bluuebunny/crossref_metadata_2025 huggingface dataset:
The inhibition of Wnt/β-catenin signalling by 1α,25-dihydroxyvitamin D3 is abrogated by Snail1 in human colon cancer cells
Authors: Larriba María Jesús , Valle Noelia , Pálmer Héctor G , Ordóñez-Morán Paloma , Álvarez-Díaz Silvia , Becker Karl-Friedrich , Gamallo Carlos , de Herreros Antonio García , González-Sancho José Manuel , Muñoz Alberto
Published: March 2007

The Wnt/β-catenin signalling pathway is activated in 90% of human colon cancers by nuclear accumulation of β-catenin protein due to its own mutation or to that of adenomatous polyposis coli. In the nucleus, β-catenin regulates gene expression promoting cell proliferation, migration and invasiveness. 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits β-catenin signalling by inducing its binding to vitamin D receptor (VDR) and by promoting β-catenin nuclear export. The transcription factor Snail1 represses VDR expression and we demonstrate here that Snail1 also abolishes the nuclear export of β-catenin induced by 1,25(OH)2D3 in SW480-ADH cells. Accordingly, Snail1 relieves the inhibition exerted by 1,25(OH)2D3 on genes whose expression is driven by β-catenin, such as c-MYC, ectodermal-neural cortex-1 (ENC-1) or ephrin receptor B2 (EPHB2). In addition, Snail1 abrogates the inhibitory effect of 1,25(OH)2D3 on cell proliferation and migration. In xenografted mice, Snail1 impedes the nuclear export of β-catenin and the inhibition of ENC-1 expression induced by EB1089, a 1,25(OH)2D3 analogue. The elevation of endogenous SNAIL1 protein levels reproduces the effect of an ectopic Snail1 gene. Remarkably, the expression of exogenous VDR in cells with high levels of Snail1 normalizes the transcriptional responses to 1,25(OH)2D3. However, this exogenous VDR failed to fully restore the blockage of the Wnt/β-catenin pathway by 1,25(OH)2D3. This suggests that the effects of Snail1 on this pathway are not merely due to the repression of VDR gene. We conclude that Snail1 is a positive regulator of the Wnt/β-catenin signalling pathway in part through the abrogation of the inhibitory action of 1,25(OH)2D3.
The Ras effectors NORE1A and RASSF1A are frequently inactivated in pheochromocytoma and abdominal paraganglioma
Authors: Geli Janos , Kiss Nimrod , Lanner Fredrik , Foukakis Theodoros , Natalishvili Natalia , Larsson Olle , Kogner Per , Höög Anders , Clark Geoffrey J , Ekström Tomas J , Bäckdahl Martin , Farnebo Filip , Larsson Catharina
Published: March 2007

NORE1A (RASSF5) and RASSF1A are newly described Ras effectors with tumour suppressor functions. Both molecules are frequently inactivated in various cancers. In this study, we aimed to explore the potential involvement of NORE1A and RASSF1A in pheochromocytoma and abdominal paraganglioma tumorigenesis. A panel of 54 primary tumours was analysed for NORE1A and RASSF1A mRNA expression by TaqMan quantitative RT-PCR. Furthermore, NORE1A and RASSF1A promoter methylation was assessed by combined bisulphite restriction endonuclease assay and methylation-sensitive Pyrosequencing respectively. The anti-tumorigenic role of NORE1A was functionally investigated in Nore1A-transfected PC12 rat pheochromocytoma cells by fluorescent inhibition of caspase activity and soft agar assays. Significantly suppressed NORE1A and RASSF1A mRNA levels were detected in primary tumours compared with normal adrenal medulla (P<0.001). Methylation of the NORE1A promoter was not observed in primary tumours. On the other hand, 9% (5/54) of the primary tumours examined showed RASSF1A promoter methylation greater than 20% as detected by Pyrosequencing. Methylation of the RASSF1A promoter was significantly associated with malignant behaviour (P<0.05). Transient expression of Nore1a resulted in enhanced apoptosis and impaired colony formation in soft agar. Our study provides evidence that NORE1A and RASSF1A are frequently suppressed in pheochromocytoma and abdominal paraganglioma. Silencing of NORE1A contributes to the transformed phenotype in these tumours.
Adrenocortical cancer: pathophysiology and clinical management
Authors: Libè Rossella , Fratticci Amato , Bertherat Jérôme
Published: March 2007

Adrenocortical cancer (ACC) is a rare tumor with a poor prognosis. By contrast, benign adrenocortical tumors are frequent, underlying the importance of a correct diagnosis of malignancy of such tumors. ACC can be diagnosed by the investigation of endocrine signs of steroid excess, symptoms due to tumor growth or an adrenal incidentaloma. Hormonal investigations demonstrate in most ACC steroid oversecretion, the dominant characteristics being a co-secretion of cortisol and androgens. Imaging by CT-scan or MRI shows a large heterogeneous tumor with a low fat content. Careful pathological investigation with the assessment of the Weiss score is important for the diagnosis of malignancy. Molecular markers can also be helpful and in the future might be important for prognosis. Tumors localized to the adrenal gland (McFarlane stages 1 and 2) have a better outcome than invasive and metastatic tumors (stages 3 and 4). Tumor removal by a specialized team is crucial for treatment and should always aim at complete removal. In patients with metastatic or progressive disease, medical treatment is started with mitotane that requires a close monitoring of its blood level. Surgery is indicated when possible for local recurrence but also in some cases of metastasis. Local treatment (radiofrequency, chemoembolization, and radiation therapy) can have some indications for metastatic disease. In patients with disease progression cytotoxic chemotherapy can be used. Despite the best care, the overall prognosis of ACC is poor with a 5-year survival rate below 30% in most series. Therefore, progress in the understanding of the pathophysiology of ACC is important. Despite the rarity of ACC, significant advances have been made in the understanding of its pathogenesis the last decade. These progresses came mainly from the study of the genetics of ACC, both at the germline level in rare familial diseases, and at the somatic level by the study of molecular alterations in sporadic tumors. These advances underline the importance of genetic alterations in ACC development and point-out to various chromosomal regions (2, 11p15, 11q, 17p13) and genes (IGF-II, p53, β-catenin, ACTH receptor). This review will summarize these advances as well as the current clinical management of ACC.
The association between primary hyperparathyroidism and malignancy: nationwide cohort analysis on cancer incidence after parathyroidectomy
Authors: Nilsson Inga-Lena , Zedenius Jan , Yin Li , Ekbom Anders
Published: March 2007

In order to evaluate the link between primary hyperparathyroidism (pHPT) and malignancies, cases subjected to parathyroid adenomectomy (PTX) during 1958–1997 in Sweden were identified by analyzing the National Swedish Cancer Registry. To minimize the influence of confounding by detection, cases with malignant disease diagnosed before or at the same time as pHPT or during the first year after PTX were excluded. Altogether 9782 cases (7642♀) were included and followed for up to 40 years. Thus, the study comprises 89 571 person-years of observation. The incidence of malignancies was compared with that in the Swedish population standardized for age, sex, and calendar year. An increased overall incidence of cancer was demonstrated in both genders (standardized incidence ratio (SIR) 1.43, 95% confidence interval (CI) 1.35–1.52). This remain unchanged beyond 15 years after PTX. Breast cancer contributed a quarter of the cancer incidence in women (SIR 1.44, 95% CI 1.25–1.62). An increased risk of kidney (SIR 2.40, 95% CI 1.72–3.25), colonic (SIR 1.46, 95% CI 1.19–1.77), and squamous cell skin cancer (SIR 2.79, 95% CI 2.25–3.43) was found in both genders. The risk of endocrine and pancreas cancer was increased in the minority of patients who had their PTX before the age of 40. We conclude that pHPT is associated with an increased risk of developing malignancies that persists even after PTX. This suggests a causal disassociation with the biochemical derangements caused by parathyroid adenoma, while potentially common etiological mechanisms may include genetic predisposition or acquired disability to withstand environmental influence.
Osteoblast-conditioned medium promotes proliferation and sensitizes breast cancer cells to imatinib treatment
Authors: Brama Marina , Basciani Sabrina , Cherubini Sara , Mariani Stefania , Migliaccio Silvia , Arizzi Mario , Rosano Giuseppe , Spera Giovanni , Gnessi Lucio
Published: March 2007

Inhibition of platelet-derived growth factor receptor (PDGFR) signaling restricts the growth of human breast cancer in the bone of nude mice. We hypothesized that osteoblast-secreted substances may alter the response capacity of breast cancer cells to the PDGFRs tyrosine kinase inhibitor imatinib mesylate. We found that osteoblast-conditioned medium (OCM) increases the proliferation rate of the estrogen receptor negative (ER−) MDA-MB-231 and of the ER+ MCF-7 human breast cancer cell lines and the growth-promoting effect on ER+ cells is independent from estrogen. OCM significantly improved the dose- and the time-dependent sensitivity of the tumor cells to the anti-proliferative effect of imatinib. We also found that MDA-MB-231 and MCF-7 cells express the two PDGFRs subtypes, PDGFR-α and PDGFR-β, and OCM treatment increases the expression of the PDGFRs. Furthermore, imatinib inhibited the phosphorylation rate of its target tyrosine kinase receptors. We conclude that bone microenvironment, through osteoblast-secreted substances may cause estrogen-independent proliferation of breast cancer cells by a mechanism mediated by the induction of PDGFRs expression. The enhanced sensitivity of OCM-treated breast cancer cells to imatinib would justify investigation on the efficacy of imatinib in bone breast cancer metastasis.
The ubiquitin-binding protein p62 is expressed in breast cancers showing features of aggressive disease
Authors: Rolland Phil , Madjd Zahra , Durrant Lindy , Ellis Ian O , Layfield Rob , Spendlove Ian
Published: March 2007

p62 is a multi-functional protein, which induces nuclear factor-κB (NFκB) activation through multiple upstream signalling pathways, including those triggered by the epidermal growth factor (EGF) family of receptors. We hypothesised that p62 overexpression increased EGF family receptor expression and worse outcome in breast cancer would be associated. We stained a tissue microarray representing 523 breast cancers using a commercial guinea pig anti-human p62 sera and standard immunohistochemical methods to address this. Out of n = 106 tumours, 20.3% stained positively. p62 expression correlated with grade (P = 0.010) and distant metastasis (P = 0.04) and EGF receptor (EGFR) (P = 0.012), HER2 (P = 0.016), HER3 (P = 0.007) and HER4 (0.002) expressions. Though expression correlated with reduced 5-year survival (58.5 vs 73.6%), there was no association with overall disease specific survival. p62 expression may represent a marker of activation of the NFκB pathway.
Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells
Authors: Di Florio Alessia , Capurso Gabriele , Milione Massimo , Panzuto Francesco , Geremia Raffaele , Fave Gianfranco Delle , Sette Claudio
Published: March 2007

Pancreatic endocrine tumours (PETs) are rare and ‘indolent’ neoplasms that usually develop metastatic lesions and exhibit poor response to standard medical treatments. Few studies have investigated pathways responsible for PET cell growth and invasion and no alternative therapeutic strategies have been proposed. In a recent microarray analysis for genes up-regulated in PETs, we have described the up-regulation of soluble Src family tyrosine kinases in this neoplasia, which may represent potentially promising candidates for therapy. Herein, we have investigated the expression and function of Src family kinases in PETS and PET cell lines. Western blot analysis indicated that Src is highly abundant in the PET cell lines CM and QGP-1. Immunohistochemistry and Western blot analyses showed that Src is up-regulated also in human PET lesions. Pharmacological inhibition of Src family kinases by the specific inhibitor PP2 strongly interfered with adhesion, spreading and migration of PET cell lines. Accordingly, the actin cytoskeleton was profoundly altered after inhibition of Src kinases, whereas even prolonged incubation with PP2 exerted no effect on cell cycle progression and/or apoptosis of PET cells. A transient increase in tyrosine phosphorylation of a subset of proteins was observed in QGP-1 cells adhering to the plate, with a peak at 75 min after seeding, when approximately 80% of cells were attached. Inhibition of Src kinases caused a dramatic reduction in the phosphorylation of proteins with different molecular weight that were isolated from the cell extracts by anti-phosphotyrosine immunoprecipitation or pull-down with the SH2 domain of Src. Among them, the docking protein p130Cas interacted with Src and is a major substrate of the Src kinases in QGP-1 cells undergoing adhesion. Our results suggest that Src kinases play a specific role during adhesion, spreading and migration of PET cells and may indicate therapeutical approaches directed to limiting the metastatic potential of these cells.
Nonlinear FE analysis of cracks in tension and shear
Authors: Kesse G. , Lees J. M.
Published: March 2007

Smeared-crack finite element (FE) analyses of reinforced-concrete beams strengthened with prestressed carbonfibre-reinforced polymer (CFRP) shear straps have shown that, at high load levels, the stresses in the straps predicted by the FE analyses were less than the observed experimental values. As the straps are elastic and brittle it is important to investigate this anomaly since otherwise the FE predictions of CFRP shear-strengthened structures could prove to be unconservative. It was postulated that the concrete crack models used in the analyses were inadequate and thus the current work focuses on the FE modelling of cracks subjected to tension and shearing actions. Details of nonlinear FE analyses of the crack behaviour are presented and it is concluded that it is necessary to incorporate advanced crack models in order accurately to predict the stress in the CFRP reinforcing elements.
Fire resistance of carbon FRP reinforced-concrete beams
Authors: Rafi M. M. , Nadjai A. , Ali F.
Published: March 2007

The establishment of the fire resistance of concrete structures reinforced with fibre-reinforced polymer (FRP) bars is a prerequisite to the widespread applications of fibrous rods in buildings. This paper presents the results of an experimental study, which was conducted to investigate fire performance of the concrete beams reinforced with carbon FRP (CFRP) bars. The beams were designed over-reinforced and were subjected to standard heating curve in a floor furnace. Full service load was applied half an hour before the start of the heating test and was kept constant for the duration of the test. A non-uniform temperature distribution was found across the height of the cross-section. The CFRP reinforced beams were stiffer than similar steel-reinforced beams and failed by the crushing of concrete in compression.
Mechanical properties of high-performance hybrid-fibre-reinforced cementitious composites (HPHFRCCs)
Authors: Yun H.-D. , Yang I.-S. , Kim S.-W. , Jeon E. , Choi C.-S. , Fukuyama H.
Published: March 2007

Specially processed steel cord (SC) macrofibres, each consisting of five twisted steel fibres, are used to improve the post-cracking behaviour of cementitious composites. The long steel cords have a large diameter, and are characterised by high tensile strength, frictional bond strength and flexural rigidity. In addition to these steel cord macrofibres, microfibres are used to enhance the snubbing strength and total tensile behaviour of the composite. The two specific hybrid fibre blends studied in the present paper are SC and polyethylene (PE), as well as SC and polyvinyl alcohol (PVA) fibres. The objectives of the current study are to explore the mechanisms by which fibres interact with the composite matrix, and to provide a rigorous characterisation of the performance achievable with hybrid-fibre-reinforced cementitious composites (HFRCCs). Cement-based composites containing large volume fractions (1·0∼2·3%) of various hybrid fibres were compared in terms of flow and fibre dispersion, as well as compressive, splitting tensile, flexural and uniaxial tensile properties. The workability of HFRCCs is governed by the high surface area of the microfibres. The results confirm that the flexural strength, tensile strength and ductility (pseudo-strain-hardening) of HFRCCs are tremendously improved in comparison with mortar or monofibre systems. Furthermore, there is a synergy effect in the microfibre and macrofibre hybrid systems.
Estradiol-Dependent Decrease in the Orexigenic Potency of Ghrelin in Female Rats
Authors: Clegg Deborah J. , Brown Lynda M. , Zigman Jeffrey M. , Kemp Christopher J. , Strader April D. , Benoit Stephen C. , Woods Stephen C. , Mangiaracina Michela , Geary Nori
Published: March 2007

Ghrelin, the only known orexigenic gut hormone, is secreted mainly from the stomach, increases with fasting and before meal initiation in humans and rats, and increases food intake after central or peripheral administration. To investigate sex differences in the action of ghrelin, we assessed the effects of exogenous ghrelin in intact male and female rats, the effects of exogenous ghrelin in ovariectomized (OVX) and estradiol (E2)-treated female rats, as well as the effects of OVX on plasma ghrelin and hypothalamic orexigneic neuropeptide expression in rats and on food intake and weight gain in transgenic mice lacking the ghrelin receptor (Ghsr−/− mice). Male and OVX female rats were significantly more sensitive than intact female rats to the orexigenic effects of both centrally (intra–third ventricular, i3vt, 0.01, 0.1, and 1.0 nmol) and systemically (ip, 3, 6, and 9 nmol) administered ghrelin. This difference is likely to be estradiol dependent because E2 attenuated the orexigenic action of ghrelin in OVX female and male rats. Furthermore, OVX increased food intake and body weight in wild-type mice, but not in Ghsr−/− mice, suggesting that OVX increases food intake by releasing ghrelin from a tonic inhibitory effect of estradiol. In addition, following OVX, there was an increase in plasma ghrelin that was temporally associated with increased food intake, body weight, and hypothalamic neuropeptide Y and Agouti-related protein mRNA expression. Collectively, these data suggest that estradiol inhibits the orexigenic action of ghrelin in females, that weight gain associated with OVX is ghrelin mediated, and that this endocrine interaction may account for an important sex differences in food intake and the regulation of body weight.
Cx36-Mediated Coupling Reduces β-Cell Heterogeneity, Confines the Stimulating Glucose Concentration Range, and Affects Insulin Release Kinetics
Authors: Speier Stephan , Gjinovci Asllan , Charollais Anne , Meda Paolo , Rupnik Marjan
Published: March 2007

We studied the effect of gap junctional coupling on the excitability of β-cells in slices of pancreas, which provide a normal environment for islet cells. The electrophysiological properties of β-cells from mice (C57Bl/6 background) lacking the gap junction protein connexin36 (Cx36−/−) were compared with heterozygous (Cx36+/−) and wild-type littermates (Cx36+/+) and with frequently used wild-type NMRI mice. Most electrophysiological characteristics of β-cells were found to be unchanged after the knockout of Cx36, except the density of Ca2+ channels, which was increased in uncoupled cells. With closed ATP-sensitive K+ (KATP) channels, the electrically coupled β-cells of Cx36+/+ and Cx36+/− mice were hyperpolarized by the membrane potential of adjacent, inactive cells. Additionally, the hyperpolarization of one β-cell could attenuate or even stop the electrical activity of nearby coupled cells. In contrast, β-cells of Cx36−/− littermates with blocked KATP channels rapidly depolarized and exhibited a continuous electrical activity. Absence of electrical coupling modified the electrophysiological properties of β-cells consistent with the reported increase in basal insulin release and altered the switch on/off response of β-cells during an acute drop of the glucose concentration. Our data indicate an important role for Cx36-gap junctions in modulating stimulation threshold and kinetics of insulin release.
Effects of Diazoxide on Gene Expression in Rat Pancreatic Islets Are Largely Linked to Elevated Glucose and Potentially Serve to Enhance β-Cell Sensitivity
Authors: Ma Zuheng , Portwood Neil , Brodin David , Grill Valdemar , Björklund Anneli
Published: March 2007

Diazoxide enhances glucose-induced insulin secretion from β-cells through mechanisms that are not fully elucidated. Here, we used microarray analysis (Affymetrix) to investigate effects of diazoxide. Pancreatic islets were cultured overnight at 27, 11, or 5.5 mmol/l glucose with or without diazoxide. Inclusion of diazoxide upregulated altogether 211 genes (signal log2 ratio ≥0.5) and downregulated 200 genes (signal log2 ratio −0.5 or lower), and 92% of diazoxide's effects (up- and downregulation) were observed only after coculture with 11 or 27 mmol/l glucose. We found that 11 mmol/l diazoxide upregulated 97 genes and downregulated 21 genes. Increasing the glucose concentration to 27 mmol/l markedly shifted these proportions toward downregulation (101 genes upregulated and 160 genes downregulated). At 27 mmol/l glucose, most genes downregulated by diazoxide were oppositely affected by glucose (80%). Diazoxide influenced expression of several genes central to β-cell metabolism. Diazoxide downregulated genes of fatty acid oxidation, upregulated genes of fatty acid synthesis, and downregulated uncoupling protein 2 and lactic acid dehydrogenase. Diazoxide upregulated certain genes known to support β-cell functionality, such as NKX6.1 and PDX1. Long-term elevated glucose is permissive for most of diazoxide's effects on gene expression, the proportion of effects shifting to downregulation with increasing glucose concentration. Effects of diazoxide on gene expression could serve to enhance β-cell functionality during continuous hyperglycemia.
Nephrin Is Critical for the Action of Insulin on Human Glomerular Podocytes
Authors: Coward Richard J.M. , Welsh Gavin I. , Koziell Ania , Hussain Sagair , Lennon Rachel , Ni Lan , Tavaré Jeremy M. , Mathieson Peter W. , Saleem Moin A.
Published: March 2007

The leading causes of albuminuria and end-stage renal failure are secondary to abnormalities in the production or cellular action of insulin, including diabetes and hyperinsulinemic metabolic syndrome. The human glomerular podocyte is a critical cell for maintaining the filtration barrier of the kidney and preventing albuminuria. We have recently shown this cell to be insulin sensitive with respect to glucose uptake, with kinetics similar to muscle cells. We now show that the podocyte protein nephrin is essential for this process. Conditionally immortalized podocytes from two different patients with nephrin mutations (natural human nephrin mutant models) were unresponsive to insulin. Knocking nephrin down with siRNA in wild-type podocytes abrogated the insulin response, and stable nephrin transfection of nephrin-deficient podocytes rescued their insulin response. Mechanistically, we show that nephrin allows the GLUT1- and GLUT4-rich vesicles to fuse with the membrane of this cell. Furthermore, we show that the COOH of nephrin interacts with the vesicular SNARE protein VAMP2 in vitro and ex vivo (using yeast-2 hybrid and coimmunoprecipitation studies). This work demonstrates a previously unsuspected role of nephrin in vesicular docking and insulin responsiveness of podocytes.
Single Nucleotide Polymorphisms of the Peroxisome Proliferator–Activated Receptor-α Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes
Authors: Andrulionytė Laura , Kuulasmaa Teemu , Chiasson Jean-Louis , Laakso Markku ,   for the STOP-NIDDM Study Group
Published: March 2007

Peroxisome proliferator–activated receptor (PPAR) α, a transcription factor of the nuclear receptor superfamily, regulates fatty acid oxidation. We evaluated the association of single nucleotide polymorphisms (SNPs) of the PPAR-α gene (PPARA) with the conversion from impaired glucose tolerance to type 2 diabetes in 767 subjects of the STOP-NIDDM trial in order to investigate the effect of acarbose in comparison with placebo on the prevention of diabetes. In the placebo group, the G (162V) allele of rs1800206 increased the risk for diabetes by 1.9-fold (95% CI 1.05–3.58) and was associated with elevated levels of plasma glucose and insulin. The effect of this allele on the risk of diabetes in the placebo group was enhanced by the simultaneous presence of the risk alleles of the PPAR-γ2, PPAR-γ coactivator 1α, and hepatic nuclear factor 4α genes (odds ratios 2.2, 2.5, and 3.4, respectively). In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7- and 2.7-fold increased risk for diabetes. Our data indicate that SNPs of PPARA increase the risk of type 2 diabetes alone and in combination with the SNPs of other genes acting closely with PPAR-α.
Renal Effects of S18886 (Terutroban), a TP Receptor Antagonist, in an Experimental Model of Type 2 Diabetes
Authors: Šebeková Katarína , Eifert Timo , Klassen André , Heidland August , Amann Kerstin
Published: March 2007

Thromboxane A2 (TxA2) is assumed to contribute to the development of diabetes complications, including nephropathy. We investigated whether the selective thromboxane-prostanoid endoperoxide receptor antagonist, S18886, ameliorates renal damage in uninephrectomized (UNX) obese Zucker rats (OZR). S18886, at doses of 10 (S18886-10) and 30 (S18886-30) mg · kg−1 · day−1, was administered to UNX-OZR by gavage over 8 weeks (n = 8 each group). UNX lean rats (n = 12) and OZR rats that received placebo (OZR-PLAC, n = 8) served as controls. As compared with the OZR-PLAC, S18886 had no significant effect on the elevated blood pressure and the enhanced creatinine clearance, while augmented proteinuria was partially prevented (−12 and −37%, low and high dose, respectively; NS). The increased excretion of transforming growth factor β1 (TGF-β1) and of the thromboxane metabolite 2,3-dinor thromboxane B2 (TxB2) was lowered (P < 0.05). S18886 prevented both the enhanced mesangiolysis (P < 0.01) in the OZR-PLAC as well as enlargement and degeneration of podocytes. In the blood, S18886-30 augmented the antioxidant enzymes (P < 0.01) and lessened the increase of plasma advanced oxidation protein products (−25%, NS). Body weight, hyperglycemia, and dyslipidemia remained uninfluenced under both doses of treatment. S18886 has renoprotective properties in the model of UNX-OZR. It prevents mesangiolysis, reduces urinary TGF-β1 and 2,3-dinor-TxB2 excretion, and enhances the antioxidative defense.
n-3 Fatty Acids Preserve Insulin Sensitivity In Vivo in a Peroxisome Proliferator–Activated Receptor-α–Dependent Manner
Authors: Neschen Susanne , Morino Katsutaro , Dong Jianying , Wang-Fischer Yanlin , Cline Gary W. , Romanelli Anthony J. , Rossbacher Jörg C. , Moore Irene K. , Regittnig Werner , Munoz David S. , Kim Jung H. , Shulman Gerald I.
Published: March 2007

Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet–induced insulin resistance through peroxisome proliferator–activated receptor (PPAR)-α activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-α null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P < 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production [HGP], P < 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-α null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-α null safflower oil–fed mice). In PPAR-α null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P < 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet–induced hepatic insulin resistance in a PPAR-α–and diacylglycerol-dependent manner.
Acute Hyperglycemia Induces a Global Downregulation of Gene Expression in Adipose Tissue and Skeletal Muscle of Healthy Subjects
Authors: Meugnier Emmanuelle , Faraj May , Rome Sophie , Beauregard Geneviève , Michaut Angélique , Pelloux Véronique , Chiasson Jean-Louis , Laville Martine , Clement Karine , Vidal Hubert , Rabasa-Lhoret Rémi
Published: March 2007

To define the effects of acute hyperglycemia per se (i.e., without the confounding effect of hyperinsulinemia) in human tissues in vivo, we performed global gene expression analysis using microarrays in vastus lateralis muscle and subcutaneous abdominal adipose tissue of seven healthy men during a hyperglycemic-euinsulinemic clamp with infusion of somatostatin to inhibit endogenous insulin release. We found that doubling fasting blood glucose values while maintaining plasma insulin in the fasting range modifies the expression of 316 genes in skeletal muscle and 336 genes in adipose tissue. More than 80% of them were downregulated during the clamp, indicating a drastic effect of acute high glucose, in the absence of insulin, on mRNA levels in human fat and muscle tissues. Almost all the biological pathways were affected, suggesting a generalized effect of hyperglycemia. The induction of genes from the metallothionein family, related to detoxification and free radical scavenging, indicated that hyperglycemia-induced oxidative stress could be involved in the observed modifications. Because the duration and the concentration of the experimental hyperglycemia were close to what is observed during a postprandial glucose excursion in diabetic patients, these data suggest that modifications of gene expression could be an additional effect of glucose toxicity in vivo.
A Genome-Wide Linkage Scan for Diabetic Retinopathy Susceptibility Genes in Mexican Americans With Type 2 Diabetes From Starr County, Texas
Authors: Hallman D. Michael , Boerwinkle Eric , Gonzalez Victor H. , Klein Barbara E. K. , Klein Ronald , Hanis Craig L.
Published: March 2007

We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy, the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67 at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5 (2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive evidence on four. Candidate genes were identified in most implicated regions.
Zinc, Not Insulin, Regulates the Rat α-Cell Response to Hypoglycemia In Vivo
Authors: Zhou Huarong , Zhang Tao , Harmon Jamie S. , Bryan Joseph , Robertson R. Paul
Published: March 2007

The intraislet insulin hypothesis proposes that the decrement in β-cell insulin secretion during hypoglycemia provides an activation signal for α-cells to release glucagon. A more recent hypothesis proposes that zinc atoms suppress glucagon secretion via their ability to open α-cell ATP-sensitive K+ channels. Since insulin binds zinc, and zinc is cosecreted with insulin, we tested whether decreased zinc delivery to the α-cell activates glucagon secretion. In streptozotocin-induced diabetic Wistar rats, we observed that switching off intrapancreatic artery insulin infusions in vivo during hypoglycemia greatly improved glucagon secretion (area under the curve [AUC]: control group 240 ± 261 and experimental group 4,346 ± 1,259 pg · ml−1 · 90 min−1; n = 5, P < 0.02). Switching off pancreatic artery infusions of zinc chloride during hypoglycemia also improved the glucagon response (AUC: control group 817 ± 107 and experimental group 3,445 ± 573 pg · ml−1 · 90 min−1; n = 6, P < 0.01). However, switching off zinc-free insulin infusions had no effect. Studies of glucose uptake in muscle and liver cell lines verified that the zinc-free insulin was biologically active. We conclude that zinc atoms, not the insulin molecule itself, provide the switch-off signal from the β-cell to the α-cell to initiate glucagon secretion during hypoglycemia.
Toward Further Mapping of the Association Between the IL2RA Locus and Type 1 Diabetes
Authors: Qu Hui-Qi , Montpetit Alexander , Ge Bing , Hudson Thomas J. , Polychronakos Constantin
Published: March 2007

A novel type 1 diabetes locus was mapped to the interleukin-2 receptor α gene (IL2RA) on chromosome 10p15.1, encoding an important modulator of immunity. The aim of the current study was to confirm the association of IL2RA with type 1 diabetes and to attempt further mapping of the genetic effect with a new set of 12 single nucleotide polymorphisms (SNPs). We genotyped 949 nuclear family trios with one type 1 diabetes–affected offspring and two parents (2,847 individuals). Two of the 12 IL2RA SNPs genotyped (rs706778 and rs3118470) had statistically significant type 1 diabetes association (P = 6.96 × 10−4 and 8.63 × 10−4, respectively). Both SNPs are located in the 5′ end of the long intron 1 within 3 kb of each other and are in high linkage disequilibrium (D′ = 0.997, r2 = 0.613). The A-C haplotype (frequency = 0.331) was associated with increased type 1 diabetes risk (P = 3.02 × 10−4). Our study identifies two markers in the IL2RA gene that are significantly associated with type 1 diabetes, supporting IL2RA as a promising candidate gene for type 1 diabetes and suggesting a potential role of IL2Rα in the pathogenesis of type 1 diabetes, likely involving regulatory T-cells.
Visceral Fat Adipokine Secretion Is Associated With Systemic Inflammation in Obese Humans
Authors: Fontana Luigi , Eagon J. Christopher , Trujillo Maria E. , Scherer Philipp E. , Klein Samuel
Published: March 2007

Although excess visceral fat is associated with noninfectious inflammation, it is not clear whether visceral fat is simply associated with or actually causes metabolic disease in humans. To evaluate the hypothesis that visceral fat promotes systemic inflammation by secreting inflammatory adipokines into the portal circulation that drains visceral fat, we determined adipokine arteriovenous concentration differences across visceral fat, by obtaining portal vein and radial artery blood samples, in 25 extremely obese subjects (mean ± SD BMI 54.7 ± 12.6 kg/m2) during gastric bypass surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Mean plasma interleukin (IL)-6 concentration was ∼50% greater in the portal vein than in the radial artery in obese subjects (P = 0.007). Portal vein IL-6 concentration correlated directly with systemic C-reactive protein concentrations (r = 0.544, P = 0.005). Mean plasma leptin concentration was ∼20% lower in the portal vein than in the radial artery in obese subjects (P = 0.0002). Plasma tumor necrosis factor-α, resistin, macrophage chemoattractant protein-1, and adiponectin concentrations were similar in the portal vein and radial artery in obese subjects. These data suggest that visceral fat is an important site for IL-6 secretion and provide a potential mechanistic link between visceral fat and systemic inflammation in people with abdominal obesity.
Adding Insulin Glargine Versus Rosiglitazone
Authors: Vinik Aaron I. , Zhang Quanwu
Published: March 2007

OBJECTIVE—We sought to assess health-related quality of life (HRQOL) in patients with type 2 diabetes treated with insulin glargine or rosiglitazone as add-on therapy to sulfonylurea plus metformin.

RESEARCH DESIGN AND METHODS—HRQOL was evaluated in 217 subjects uncontrolled with sulfonylurea plus metformin, enrolled in a 24-week, multicenter, randomized, open-label, parallel-group trial of add-on insulin glargine versus rosiglitazone. A 40-item, self-administered questionnaire at baseline and at weeks 2, 6, 12, 18, and 24 was given, including the 34-item Diabetes Symptom Checklist-Revised (DSC-R), a 5-item mental health scale from the 36-item Short-Form Health Survey (SF-36), and a single-item health rating from the SF-36. These assessments do not specify route of therapy.

RESULTS—Both treatment groups showed similar improvements in glycemic control from baseline to week 24 (change in A1C: −1.66% in the insulin glargine group, −1.51% in the rosiglitazone group, P = 0.1446). Both groups also showed improvement in HRQOL, although subjects treated with insulin glargine experienced significantly greater improvements compared with rosiglitazone in the DSC-R total symptom score (P = 0.005), total symptom distress score (P = 0.03), individual domain scores for mood symptoms (P = 0.007), ophthalmologic symptoms (P = 0.007), ophthalmologic distress (P = 0.013), fatigue distress (P = 0.033), and SF-36 perception of general health (P = 0.047).

CONCLUSIONS—Although addition of insulin glargine and rosiglitazone achieved comparable improvements in glycemic control, insulin glargine was associated with greater improvements in HRQOL, indicating that other factors (e.g., safety profile and nonglycemic actions) may further enhance HRQOL in patients with type 2 diabetes.
Serum Selenium and Diabetes in U.S. Adults
Authors: Bleys Joachim , Navas-Acien Ana , Guallar Eliseo
Published: March 2007

OBJECTIVE—The purpose of this study was to examine the relationship between serum selenium levels and the prevalence of diabetes among U.S. adults.

RESEARCH DESIGN AND METHODS—We conducted a cross-sectional analysis of 8,876 adults ≥20 years of age who participated in the Third National Health and Nutrition Examination Survey. Diabetes was defined as the presence of a fasting plasma glucose ≥126 mg/dl, a self-report of a physician diagnosis of diabetes, or current use of insulin or oral hypoglycemic medication. Serum selenium was measured by atomic absorption spectrometry.

RESULTS—Mean serum selenium levels in participants with and without diabetes were 126.5 and 125.7 ng/ml, respectively. Age-, sex-, race-, and BMI-adjusted mean selenium levels were 126.8 ng/ml in participants with diabetes and 124.7 ng/ml in participants without diabetes (adjusted difference 2.1 ng/ml [95% CI 0.4–3.8]; P = 0.02). The multivariable adjusted odds ratio for diabetes comparing the highest to the lowest quintile of serum selenium was 1.57 [1.16–2.13]. However, the association between high serum selenium and the prevalence of diabetes was nonlinear, with no clear trend in quintiles 2–4.

CONCLUSIONS—In a probability sample of the U.S. population, high serum selenium levels were positively associated with the prevalence of diabetes. Until findings from prospective studies and randomized controlled trials are available, selenium intake, including selenium supplementation, should not be recommended for primary or secondary diabetes prevention in populations with adequate selenium status such as the U.S. population.
The Risk of Hip Fractures in Older Individuals With Diabetes
Authors: Lipscombe Lorraine L. , Jamal Sophie A. , Booth Gillian L. , Hawker Gillian A.
Published: March 2007

OBJECTIVE—Compared with men and women without diabetes, individuals with type 2 diabetes have higher bone mineral density (BMD). However, they may still be at increased risk for hip fractures. Using population-based Ontario health care data, we compared the risk of hip fractures among men and women with and without diabetes.

RESEARCH DESIGN AND METHODS—Using a retrospective cohort design, we identified Ontario residents aged ≥66 years with diabetes from a validated registry from 1994 to 1995 (n = 197,412) and followed them for their first hip fracture until 31 March 2003 (mean 6.1-year follow-up). Hip fracture rates were compared with those of age-matched Ontario residents without diabetes (n = 401,400), and results were stratified by sex and adjusted for age and other covariates.

RESULTS—Compared with individuals without diabetes, individuals with diabetes had greater comorbidity, were less likely to have had a BMD test, and were more likely to be taking medications that increase risk of falling and decrease BMD. After adjusting for these differences and age, we found that diabetes increased fracture risk in both men (hazard ratio 1.18 [95% CI 1.12–1.24], P < 0.0001) and women (1.11 [1.08–1.15], P < 0.0001).

CONCLUSIONS—Men and women with diabetes have a higher risk of hip fractures compared with individuals without diabetes. Further research to elucidate the mechanisms underlying this increased risk of fracture is needed, as well as increased attention to fracture prevention strategies in patients with diabetes.
The Effect of Cinnamon on A1C Among Adolescents With Type 1 Diabetes
Authors: Altschuler Justin A. , Casella Samuel J. , MacKenzie Todd A. , Curtis Kevin M.
Published: March 2007

OBJECTIVE—The purpose of this study was to determine the effect of cinnamon on glycemic control in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS—Using a prospective, double-blind, placebo-controlled design, 72 adolescent type 1 diabetic subjects were treated in an outpatient setting with cinnamon (1 g/day) or an equivalent-appearing placebo for 90 days. A1C, total daily insulin intake, and adverse events were recorded and compared between groups.

RESULTS—There were no significant differences in final A1C (8.8 vs. 8.7, P = 0.88), change in A1C (0.3 vs. 0.0, P = 0.13), total daily insulin intake, or number of hypoglycemic episodes between the cinnamon and placebo arms.

CONCLUSIONS—Cinnamon is not effective for improving glycemic control in adolescents with type 1 diabetes.
Prenatal Exposures and Glucose Metabolism in Adulthood
Authors: Thomas Claudia , Hyppönen Elina , Power Chris
Published: March 2007

OBJECTIVE—Birth weight has been associated with the risk of type 2 diabetes in several studies. We investigated whether prenatal influences on birth weight (gestational age, parity, preeclampsia, prepregnancy BMI, smoking during pregnancy, and socioeconomic position [SEP]) were associated with glucose metabolism in midlife and the role of birth weight for gestational age (BGA) and adult adiposity in mediating these associations.

RESEARCH DESIGN AND METHODS—Data from 7,518 participants of the 1958 British Birth Cohort with information on A1C at age 45 years were analyzed. Associations between prenatal exposures and A1C ≥6% were examined using a series of logistic regression models. The basic model consisted of all prenatal factors (except parity) adjusted for sex and family history of type 2 diabetes. Further adjustments included BGA only, concurrent adiposity only (BMI and waist circumference), and BGA plus adiposity.

RESULTS—In the basic model, preeclampsia (odds ratio 1.78 [95% CI 1.14–2.80]), prepregnancy BMI ≥25 kg/m2 (1.90 [1.45–2.47]), maternal smoking (1.33 [1.04–1.71]), and manual SEP (1.87 [1.36–2.58]) were independently associated with A1C at 45 years of age. Adjustment for BGA had little impact on the prenatal factors/A1C associations, whereas adjustment for adult adiposity at 45 years substantially reduced associations for prepregnancy BMI, smoking during pregnancy, and SEP.

CONCLUSIONS—Prenatal exposures were related to blood glucose levels in mid-adulthood. Associations for several prenatal factors were largely mediated through adult adiposity but surprisingly not through birth weight. Prenatal exposures are likely to have the strongest effect on glucose metabolism indirectly through their influence on adiposity.
Maternal Glycemic Control and Hypoglycemia in Type 1 Diabetic Pregnancy
Authors: Mathiesen Elisabeth R. , Kinsley Brendan , Amiel Stephanie A. , Heller Simon , McCance David , Duran Santiago , Bellaire Shannon , Raben Anne ,   on behalf of the Insulin Aspart Pregnancy Study Group
Published: March 2007

OBJECTIVE—To assess the safety and efficacy of insulin aspart (IAsp) versus regular human insulin (HI) in basal-bolus therapy with NPH insulin in pregnant women with type 1 diabetes.

RESEARCH DESIGN AND METHODS—Subjects (n = 322) who were pregnant or planning pregnancy were randomized to IAsp or HI as meal-time insulin in an open-label, parallel-group, multicenter study. Subjects had A1C ≤8% at confirmation of pregnancy. Insulin doses were titrated toward predefined glucose targets and A1C <6.5%. Outcomes assessed included risk of major maternal hypoglycemia, A1C, plasma glucose profiles, and maternal safety outcomes.

RESULTS—Major hypoglycemia occurred at a rate of 1.4 vs. 2.1 episodes/year exposure with IAsp and HI, respectively (relative risk 0.720 [95% CI 0.36–1.46]). Risk of major/major nocturnal hypoglycemia was 52% (RR 0.48 [0.20–1.143]; P = NS) lower with IAsp compared with HI. A1C was comparable with human insulin in second (IAsp-HI −0.04 [−0.18 to 0.11]) and third (−0.08 [−0.23 to 0.06]) trimesters. A total of 80% of subjects achieved an A1C ≤6.5%. At the end of first and third trimesters, average postprandial plasma glucose increments were significantly lower with IAsp than HI (P = 0.003 and P = 0.044, respectively), as were mean plasma glucose levels 90 min after breakfast (P = 0.044 and P = 0.001, respectively). Maternal safety profiles and pregnancy outcomes were similar between treatments.

CONCLUSIONS—IAsp is at least as safe and effective as HI when used in basal-bolus therapy with NPH insulin in pregnant women with type 1 diabetes and may potentially offer some benefits in terms of postprandial glucose control and preventing severe hypoglycemia.