependent mechanism. In vivo, however, the lipoatrophic adipose tissue of CLA-treated mice was notable for a dramatic increase in macrophage infiltration and gene expression. Thus, CLA supplementation directly induces inflammatory gene expression in adipocytes and also promotes macrophage infiltration into adipose tissue to a local inflammatory state that contributes to insulin resistance.
HLA Genotyping Supports a Nonautoimmune Etiology in Patients Diagnosed With Diabetes Under the Age of 6 Months
Authors: Edghill Emma L. , Dix Rachel J. , Flanagan Sarah E. , Bingley Polly J. , Hattersley Andrew T. , Ellard Sian , Gillespie Kathleen M.
Published: May 2006

Children with permanent diabetes are usually assumed to have type 1 diabetes. It has recently been shown that there are genetic subgroups of diabetes that are often diagnosed during the neonatal period but may present later. A recent Italian study proposed that type 1 diabetes is rare before 6 months of age. We aimed to examine genetic susceptibility to type 1 diabetes in patients diagnosed with diabetes before the age of 2 years. We analyzed HLA class II genotypes, markers of autoimmune diabetes, in 187 children with permanent diabetes diagnosed at <2 years of age. Of the 79 subjects diagnosed at <6 months of age, 41% (95% CI 0.30–0.51) had type 1 diabetes–associated high-risk genotypes, a proportion similar to that in healthy population control subjects (44%, P = 0.56). This group included 32 patients with mutations in the KCNJ11 gene, which encodes Kir6.2 (44% high-risk HLA class II genotypes), and 47 in whom the etiology of diabetes was unknown (38% high-risk HLA class II genotypes). Of 108 patients diagnosed between 6 and 24 months of age, 93% (0.86–0.99) had high-risk HLA class II genotypes compared with 44% of the population control subjects (P < 0.0001). We conclude that infants diagnosed with diabetes before 6 months of age are unlikely to have autoimmune type 1 diabetes and are most likely to have a monogenic etiology.
Adipose Tissue
Authors: Scherer Philipp E.
Published: May 2006

Adipose tissue, when carried around in excessive amounts, predisposes to a large number of diseases. Epidemiological data show that the prevalence of obesity has significantly increased over the past 20 years and continues to do so at an alarming rate. Here, some molecular aspects of the key constituent of adipose tissue, the adipocyte, are reviewed. While the adipocyte has been studied for many years and remarkable insights have been gained about some processes, many areas of the physiology of the fat cell remain unexplored. Our understanding of how cellular events in the adipocyte affect the local environment through paracrine interactions and how systemic effects are achieved through endocrine interactions is rudimentary. While storage and release of lipids are major functions of adipocytes, the adipocyte also uses specific lipid molecules for intracellular signaling and uses a host of protein factors to communicate with essentially every organ system in the body. The intensity and complexity of these signals are highly regulated, differ in each fat pad, and are dramatically affected by various disease states.
An Open, Randomized, Parallel-Group Study to Compare the Efficacy and Safety Profile of Inhaled Human Insulin (Exubera) With Metformin as Adjunctive Therapy in Patients With Type 2 Diabetes Poorly Controlled on a Sulfonylurea
Authors: Barnett Anthony H. , Dreyer Manfred , Lange Peter , Serdarevic-Pehar Marjana ,   on behalf of the Exubera Phase III Study Group
Published: May 2006

OBJECTIVE—To compare the efficacy and safety profile of adding inhaled human insulin (INH; Exubera) or metformin to sulfonylurea monotherapy in patients with poorly controlled type 2 diabetes.

RESEARCH DESIGN AND METHODS—We performed an open-label, parallel, 24-week, multicenter trial. At week −1, patients uncontrolled on sulfonylurea monotherapy were divided into two HbA1c (A1C) arms: ≥8 to ≤9.5% (moderately high) and >9.5 to ≤12% (very high). Patients were randomized to adjunctive premeal INH (n = 225) or metformin (n = 202). The primary efficacy end point was change in A1C from baseline.

RESULTS—In the A1C >9.5% arm, INH demonstrated a significantly greater reduction in A1C than metformin. Mean adjusted changes from baseline were −2.17 and −1.79%, respectively; between-treatment difference was −0.38% (95% CI −0.63 to −0.14, P = 0.002). In the A1C ≤9.5% arm, mean adjusted A1C changes were −1.94 and −1.87%, respectively (−0.07% [−0.33 to 0.19], P = 0.610), consistent with the noninferiority criterion. Hypoglycemia (events/subject-month) was greater in the INH (0.33) than in the metformin (0.15) group (risk ratio 2.16 [95% CI 1.67–2.78]), but there were no associated discontinuations. Other adverse events, except increased cough in the INH group, were similar. At week 24, changes in pulmonary function parameters were small and comparable between groups. Insulin antibody binding increased more with INH but did not have any associated clinical manifestations.

CONCLUSIONS—In patients with type 2 diabetes poorly controlled on a sulfonylurea (A1C >9.5%), the addition of premeal INH significantly improves glycemic control compared with adjunctive metformin and is well tolerated.
Induction of interferon‐α by immune complexes or liposomes containing systemic lupus erythematosus autoantigen– and Sjögren's syndrome autoantigen–associated RNA
Authors: Lövgren Tanja , Eloranta Maija‐Leena , Kastner Berthold , Wahren‐Herlenius Marie , Alm Gunnar V. , Rönnblom Lars
Published: May 2006

Objective

To investigate the ability of systemic lupus erythematosus (SLE) autoantigen– and Sjögren's syndrome (SS) autoantigen–associated U1 small nuclear RNA (U1 snRNA) and hY1RNA to induce interferon‐α (IFNα) production.

Methods

In vitro–transcribed U1 snRNA or hY1RNA and lipofectin were added to peripheral blood mononuclear cell (PBMC) cultures. Purified U1 snRNP particles and IgG from SLE patients (SLE‐IgG) were added to cultures of PBMCs, enriched monocytes, or natural interferon–producing cells (NIPCs); the latter are also known as plasmacytoid dendritic cells (pDC). Cells were double‐stained for IFNα and either blood dendritic cell antigen 2 (NIPCs/pDC) or CD14 (monocytes) and then analyzed by flow cytometry. In some experiments, RNase or inhibitors of Fcγ receptor IIa (FcγRIIa) (specific antibodies), endocytosis (chloroquine, bafilomycin A), or Toll‐like receptors (TLRs; oligodeoxynucleotide 2088) were used. The produced IFNα was measured by immunoassay.

Results

Lipofected U1 snRNA and hY1RNA both induced IFNα production in monocytes, but not in NIPC/pDC. In contrast, U1 snRNP combined with SLE‐IgG induced IFNα production only in NIPCs/pDC, and this response was decreased by RNase treatment or inhibition of the FcγRIIa, the endocytosis pathways, or the TLRs.

Conclusion

Our finding that U1 snRNA and hY1RNA have IFNα‐inducing capacity indicates that immune complexes containing such RNA, for example U1 snRNP particles, can be at least partly responsible for the ongoing IFNα production seen in SLE and SS. These results may help to explain the molecular mechanisms behind the pathogenesis of these and other autoimmune diseases in which autoantibodies to RNA‐ binding proteins occur.
Identification of synovial biomarkers of response to experimental treatment in early‐phase clinical trials in spondylarthritis
Authors: Kruithof Elli , De Rycke Leen , Vandooren Bernard , De Keyser Filip , FitzGerald Oliver , McInnes Iain , Tak Paul P. , Bresnihan Barry , Veys Eric M. , Baeten Dominique ,   OMERACT Special Interest Group on Synovial Analysis in Clinical Trials
Published: May 2006

Objective

To identify biomarkers for effective treatment in early‐phase clinical trials of spondylarthritis (SpA), by analyzing which synovial features can be reliably identified in patients with SpA.

Methods

Synovial biopsies were performed at weeks 0 and 12 in 20 SpA patients treated with infliximab, 20 treated with etanercept, and 12 who were not treated. Primary clinical outcome measures were patient and physician global assessment of disease activity. Extensive histologic evaluation included assessment of lining layer hyperplasia, vascularity, markers of cellular infiltration, and metalloproteinases (MMPs) in the lining and sublining layers.

Results

Changes in levels of CD163 (resident tissue macrophages) in the lining, and CD163, MMP‐3, and myeloid‐related protein 14 (MRP‐14; infiltrating myeloid cells) in the sublining correlated significantly with changes in the primary clinical outcomes. Comparison between responders (n = 35) and nonresponders (n = 17) showed differences in the degree of change in the levels of CD163 in the lining and CD163, MMP‐3, and CD3 in the sublining, whereas trends in change in the levels of MRP‐8 and MRP‐14 in the lining and sublining were similar in the 2 groups. Accordingly, the highest differences in standardized response means (SRMs) between the 2 groups were found for CD163 in the lining, MMP‐3, CD163, CD3, and MRP‐8 in the sublining, and the level of polymorphonuclear cells (PMNs). When comparing treated and untreated patients, high differences in SRMs were again found for CD163 in the lining, MMP‐3, CD163, and MRP‐8 in the sublining, and PMNs. These parameters performed prognostically as well as the erythrocyte sedimentation rate and better than the C‐reactive protein level. Class prediction analysis yielded a 90% correct prediction using 8 synovial parameters, as follows: lining and sublining CD163, MRP‐8, and MRP‐14, sublining MMP‐3, and PMNs. In validation analyses with independent samples, effective treatment was correctly predicted in 24 of 30 SpA patients and in 2 of 2 placebo‐treated patients.

Conclusion

Changes in synovial macrophage subsets, PMN levels, and MMP‐3 expression reflect response to treatment in SpA. The ability of these parameters to correctly identify effective therapy makes them interesting biomarkers for use in early‐phase clinical trials in SpA.
Intravenous ibandronate injections in postmenopausal women with osteoporosis: One‐year results from the dosing intravenous administration study
Authors: Delmas Pierre D. , Adami Silvano , Strugala Cezary , Stakkestad Jacob A. , Reginster Jean‐Yves , Felsenberg Dieter , Christiansen Claus , Civitelli Roberto , Drezner Marc K. , Recker Robert R. , Bolognese Michael , Hughes Claire , Masanauskaite Daiva , Ward Penelope , Sambrook Philip , Reid David M.
Published: May 2006

Objective

Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen‐containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis.

Methods

In a randomized, double‐blind, double‐dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55–80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2−L4] bone mineral density [BMD] T score less than −2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C‐telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability.

Results

At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function.

Conclusion

As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated.
Scientific research activity and communication measured with cybermetrics indicators
Authors: Aguillo Isidro F. , Granadino Begoña , Ortega José L. , Prieto José A.
Published: May 2006

To test feasibility of cybermetric indicators for describing and ranking university activities as shown in their Web sites, a large set of 9,330 institutions worldwide was compiled and analyzed. Using search engines' advanced features, size (number of pages), visibility (number of external inlinks), and number of rich files (pdf, ps, doc, ppt, and xls formats) were obtained for each of the institutional domains of the universities. We found a statistically significant correlation between a Web ranking built on a combination of Webometric data and other university rankings based on bibliometric and other indicators. Results show that cybermetric measures could be useful for reflecting the contribution of technologically oriented institutions, increasing the visibility of developing countries, and improving the rankings based on Science Citation Index (SCI) data with known biases.
Estimation of strength in different extra Watson–Crick hydrogen bonds in DNA double helices through quantum chemical studies
Authors: Bandyopadhyay D. , Bhattacharyya D.
Published: May 2006

It was shown earlier, from database analysis, model building studies, and molecular dynamics simulations that formation of cross‐strand bifurcated or Extra Watson–Crick hydrogen (EWC) bonds between successive base pairs may lead to extra rigidity to DNA double helices of certain sequences. The strengths of these hydrogen bonds are debatable, however, as they do not have standard linear geometry criterion. We have therefore carried out detailed ab initio quantum chemical studies using RHF/6‐31G(2d,2p) and B3LYP/6‐31G(2p,2d) basis sets to determine strengths of several bent hydrogen bonds with different donor and acceptors. Interaction energy calculations, corrected for the basis set superposition errors, suggest that N—H···O type bent EWC hydrogen bonds are possible along same strands or across the strands between successive base pairs, leading to significant stability (ca. 4–9 kcal/mol). The N—H···N and C—H···O type interactions, however, are not so stabilizing. Hence, consideration of EWC N—H···O H‐bonds can lead to a better understanding of DNA sequence directed structural features. © 2006 Wiley Periodicals, Inc. Biopolymers 83:313–325, 2006

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Simplified estimation method of the largest eigenvalue distribution in Nakagami–Rice MIMO channel
Authors: Tsuruta Makoto , Karasawa Yoshio
Published: May 2006

In this paper, we propose a simple method for accurately calculating the probability distribution of the largest eigenvalue of the correlation matrix of a MIMO propagation channel in a Nakagami–Rice fading environment including direct signals. The results determined by the proposed approximation method were compared to the results of a computer simulation and exhibited accurate matches. We discuss the channel capacity in a Nakagami–Rice fading environment. In this environment, the largest eigenvalue clearly dominates, and maximum ratio combining transfers are clearly useful. © 2006 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 89(11): 68–77, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20210
Tiny GPS receiver for space application
Authors: Saito Hirobumi , Hamada Yusuke , Shinkai Kenji , Sasaki Hiroyuki , Kuroki Seiji
Published: May 2006

GPS receivers used in car navigation and other applications have been downsized to dozens of grams, with significant gains in power conservation. With the assistance of a vehicle GPS manufacturer, a vehicle GPS receiver has been modified and a space application GPS receiver with ultralow power consumption that generates pseudo‐range data has been developed. We expanded the frequency search range for the GPS receiver, and we conducted on‐orbit simulations using a GPS simulator and confirmed that the positioning accuracy performance of the receiver is less than 1 m. It has also been confirmed that the receiver has a 20‐krad radiation tolerance and that it is latch‐up‐free with respect to 200‐MeV protons. The GPS receiver will be deployed on the small scientific satellite INDEX which is under development by the Aerospace Science Research Department of the Japan Aerospace Exploration Agency. © 2006 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 89(11): 56–67, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20234
An array antenna assisted digital terrestrial television broadcasting receiver with vehicle speed estimation and Doppler spread compensation
Authors: Nagai Norikazu , Takayanagi Hideaki , Saito Masato , Okada Minoru , Yamamoto Heiichi
Published: May 2006

For digital terrestrial broadcasting, OFDM (Orthogonal Frequency Division Multiplexing) is used as the transmission system. While OFDM is robust to frequency‐selective fading due to delayed waves in a multipath environment, it is not resistant to Doppler spread for reception during movement. When the digital terrestrial broadcast is received while a vehicle is in motion, this weakness is a serious problem. The present authors have proposed a method for correcting Doppler spread by effectively canceling the motion of the moving body based on an array antenna to estimate the received signal at a point stationary to the ground. In the present paper, an algorithm is developed for estimating, from the received signal, the speed of movement of the vehicle, which was considered known in the previous method. A digital terrestrial broadcasting receiver is proposed for compensating the Doppler spread by estimating the speed of movement of the vehicle. By computer simulation, it is shown that the proposed algorithm can accurately estimate the speed of movement and that the bit error rate of reception of digital terrestrial broadcasts while in motion can be significantly improved. © 2006 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 89(11): 46–55, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20260
A distributed queue layered network suppressing slot discarding
Authors: Enzaki Takeshi , Ata Shingo , Oka Ikuo , Fujiwara Chikato
Published: May 2006

In this paper, a layered network that interconnects a distributed queue subnetwork with another distributed queue bridge network is considered. As slot control scheme in this network, a loopback retransmission scheme preventing slot discarding and an adaptive node load control function are proposed. In the communication within the subnetwork, no transmitted slot is discarded during processing. However, it is necessary to consider protection against discarding due to buffer overflow in the bridge of the distributed queue bridge network interconnecting the subnetworks. In order to prevent reduction of slot use efficiency caused by discarding in the bridge, it is desirable to eliminate discarding. Also, in order to prevent discarding of slots arriving at the bridge from the subnetworks, slot transmission at each node must be controlled. In this paper, in order to prevent slot discarding caused by buffer overflow of the bridge, a method is proposed for loopback retransmission of the slot on the bridge network or subnetwork. It is shown that discarding can be eliminated. Also, the effectiveness of the method is confirmed by computer simulation. © 2006 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 89(11): 35–45, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20267