bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of chronic undernutrition and leptin on GOAT mRNA levels in rat stomach mucosa
Authors: González C Ruth , Vázquez María J , López Miguel , Diéguez Carlos
Published: October 2008

The most unique feature of ghrelin is the acyl-modification of a hydroxyl group of the Ser3 in the N-terminus. The Ser3 is commonly modified by n-octanoic acid in vertebrates being needed for its biological effects, at least in terms of feeding. Therefore, a critical question regarding the role of ghrelin was to characterize the mechanism involved in its acylation. The acyltransferase that catalyzes ghrelin octanoylation has been recently identified and named ghrelin O-acyltransferase (GOAT). The aim of this study was to clarify the physiological implications of GOAT in the regulation of energy balance, by assessing the effect of undernutrition, as well as fasting in adult male rats. We have determined GOAT mRNA expression levels by real time-PCR in the stomach mucosa. Our results show that chronic food restriction led to an increase in GOAT mRNA, particularly following long-term chronic malnutrition (21 days). Furthermore, following 48 h complete fasting, a situation with high-circulating ghrelin levels, we found similar mRNA expression of GOAT in fed and fasted rats; exogenous leptin administration markedly increase GOAT mRNA levels in the stomach mucosa of fasted rats. These findings suggest that increased GOAT mRNA levels may have a role in mediating the physiological responses to chronic undernutrition and could represent an adaptive response to prevent long-lasting alterations in energy balance and body weight homeostasis. Furthermore, our data also offer mechanistic insights into the reason why during fasting acylated ghrelin levels are not increased at a time when a marked increase in an orexigenic signal as important as acylated ghrelin will be expected.
Prediabetic and diabetic in vivo modification of circulating low-density lipoprotein attenuates its stimulatory effect on adrenal aldosterone and cortisol secretion
Authors: Kopprasch Steffi , Pietzsch Jens , Ansurudeen Ishrath , Graessler Juergen , Krug Alexander W , Ehrhart-Bornstein Monika , Bornstein Stefan R
Published: October 2008

Modification of low-density lipoprotein (LDL) and abnormal aldosterone and cortisol metabolism have been implicated in the pathogenesis of type 2 diabetes (DM2) and diabetic vascular disease. Since LDL serves as a major cholesterol source for adrenal steroidogenesis, we investigated whether LDL modification in prediabetic and diabetic subjects influences adrenocortical aldosterone and cortisol release. LDL was isolated from 30 subjects with normal glucose tolerance (NGT-LDL), 30 subjects with impaired glucose tolerance (IGT-LDL), and 26 patients with DM2 (DM2-LDL). Oxidation and glycoxidation characteristics of LDL apolipoprotein B100 of each individual was assessed by gas chromatography–mass spectrometry analysis. Human adrenocortical cells (NCI-H295R) were incubated for 24 h with 100 μg/ml LDL and after removal of supernatants stimulated for a further 24 h with angiotensin II (AngII). In supernatants, aldosterone and cortisol secretion was measured. IGT-LDL and DM2-LDL were substantially more modified than NGT-LDL. Each of the five measured oxidation/glycoxidation markers was significantly positively associated with glycemic control, measured as HbA1c. LDL from all subjects stimulated both the basal and AngII-induced aldosterone and cortisol release from adrenocortical cells. However, hormone secretion was significantly inversely related to the degree of LDL oxidation/glycoxidation. We conclude that LDL modifications in IGT and DM2 subjects may have significant clinical benefits by counteracting prediabetic and diabetic overactivity of the renin–angiotensin–aldosterone system and enhanced cortisol generation.
Nuclear receptor co-regulator Krüppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus
Authors: Pabona J M P , Velarde M C , Zeng Z , Simmen F A , Simmen R C M
Published: October 2008

Estrogen, acting through its cognate receptor estrogen receptor-α (ESR1), is a critical regulator of uterine endometrial epithelial proliferation. Although the dynamic communication between endometrial stromal (ST) and epithelial cells is considered to be an important component in this process, key molecular players in particular compartments remain poorly defined. Here, we used mice null for Krüppel-like factor 9 (KLF9) to evaluate the contribution of this nuclear protein in ST–epithelial interactions underlying proliferative effects of estrogen. We found that in ovariectomized mice administered estradiol-17β (E2) for 24 h,Klf9null mutation resulted in lack of E2-induced proliferative response in all endometrial compartments. We demonstrated a negative association betweenKlf9expression and nuclear levels of ESR1 transcriptional corepressor prohibitin (PHB) 2 in uterine ST and epithelial cells of E2-treated wild-type (WT) andKlf9null mice. In early pregnancy uteri of WT mice, the temporal pattern ofKlf9transcript levels was inversely associated with that ofPhb2. Deletion ofKlf9up-regulated uterinePhb2expression and increased PHB2 nuclear localization in endometrial ST and epithelial cells, with no effects on the expression of the relatedPhb1. In the human endometrial ST cell line treated with E2for 24 h,Klf9siRNA targeting augmented PHB2 transcript and increased nuclear PHB2 protein levels, albeit this effect was not to the extent seenin vivowithKlf9null mutants. Our findings suggest a novel mechanism for control of estrogen-induced luminal epithelial proliferation involving ST KLF9 regulation of paracrine factor(s) to repress epithelial expression of corepressor PHB2.
Extrapolation concepts for dealing with multiple contamination in environmental risk assessment
Authors: Altenburger Rolf , Greco William R
Published: October 2008

Mixture exposure against several stressors is what organisms in the environment typically experience, and combined effects resulting from this are well documented. Risk management often still focuses on the assessment of individual priority compounds. Because of the large number of possible mixtures and their variability in time, experimental investigation of every conceivable mixture for their adverse effects is not a viable option. Instead, during the past decade, modeling approaches have been discussed in ecotoxicology that allow the prediction of expected combination effects based on the knowledge of the biological activity of the individual components. This contribution summarizes mixture exposure situations where consensus has been achieved about extrapolation techniques. In particular, for simultaneous exposure and for sequential exposure with no intervening recovery, currently available evidence demonstrates reasonable predictability of combined effects from the information of the individual mixture components. By contrast, when organisms are exposed to pulsed exposure with recovery periods or when nonchemical stressors interfere, there is still an open research field as how to account for these types of interaction.
The Acquisition and Processing of Vertical Seismic Profile in Horizontal Wells Erb West Field, Sabah, Malaysia
Authors: Hocker C. , Track A. , Cao D. , Williams R. , Dupal L. , Shapiro B.
Published: October 2008

Three Vertical Seismic Profiles and one well shoot mere acquired as pari of the EWDP-A revisit-3 horizontal drilling campaign in the Erb West field. The main objective in acquiring this data was to derive a reliable velocity model for the overburden in the main part of the field. By positioning the geophones in the horizontal section, and below the heavily faulted overburden, allowed for correct imaging of reservoirs immediaiely belozu the wellbore and the dipping horizons that subcrop the Shallow Regional Unconformity. Also an attempt will be made to integrate the VSP rcsults with the newly acquired surface 3D seismic to help identify multiple patiems, and to guide the derivation of velocities for stacking and migration.

The acquisition involves the deployment of, a 3- component, gimbal-mounted seismic geophone that is drill pipe conveyed into the well. As the tool is pushed into the hole, it is siopped at pre-determined stations, rigidly coupled to the casing, and acoustically isolated from the drillpipe to provide a good signal-to-noise ratio. The seismic source is positioned directly over the sensor, and a serie.s of shots are recorded at euch Station.

The main problem with processing VSP data acquired in a horizontal well is the Separation of the upgoing from the downgoing wavefields. In conventional VSP Processing this is accomplished by the geophone being vertically displaced in the wellbore. In the Erb West field, this was accomplished by using the downgoing wavefield obtained over the build up section together with differences in moveout betzoeen the direct arrivals and reflected events from structurally tilted reflectors beneath the horizontal part of the hole. This all ozo ed for the creation of a high resolution seismic image in the vicinity of the well.
Rethinking Middle Woodland Settlement and Subsistence Patterns in the Middle and Lower Delaware Valley
Authors: Schindler Bill
Published: October 2008

Assumptions concerning Middle Woodland (A.D. 1–1000) settlement and subsistence patterns in the Delaware Valley are based largely upon the presumed exploitation of the upstream migration of adult anadromous fish. This relatively narrow perception of the migratory fish resource is incomplete and should be expanded to include not only other phases of anadromous fish life cycles but other migratory fish as well. Archaeological, biological, and experimental data are combined to offer a holistic representation of the migratory fish resource in the Delaware Valley during the Middle Woodland period and its impact on our understanding of Middle Woodland life.
Forty Years Later: What Have We Learned about the Earliest Human Occupations of Santa Rosa Island, California?
Authors: Reeder Leslie A. , Rick Torben C. , Erlandson Jon M.
Published: October 2008

California's Channel Islands have emerged as an important location for documenting the cultures and lifeways of the earliest peoples who settled the Pacific Coast of North America. Much of this began with Phil Orr's archaeological, paleontological, and geological research on Santa Rosa Island from the 1940s to 1960s. Generating several controversial theories, including the possibility of mammoth hunters on the islands over 40,000 years ago, many of Orr's interpretations have not stood the test of scientific scrutiny. However, much of what we know about the island today is based on Orr's extensive archaeological survey and excavation work. Here we provide an overview and analysis of Orr's research on the earliest peoples of Santa Rosa Island and update what has been learned in the 40 years since Orr's (1968) Prehistory of Santa Rosa Island was published. In 1968, Orr tentatively identified seven archaeological sites dating to the terminal Pleistocene and Early Holocene, all located on the northwest coast of Santa Rosa. Today, at least 18 sites are known to date within this same time range and their distribution has been expanded to other areas of the island. Current data show that Santa Rosa Island has one of the longest records of coastal occupation in the Americas, beginning at least 13,000 calendar years ago and extending into historic times.
Clovis Type-Site, Blackwater Draw, New Mexico: A History, 1929-2009
Authors: Boldurian Anthony T.
Published: October 2008

A brief history is presented along with new archival images of archaeology over the past 80 years at Blackwater Locality No.1, New Mexico, also known as the Clovis “type-site.” Despite a wealth of published information, frequently this site is perceived mainly as a Paleoindian kill/butchery locale. In fact, at Clovis are discrete clusters of occupational debris, including camps, caches, and hand-dug wells around an early post-Pleistocene pond. This spatial diversity is contained in a deeply stratified alluvial/aeolian sequence with well-preserved animal and plant remains spanning the entire Paleoindian period. The Blackwater Draw provided one of the first research venues for geoarchaeology and paleoecology in America. Explorations at Clovis often took place alongside destructive gravel mining. Today, the Clovis site is a model of conservation, research, and public education.
Middle/Late Archaic Occupations on the Southern Edge of the Edwards Plateau, Camp Bullis, Texas
Authors: Pagoulatos Peter
Published: October 2008

Middle/Late Archaic (6,000-1,200 B.P.) land use of south-central Texas is poorly understood. Current data indicate that aboriginal populations exhibited a complex series of seasonal movements, based upon seasonal availability of resources. Site distributions produce a dual, or two-level settlement pattern, in which generalized base camps were situated along low terraces and floodplains proximate to Salado Creek, where populations exploited a variety of mammal and wild plant resources during the warmer (summer-fall) months. Conversely, sites predominantly contained within adjacent drainage systems may represent more specialized burned rock mounds and extractive stations. While burned rock mounds generally tend to be found on elevated terraces along smaller, feeder tributaries, and more specialized extractive stations are usually found even farther from major streams and on even higher elevated (upland) landforms, both of these site types tend to exhibit south-facings, which might imply occupation of these areas during the colder months (winter-early spring) of the year.
Determination of an Optimal Operating Schedule for Thermal Units with an Energy Storage System
Authors: Senjyu Tomonobu , Chakraborty Shantanu , Saber Ahmed Yousuf , Yona Atsushi , Funabashi Toshihisa
Published: October 2008

This paper presents a determination methodology for finding optimal operation schedules of thermal units (namely unit commitment) integrated with an energy storage system (ESS) to minimize total operating costs. A generic ESS formulation along with a method for solving unit commitment (UC) of thermal units with ESS is proposed to serve this purpose. The problem of unit commitment with an ESS is solved using the Priority List method. Intelligent Genetic algorithm (GA) is included in the algorithm for generating new and potential solutions. The proposed method consists of two steps. The first step is to determine the schedule of ESS and the schedule of thermal units. The second step is to dispatch the hourly output of thermal units and the ESS which comply a minimized total production cost. The proposed method is applied to a power system with ten thermal units and a large ESS. The presented simulation results show that the schedule of thermal units with an ESS of a particular life cycle, achieved by the proposed method, minimizes the operating cost. The discussion regarding the determination of schedule thermal units (TU) along with the integrated ESS may interest many types of ESS due to their generalized formulations.
Photovoltaic Generating Units as Reactive Supply Ancillary Service Providers
Authors: Delfino Federico , Procopio Renato
Published: October 2008

This paper addresses the issue of the application of PhotoVoltaic (PV) Distributed Generation (DG) units for supplying reactive power to the grid. In order to reach this aim, an advanced control scheme to suitably drive the injection of both active and reactive power into a MV radial distribution grid has been developed. Such algorithm allows a decoupled control of active and reactive power by properly adjusting the modulating signals of a PWM interface converter with the grid. A closed loop regulation scheme has been derived and guidelines for the choices of the reference quantities and for the design of the regulators are provided. The control algorithm has been applied to a real MV grid-connected PV power plant, which has been simulated in the PSCAD  EMTDC electromagnetic environment, in order to represent, with high detail, every system component and to thoroughly analyze the occurring electromagnetic transients. The positive effect of reactive power support to the grid from the PV unit has been highlighted, showing benefits on the grid current and voltage profiles with respect to the classical configuration, where the DG system behaves as a sole active power source.
Effect of Control Parameters on Differential Evolution based Combined Economic Emission Dispatch with Valve-Point Loading and Transmission Loss
Authors: Mandal Kamal K. , Chakraborty N.
Published: October 2008

Differential evolution (DE) has been proved to be a powerful evolutionary algorithm for global optimization in many engineering problems. The performance of this type of evolutionary algorithms is heavily dependent on the setting of control parameters. Proper selection of the control parameters is very important for the success of the algorithm. Optimal settings of control parameters of differential evolution depend on the specific problem under consideration. In this paper, a study of control parameters on differential evolution based combined economic emission dispatch with valve-point loading and transmission loss is conducted empirically. The problem is formulated considering equality constraints on power balance and inequality constraints on generation capacity limits as well as the transmission losses and effects of valve point loadings. The feasibility of the proposed method is demonstrated on a fourteen-generator system. The results of the effect of the variation of different parameters are presented systematically and it is observed that the search algorithm may fail in finding the optimal value if the parameter selection is not done with proper attention.
Transmission Network Expansion Planning with Security Constraints and Uncertainty in Load Specifications
Authors: Verma Ashu , Bijwe Pradeep R. , Panigrahi Bijaya Ketan
Published: October 2008

Transmission network expansion planning is a very critical problem due to not only the huge investment cost involved, but also the associated security issues. Any long range planning problem is confronted with the challenge of non-statistical uncertainty in the data. Although large number of papers have been published in this area, the efforts to tackle the above mentioned security and uncertainty issues have been relatively very few, due to the formidable complexity involved. This paper tries to bridge this gap by proposing a technique to tackle these problems. Boundary DC power flow is used to ascertain the worst power flows on the lines. A simple basic binary Genetic algorithm is used to solve the optimization problem as an illustration. Results for two sample test systems have been obtained to demonstrate the potential of the proposed method.
A Multi-Criteria Decision Framework for Optimal Augmentation of Transmission Grid - Addressing a Tool for Sensitive Zone Detection in Electricity Market
Authors: Hesamzadeh Mohammad R. , Hosseinzadeh Nasser , Wolfs Peter J
Published: October 2008

Transmission system structure has an essential effect on the reliability of the power system and electricity market performance, especially when producers bid strategically. As part of on-going research on the design of a robust algorithm for expansion planning of the transmission grid in the Australian electricity market, this paper presents a framework which addresses: (1) the security of power delivery to the load points of the transmission system in case of single line outages; (2) the minimization of transmission system lost load; (3) an efficient electricity market for market participants; (4) construction and maintenance costs of transmission augmentation options; and (5) operation efficiency of the transmission grid.The suggested algorithm benefits from the dynamic programming and sensitivity analysis approaches along with the aggregation method in its multi-criteria decision-making to locate the optimum configuration of a future transmission system. A set of indices, which account for impacts of the augmentation options of the transmission grid on five aforementioned reliability and market criteria, are proposed and used in the optimum framework for expansion planning of the transmission grid.Although the methodology is promising for expansion planning of the transmission system, considering the sensitivity analysis concept employed, the proposed methodology would be suitable to detect the sensitive areas of the transmission system to be expanded. The tool would be very useful in the case of large scale power systems for a smart reduction of the transmission expansion options.The proposed methodology has been applied to a 6-bus and a modified IEEE 30-bus test system to show the effectiveness of the sensitivity-based algorithm.
Effect of Endothelium-Specific Insulin Resistance on Endothelial Function In Vivo
Authors: Duncan Edward R. , Crossey Paul A. , Walker Simon , Anilkumar Narayana , Poston Lucilla , Douglas Gillian , Ezzat Vivienne A. , Wheatcroft Stephen B. , Shah Ajay M. , Kearney Mark I.
Published: October 2008

OBJECTIVE—Insulin resistance is an independent risk factor for the development of cardiovascular atherosclerosis. A key step in the development of atherosclerosis is endothelial dysfunction, manifest by a reduction in bioactivity of nitric oxide (NO). Insulin resistance is associated with endothelial dysfunction; however, the mechanistic relationship between these abnormalities and the role of impaired endothelial insulin signaling versus global insulin resistance remains unclear.

RESEARCH DESIGN AND METHODS—To examine the effects of insulin resistance specific to the endothelium, we generated a transgenic mouse with endothelium-targeted overexpression of a dominant-negative mutant human insulin receptor (ESMIRO). This receptor has a mutation (Ala-Thr1134) in its tyrosine kinase domain that disrupts insulin signaling. Humans with the Thr1134 mutation are insulin resistant. We performed metabolic and vascular characterization of this model.

RESULTS—ESMIRO mice had preserved glucose homeostasis and were normotensive. They had significant endothelial dysfunction as evidenced by blunted aortic vasorelaxant responses to acetylcholine (ACh) and calcium ionophore. Furthermore, the vascular action of insulin was lost in ESMIRO mice, and insulin-induced endothelial NO synthase (eNOS) phosphorylation was blunted. Despite this phenotype, ESMIRO mice demonstrate similar levels of eNOS mRNA and protein expression to wild type. ACh-induced relaxation was normalized by the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride. Endothelial cells of ESMIRO mice showed increased superoxide generation and increased mRNA expression of the NADPH oxidase isoforms Nox2 and Nox4.

CONCLUSIONS—Selective endothelial insulin resistance is sufficient to induce a reduction in NO bioavailability and endothelial dysfunction that is secondary to increased generation of reactive oxygen species. This arises independent of a significant metabolic phenotype.
Obesity-Related Upregulation of Monocyte Chemotactic Factors in Adipocytes
Authors: Jiao Ping , Chen Qiu , Shah Suketu , Du Jing , Tao Bo , Tzameli Iphigenia , Yan Weiqun , Xu Haiyan
Published: October 2008

OBJECTIVE—We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity.

RESEARCH DESIGN AND METHODS—Expression and regulation of members in the entire chemokine superfamily were evaluated in adipose tissue and isolated adipocytes of obese versus lean mice. Kinetics of adipose tissue macrophage infiltration was characterized by fluorescence-activated cell sorting. The effects of fatty acids on stimulation of chemokine expression in adipocytes and underlying mechanisms were investigated.

RESULTS—Six monocyte chemotactic factors were found to be predominantly upregulated in isolated adipocytes versus stromal vascular cells in obese mice for the first time, although most of them were previously reported to be upregulated in whole adipose tissue. In diet-induced obese mice, adipose tissue enlargement, increase of adipocyte number, and elevation of multiple chemokine expression precede the initiation of macrophage infiltration. Free fatty acids (FFAs) are found to be inducers for upregulating these chemokines in 3T3-L1 adipocytes, and this effect can be partially blunted by reducing Toll-like receptor 4 expression. FFAs induce expression of monocyte chemotactic factors in adipocytes via both transcription-dependent and -independent mechanisms. In contrast to the reported role of JNK as the exclusive mediator of FFA-induced monocyte chemoattractant protein-1 (MCP-1) expression in macrophages, we show a novel role of inhibitor of κB kinase-β (IKKβ) in mediating FFA-induced upregulation of all six chemokines and a role of JNK in FFA-induced upregulation of MCP-1 and MCP-3.

CONCLUSIONS—Multiple chemokines derived from adipocytes might contribute to obesity-related WAT macrophage infiltration with FFAs as potential triggers and involvement of both IKKβ and JNK pathways.
Resistance to High-Fat Diet–Induced Obesity but Exacerbated Insulin Resistance in Mice Overexpressing Preadipocyte Factor-1 (Pref-1)
Authors: Villena Josep A. , Choi Cheol Soo , Wang Yuhui , Kim Sheene , Hwang Yu-Jin , Kim Young-Bum , Cline Gary , Shulman Gerald I. , Sul Hei Sook
Published: October 2008

OBJECTIVE—White adipose tissue is a critical regulator of whole-body glucose metabolism. Preadipocyte factor-1 (Pref-1) is a secreted protein that inhibits adipocyte differentiation, both in vitro and in vivo. In this study, we have investigated the effects of Pref-1 overexpression on whole-body glucose homeostasis and its contribution to the development of insulin resistance.

RESEARCH DESIGN AND METHODS—To gain insight into the role of Pref-1 on the onset of insulin resistance and type 2 diabetes, we measured body composition and whole-body insulin-stimulated glucose metabolism during a hyperinsulinemic-euglycemic clamp in Pref-1 transgenic and wild-type control mice fed a high-fat diet.

RESULTS—Mice overexpressing Pref-1 were resistant to high-fat diet–induced obesity, as reflected by a marked reduction in adipose tissue mass. However, Pref-1–overexpressing mice were severely insulin resistant, mainly because of a reduction in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. The aggravated insulin resistance was associated with impaired insulin signaling and increased diacylglycerol content in skeletal muscle.

CONCLUSIONS—Mice overexpressing Pref-1 are insulin resistant despite being protected from diet-induced obesity and may provide a new rodent model for the study of lipodystrophic disorders.
Genome-Wide Linkage Scan in Gullah-Speaking African American Families With Type 2 Diabetes
Authors: Sale Michèle M. , Lu Lingyi , Spruill Ida J. , Fernandes Jyotika K. , Lok Kerry H. , Divers Jasmin , Langefeld Carl D. , Garvey W. Timothy
Published: October 2008

OBJECTIVE—The Gullah-speaking African American population from the Sea Islands of South Carolina is characterized by a low degree of European admixture and high rates of type 2 diabetes and diabetic complications. Affected relative pairs with type 2 diabetes were recruited through the Sea Islands Genetic African American Registry (Project SuGAR).

RESEARCH DESIGN AND METHODS—We conducted a genome-wide linkage scan, genotyping 5,974 single nucleotide polymorphisms in 471 affected subjects and 50 unaffected relatives from 197 pedigrees. Data were analyzed using a multipoint engine for rapid likelihood inference and ordered subsets analyses (OSAs) for age at type 2 diabetes diagnosis, waist circumference, waist-to-hip ratio, and BMI. We searched for heterogeneity and interactions using a conditional logistic regression likelihood approach.

RESULTS—Linkage peaks on chromosome 14 at 123–124 cM were detected for type 2 diabetes (logarithm of odds [LOD] 2.10) and for the subset with later age at type 2 diabetes diagnosis (maximum LOD 4.05). Two linkage peaks on chromosome 7 were detected at 44–45 cM for type 2 diabetes (LOD 1.18) and at 78 cM for type 2 diabetes (LOD 1.64) and the subset with earlier age at type 2 diabetes diagnosis (maximum LOD 3.93). The chromosome 14 locus and a peak on 7p at 29.5 cM were identified as important in the multilocus model. Other regions that provided modest evidence for linkage included chromosome 1 at 167.5 cM (LOD 1.51) and chromosome 3 at 121.0 cM (LOD 1.61).

CONCLUSIONS—This study revealed a novel type 2 diabetes locus in an African American population on 14q that appears to reduce age of disease onset and confirmed two loci on chromosome 7.
Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1α (HIF-1α)-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1α Expression, and Normalizes Immature Vasculature in db/db Mice
Authors: Chen Jian-Xiong , Stinnett Amanda
Published: October 2008

OBJECTIVE— Diabetic impaired angiogenesis is associated with impairment of hypoxia-inducible factor-1α (HIF-1α) as well as vasculature maturation. We investigated the potential roles and intracellular mechanisms of angiopoietin-1 (Ang-1) gene therapy on myocardial HIF-1α stabilization and vascular maturation in db/db mice.

RESEARCH DESIGN AND METHODS— db/db mice were systemically administrated adenovirus Ang-1 (Ad-CMV-Ang-1). Myocardial HIF-1α, vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), Akt, and HIF-1α–prolyl-4-hydroxylase-2 (PHD)2 expression were measured. Vasculature maturation, capillary and arteriole densities, and cardiac interstitial fibrosis were analyzed in the border zone of infarcted myocardium.

RESULTS— Systemic administration of Ad-CMV-Ang-1 results in overexpression of Ang-1 in db/db mice hearts. Ang-1 gene therapy causes a significant increase in Akt and eNOS expression and HIF-1α stabilization. This is accompanied by a significant upregulation of VEGF and HO-1 expression. Intriguingly, Ang-1 gene therapy also leads to a significant inhibition of PHD2 expression. Smooth muscle recruitment and smooth muscle coverage in the neovessels of the border zone of infarcted myocardium are severely impaired in db/db mice compared with wild-type mice. Ang-1 gene therapy rescues these abnormalities, which leads to a dramatic increase in capillary and arteriole densities and a significant reduction of cardiac hypertrophy and interstitial fibrosis at 14 days after ischemia. Taken together, our data show that Ang-1 increases myocardial vascular maturation and angiogenesis together with suppression of PHD2 and the upregulation of HIF-1α signaling.

CONCLUSIONS— Normalization of immature vasculature by Ang-1 gene therapy may represent a novel therapeutic strategy for treatment of the diabetes-associated impairment of myocardial angiogenesis.
Lower Metabolic Rate in Individuals Heterozygous for Either a Frameshift or a Functional Missense MC4R Variant
Authors: Krakoff Jonathan , Ma Lijun , Kobes Sayuko , Knowler William C. , Hanson Robert L. , Bogardus Clifton , Baier Leslie J.
Published: October 2008

OBJECTIVE—Humans with functional variants in the melanocortin 4 receptor (MC4R) are obese, hyperphagic, and hyperinsulinemic but have been reported to have no difference in energy expenditure.

RESEARCH DESIGN AND METHODS—We investigated the association of two MC4R variants, Arg165Gln (R165Q) and A insertion at nucleotide 100 (NT100), with adiposity in 3,074 full-heritage Pima Indians, a subset of whom had metabolic measures including 24-h energy expenditure (n = 252) and resting metabolic rate (RMR) (n = 364).

RESULTS—Among the 3,074 subjects, 43 were heterozygous for R165Q and 14 for NT100 (frequency = 0.007 and 0.002). Mean (± SD) BMI was higher among subjects with R165Q (39.3 ± 8.6 kg/m2) or NT100 (41.2 ± 7.8) than subjects without either variant (37.1 ± 8.4) (P = 0.04 and 0.02, adjusted for age, sex, and birth year and accounting for family membership). The 24-h energy expenditure (four with NT100; three with R165Q) or RMR (six with NT100; two with R165Q) was lower in heterozygous subjects but only met statistical significance when heterozygous subjects were combined and compared with subjects without either variant: least-squares means, 2,163 kcal/24 h (95% CI 2,035–2,291) vs. 2,307 kcal/24 h (2,285–2,328), P = 0.03 for 24-h energy expenditure, and 1,617 kcal/24 h (1,499–1,734) vs. 1,754 kcal/24 h (1,736–1,772), P = 0.02 for RMR; adjusted for age, sex, fat-free mass, and fat mass). For RMR, this difference persisted, even after accounting for family membership.

CONCLUSIONS—Pima Indians heterozygous for R165Q or NT100 in MC4R have higher BMIs and lower energy expenditure (by ∼140 kcal/day), indicating that lower energy expenditure was a component of the increased adiposity.
Atrial Natriuretic Peptide Induces Postprandial Lipid Oxidation in Humans
Authors: Birkenfeld Andreas L. , Budziarek Petra , Boschmann Michael , Moro Cedric , Adams Frauke , Franke Gabriele , Berlan Michel , Marques Marie A. , Sweep Fred C.G.J. , Luft Friedrich C. , Lafontan Max , Jordan Jens
Published: October 2008

OBJECTIVE—Atrial natriuretic peptide (ANP) regulates arterial blood pressure. In addition, ANP has recently been shown to promote human adipose tissue lipolysis through cGMP-mediated hormone-sensitive lipase activation. We hypothesized that ANP increases postprandial free fatty acid (FFA) availability and energy expenditure while decreasing arterial blood pressure.

RESEARCH DESIGN AND METHODS—We infused human ANP (25 ng · kg−1 · min−1) in 12 men (age 32 ± 0.8 years, BMI 23.3 ± 0.4 kg/m2) before, during, and 2 h after ingestion of a standardized high-fat test meal in a randomized, double-blind, cross-over fashion. Cardiovascular changes were monitored by continuous electrocardiogram and beat-by-beat blood pressure recordings. Metabolism was monitored through venous blood sampling, intramuscular and subcutaneous abdominal adipose tissue microdialysis, and indirect calorimetry.

RESULTS—ANP infusion decreased mean arterial blood pressure by 4 mmHg during the postprandial phase (P < 0.01 vs. placebo). At the same time, ANP induced lipolysis systemically (P < 0.05 vs. placebo) and locally in subcutaneous abdominal adipose tissue (P < 0.0001 vs. placebo), leading to a 50% increase in venous glycerol (P < 0.01) and FFA (P < 0.05) concentrations compared with placebo. The increase in FFA availability with ANP was paralleled by a 15% increase in lipid oxidation rates (P < 0.05 vs. placebo), driving a substantial increase in postprandial energy expenditure (P < 0.05 vs. placebo).

CONCLUSIONS—Our data identify the ANP system as a novel pathway regulating postprandial lipid oxidation, energy expenditure, and concomitantly arterial blood pressure. The findings could have therapeutic implications.
Combination Therapy With Glucagon-Like Peptide-1 and Gastrin Restores Normoglycemia in Diabetic NOD Mice
Authors: Suarez-Pinzon Wilma L. , Power Robert F. , Yan Yanhua , Wasserfall Clive , Atkinson Mark , Rabinovitch Alex
Published: October 2008

OBJECTIVE—Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic β-cell function, survival, and growth. Here, we investigated whether GLP-1 and gastrin can restore the β-cell mass and reverse hyperglycemia in NOD mice with autoimmune diabetes.

RESEARCH DESIGN AND METHODS—Acutely diabetic NOD mice were treated with GLP-1 and gastrin, separately or together, twice daily for 3 weeks. Blood glucose was measured weekly and for a further 5 weeks after treatments, after which pancreatic insulin content and β-cell mass, proliferation, neogenesis, and apoptosis were measured. Insulin autoantibodies were measured, and adoptive transfer of diabetes and syngeneic islet transplant studies were done to evaluate the effects of GLP-1 and gastrin treatment on autoimmunity.

RESULTS—Combination therapy with GLP-1 and gastrin, but not with GLP-1 or gastrin alone, restored normoglycemia in diabetic NOD mice. The GLP-1 and gastrin combination increased pancreatic insulin content, β-cell mass, and insulin-positive cells in pancreatic ducts, and β-cell apoptosis was decreased. Insulin autoantibodies were reduced in GLP-1–and gastrin-treated NOD mice, and splenocytes from these mice delayed adoptive transfer of diabetes in NOD-scid mice. Syngeneic islet grafts in GLP-1–and gastrin-treated NOD mice were infiltrated by leukocytes with a shift in cytokine expression from interferon-γ to transforming growth factor-β1, and β-cells were protected from apoptosis.

CONCLUSIONS—Combination therapy with GLP-1 and gastrin restores normoglycemia in diabetic NOD mice by increasing the pancreatic β-cell mass and downregulating the autoimmune response.
Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage
Authors: Arita Ryoichi , Hata Yasuaki , Nakao Shintaro , Kita Takeshi , Miura Muneki , Kawahara Shuhei , Zandi Souska , Almulki Lama , Tayyari Faryan , Shimokawa Hiroaki , Hafezi-Moghadam Ali , Ishibashi Tatsuro
Published: October 2008

OBJECTIVE—Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvasculopathy and therapeutic potential of fasudil, a selective ROCK inhibitor, are investigated.

RESEARCH DESIGN AND METHODS—Localization of RhoA/ROCK and Rho activity were examined in retinal tissues of rats. Impact of intravitreal fasudil administration on retinal endothelial nitric oxide synthase (eNOS) and myosin phosphatase target protein (MYPT)-1 phosphorylation, intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and endothelial damage in rat eyes were investigated. Adhesion of neutrophils from diabetic retinopathy patients or nondiabetic control subjects to cultured microvascular endothelial cells was quantified. The potential of fasudil for endothelial protection was investigated by measuring the number of adherent neutrophils and terminal transferase-mediated dUTP nick-end labeling–positive endothelial cells.

RESULTS—RhoA and ROCK colocalized predominantly in retinal microvessels. Significant Rho activation was observed in retinas of diabetic rats. Intravitreal fasudil significantly increased eNOS phosphorylation, whereas it reduced MYPT-1 phosphorylation, ICAM-1 expression, leukocyte adhesion, and the number of damaged endothelium in retinas of diabetic rats. Neutrophils from diabetic retinopathy patients showed significantly higher adhesion to cultured endothelium and caused endothelial apoptosis, which was significantly reduced by fasudil. Blockade of the Fas-FasL interaction prevented endothelial apoptosis. The protective effect of fasudil on endothelial apoptosis was significantly reversed by Nω-nitro-l-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected.

CONCLUSIONS—The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy. Fasudil protects the vascular endothelium by inhibiting neutrophil adhesion and reducing neutrophil-induced endothelial injury. ROCK inhibition may become a new strategy in the management of diabetic retinopathy, especially in its early stages.
Increased Secretion and Expression of Myostatin in Skeletal Muscle From Extremely Obese Women
Authors: Hittel Dustin S. , Berggren Jason R. , Shearer Jane , Boyle Kristen , Houmard Joseph A.
Published: October 2008

OBJECTIVE—Obesity is associated with endocrine abnormalities that predict the progression of insulin resistance to type 2 diabetes. Because skeletal muscle has been shown to secrete proteins that could be used as biomarkers, we characterized the secreted protein profile of muscle cells derived from extremely obese (BMI 48.8 ± 14.8 kg/m2; homeostasis model assessment [HOMA] 3.6 ± 1.0) relative to lean healthy subjects (BMI 25.7 ± 3.2 kg/m2; HOMA 0.8 ± 0.2).

RESEARCH DESIGN AND METHODS—We hypothesized that skeletal muscle would secrete proteins that predict the severity of obesity. To test this hypothesis, we used a “bottom-up” experimental design using stable isotope labeling by amino acids in culture (SILAC) and liquid chromatography/mass spectometry/mass spectometry (LC-MS/MS) to both identify and quantify proteins secreted from cultured myotubes derived from extremely obese compared with healthy nonobese women.

RESULTS—Using SILAC, we discovered a 2.9-fold increase in the secretion of myostatin from extremely obese human myotubes. The increased secretion and biological activity of myostatin were validated by immunoblot (3.16 ± 0.18, P < 0.01) and a myoblast proliferation assay using conditioned growth medium. Myostatin was subsequently shown to increase in skeletal muscle (23%, P < 0.05) and plasma (35%, P < 0.05) and to correlate (r2 = 0.6, P < 0.05) with the severity of insulin resistance.

CONCLUSIONS—Myostatin is a potent antianabolic regulator of muscle mass that may also play a role in energy metabolism. These findings show that increased expression of myostatin in skeletal muscle with obesity and insulin resistance results in elevated circulating myostatin. This may contribute to systemic metabolic deterioration of skeletal muscle with the progression of insulin resistance to type 2 diabetes.
Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Counterregulatory Responses to Hypoglycemia in Individuals With Type 1 Diabetes
Authors: Briscoe Vanessa J. , Ertl Andrew C. , Tate Donna B. , Davis Stephen N.
Published: October 2008

OBJECTIVE—Previous work has demonstrated that chronic administration of the serotonin reuptake inhibitor (SSRI) fluoxetine augments counterregulatory responses to hypoglycemia in healthy humans. However, virtually no information exists regarding the effects of fluoxetine on integrated physiological counterregulatory responses during hypoglycemia in type 1 diabetes. Therefore, the specific aim of this study was to test the hypothesis that 6-week use of the SSRI fluoxetine would amplify autonomic nervous system (ANS) counterregulatory responses to hypoglycemia in individuals with type 1 diabetes.

RESEARCH DESIGN AND METHODS—Eighteen type 1 diabetic patients (14 men/4 women aged 19–48 years with BMI 25 ± 3 kg/m2 and A1C 7.0 ± 0.4%) participated in randomized, double-blind 2-h hyperinsulinemic (9 pmol · kg−1 · min−1)-hypoglycemic clamp studies before and after 6 weeks of fluoxetine administration (n = 8) or identical placebo (n = 10). Glucose kinetics was determined by 3-tritiated glucose. Muscle sympathetic nerve activity (MSNA) was determined by microneurography.

RESULTS—Hypoglycemia (2.8 ± 0.1 mmol/l) and insulinemia (646 ± 52 pmol/l) were similar during all clamp studies. ANS, neuroendocrine, and metabolic counterregulatory responses remained unchanged in the placebo group. However, fluoxetine administration significantly (P < 0.05) increased key ANS (epinephrine, norepinephrine, and MSNA), metabolic (endogenous glucose production and lipolysis), and cardiovascular (systolic blood pressure) counterregulatory responses during hypoglycemia.

CONCLUSIONS—This study has demonstrated that 6-week administration of the SSRI fluoxetine can amplify ANS and metabolic counterregulatory mechanisms during moderate hypoglycemia in patients with type 1 diabetes. These data also suggest that the use of fluoxetine may be useful in increasing epinephrine responses during hypoglycemia in clinical practice.
Depression: An Important Comorbidity With Metabolic Syndrome in a General Population
Authors: Dunbar James A. , Reddy Prasuna , Davis-Lameloise Nathalie , Philpot Benjamin , Laatikainen Tiina , Kilkkinen Annamari , Bunker Stephen J. , Best James D. , Vartiainen Erkki , Kai Lo Sing , Janus Edward D.
Published: October 2008

OBJECTIVE—There is a recognized association among depression, diabetes, and cardiovascular disease. The aim of this study was to examine in a sample representative of the general population whether depression, anxiety, and psychological distress are associated with metabolic syndrome and its components.

RESEARCH DESIGN AND METHODS—Three cross-sectional surveys including clinical health measures were completed in rural regions of Australia during 2004–2006. A stratified random sample (n = 1,690, response rate 48%) of men and women aged 25–84 years was selected from the electoral roll. Metabolic syndrome was defined by the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III (NCEP ATP III), and International Diabetes Federation (IDF) criteria. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale and psychological distress by the Kessler 10 measure.

RESULTS—Metabolic syndrome was associated with depression but not psychological distress or anxiety. Participants with the metabolic syndrome had higher scores for depression (n = 409, mean score 3.41, 95% CI 3.12–3.70) than individuals without the metabolic syndrome (n = 936, mean 2.95, 95% CI 2.76–3.13). This association was also present in 338 participants with the metabolic syndrome and without diabetes (mean score 3.37, 95% CI 3.06–3.68). Large waist circumference and low HDL cholesterol showed significant and independent associations with depression.

CONCLUSIONS—Our results show an association between metabolic syndrome and depression in a heterogeneous sample. The presence of depression in individuals with the metabolic syndrome has implications for clinical management.
Effect of Parental Type 2 Diabetes on Offspring With Type 1 Diabetes
Authors: Thorn Lena M. , Forsblom Carol , Wadén Johan , Söderlund Jenny , Rosengård-Bärlund Milla , Saraheimo Markku , Heikkilä Outi , Hietala Kustaa , Pettersson-Fernholm Kim , Ilonen Jorma , Groop Per-Henrik ,   on behalf of the FinnDiane Study Group
Published: October 2008

OBJECTIVE—The purpose of this study was to study the association between a parental history of type 2 diabetes and the metabolic profile as well as the presence of the metabolic syndrome and diabetes complications in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS—This was a cross-sectional study design in 1,860 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study (620 patients with and 1,240 age-matched patients without a parental history of type 2 diabetes). Information on parental history was received from the type 1 diabetic offspring by a standardized questionnaire.

RESULTS—Patients with type 1 diabetes and a positive parental history of type 2 diabetes had a higher prevalence of the metabolic syndrome (44 vs. 38%; P = 0.013) and a metabolic profile related to insulin resistance (higher BMI, larger waist circumference, and higher triglycerides, A1C, and insulin dose per kilogram) and also had a later onset of type 1 diabetes (17.2 ± 9.2 vs. 16.1 ± 8.9 years; P = 0.008), which was also confirmed in the publicly available Diabetes Control and Complications Trial data set. In contrast, no association was observed with blood pressure, diabetes complications, or HLA genotype distribution. Parental history of type 2 diabetes was independently associated with age at onset of type 1 diabetes (odds ratio 1.02 [95% CI 1.01–1.03]), BMI (1.07 [1.02–1.12]), triglycerides (1.18 [1.03–1.35]), and insulin dose per kilogram (1.63 [1.04–2.54]).

CONCLUSIONS—Parental history of type 2 diabetes is associated with a later onset of type 1 diabetes, the metabolic syndrome, and a metabolic profile related to insulin resistance.