bluuebunny/crossref_metadata_2025 huggingface dataset:
An Energy Budget for the Olfactory Glomerulus
Authors: Nawroth Janna C. , Greer Charles A. , Chen Wei R. , Laughlin Simon B. , Shepherd Gordon M.
Published: September 2007

Energy demands are becoming recognized as an important constraint on neural signaling. The olfactory glomerulus provides a well defined system for analyzing this question. Odor stimulation elicits high-energy demands in olfactory glomeruli where olfactory axons converge onto dendrites of olfactory bulb neurons. We performed a quantitative analysis of the energy demands of each type of neuronal element within the glomerulus. This included the volumes of each element, their surface areas, and ion loads associated with membrane potentials and synaptic activation as constrained by experimental observations. In the resting state, there was a high-energy demand compared with other brain regions because of the high density of neural elements. The activated state was dominated by the energy demands of action potential propagation in afferent olfactory sensory neurons and their synaptic input to dendritic tufts, whereas subsequent dendritic potentials and dendrodendritic transmission contributed only a minor share of costs. It is proposed therefore that afferent input and axodendritic transmission account for the strong signals registered by 2-deoxyglucose and functional magnetic resonance imaging, although postsynaptic dendrites comprise at least one-half of the volume of the glomerulus. The results further suggest that presynaptic inhibition of the axon terminals by periglomerular cells plays an important role in limiting the range of excitation of the postsynaptic cells. These results provide a new quantitative basis for interpreting olfactory bulb activation patterns elicited by odor stimulation.
Molecular, Topographic, and Functional Organization of the Cerebellar Nuclei: Analysis by Three-Dimensional Mapping of the Olivonuclear Projection and Aldolase C Labeling
Authors: Sugihara Izumi , Shinoda Yoshikazu
Published: September 2007

The olivocerebellar climbing fiber projection pattern is closely correlated with the pattern of aldolase C expression in cerebellar Purkinje cells. Based on this expression pattern, the olivocerebellar projection can be classified into five “groups” of functional compartments. Each group originates from a subarea within the inferior olive that projects to multiple cortical stripes of Purkinje cells, all of which are either aldolase C positive or aldolase C negative. However, no equivalent compartmental organization has been demonstrated in the cerebellar nuclei (CN). Thus, in the CN of the rat, we systematically mapped the location of olivonuclear projections belonging to the five groups and determined their relationship to the expression of aldolase C in Purkinje cell axonal terminals.

The CN were divided into caudoventral aldolase C-positive and rostrodorsal aldolase C-negative parts. The olivonuclear terminations from the five groups projected topographically to five separate compartments within the CN that partly crossed the traditional boundaries that define the fastigial, interposed, and dentate nuclei. Each compartment had mostly uniform cytoarchitecture and the same aldolase C expression (either positive or negative) that was found in the corresponding olivocortical projection. These results suggest a new view of the organization of the CN whereby the pattern of olivonuclear terminations links portions of different CN together. We propose that each compartment in the CN, along with its corresponding olivary subarea and cortical stripes, may be related to a different aspect of motor control.
Computational Diversity in Complex Cells of Cat Primary Visual Cortex
Authors: Finn Ian M. , Ferster David
Published: September 2007

A previous study has suggested that complex cells perform a MAX-like operation on their inputs: when two bar stimuli are presented within the receptive field, regardless of their relative separation, the cell's response is similar in amplitude to the larger of the responses elicited by the individual stimuli. This description of complex cells seems at odds with the classical energy model in which complex cells receive input from multiple simple cells with overlapping receptive fields. The energy model predicts, and experiments have confirmed, that bar stimuli should facilitate or suppress one another depending on their relative separation. We have recorded intracellularly from a population of complex cells and studied their responses to paired bar stimuli in detail. A wide range of behavior was observed, from the more classical separation-dependent interactions to purely MAX-like responses. We also found that the more MAX-like a cell was, the broader its spatial-frequency tuning as measured with drifting gratings. These observations are consistent with energy models in which classical complex cells receive input from simple cells with similar preferred spatial frequencies, and MAX-like complex cells receive input from simple cells with disparate preferred spatial frequencies. Generalized energy models, then, can account for diverse modes of computation in cortical complex cells.
Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats
Authors: Belujon Pauline , Bezard Erwan , Taupignon Anne , Bioulac Bernard , Benazzouz Abdelhamid
Published: September 2007

The subthalamic nucleus (STN) plays a key role in the pathophysiology of Parkinson's disease. The modulation of the STN by norepinephrine, however, is unknown. The present study aims at characterizing the effects of systemic administration of noradrenergic agents on locomotor activity and onin vivoextracellularly recorded STN neuronal activity in intact and 6-hydroxydopamine (6-OHDA)-lesioned rats. Using selective agonists and antagonists of α1 and α2 adrenergic receptors (ARs), we show that STN neurons have functional α1- and α2-AR controlling STN firing with an impact on locomotor activity. We further demonstrate that those systemic effects are supported, at least in part, by a direct modulation of STN neuronal activity, using patch-clamp recordings of STN neurons in brain slices. These findings support the premise that hypokinesia is associated with an increased STN neuronal activity, and that improvements of parkinsonian motor abnormalities are associated with a decrease in STN activity. Our data challenge assumptions about the role of α1-AR and α2-AR in the regulation of STN neurons in both intact and 6-OHDA-lesioned rats and further ground the rationale for using α2-AR noradrenergic antagonists in Parkinson's disease, albeit via an unexpected mechanism.
Spatial Attention and the Latency of Neuronal Responses in Macaque Area V4
Authors: Lee Joonyeol , Williford Tori , Maunsell John H. R.
Published: September 2007

The effects of attention on neuronal responses in visual cortex have been likened to a change in stimulus contrast. Attention and stimulus contrast both modulate the magnitude of neuronal responses. However, changes in stimulus contrast also affect the latency of visual responses. Although many neurophysiological studies have examined how attention affects the strength of neuronal responses, few have considered whether attention affects neuronal latencies. To compare directly the effects of stimulus contrast and attention, we recorded responses from individual neurons in area V4 of macaque monkeys while they performed a task that independently controlled spatial attention and stimulus contrast. As expected, changes in stimulus contrast affected both the magnitude and latency of neuronal responses. Although attention had the expected effects on the magnitudes of neuronal responses, we did not detect statistically reliable changes in neuronal latency. A direct comparison of the effects of contrast and attention revealed a reliable difference. When a shift in spatial attention decreased response magnitude, response latency increased much less than when the same magnitude change was caused by reducing stimulus contrast. Thus, attention is distinct from contrast in the way it affects the relationship between neuronal response magnitude and latency.
Delineation of Multiple Subpallial Progenitor Domains by the Combinatorial Expression of Transcriptional Codes
Authors: Flames Nuria , Pla Ramón , Gelman Diego M. , Rubenstein John L. R. , Puelles Luis , Marín Oscar
Published: September 2007

The mammalian telencephalon is considered the most complex of all biological structures. It comprises a large number of functionally and morphologically distinct types of neurons that coordinately control most aspects of cognition and behavior. The subpallium, for example, not only gives rise to multiple neuronal types that form the basal ganglia and parts of the amygdala and septum but also is the origin of an astonishing diversity of cortical interneurons. Despite our detailed knowledge on the molecular, morphological, and physiological properties of most of these neuronal populations, the mechanisms underlying their generation are still poorly understood. Here, we comprehensively analyzed the expression patterns of several transcription factors in the ventricular zone of the developing subpallium in the mouse to generate a detailed molecular map of the different progenitor domains present in this region. Our study demonstrates that the ventricular zone of the mouse subpallium contains at least 18 domains that are uniquely defined by the combinatorial expression of several transcription factors. Furthermore, the results of microtransplantation experimentsin vivocorroborate that anatomically defined regions of the mouse subpallium, such as the medial ganglionic eminence, can be subdivided into functionally distinct domains.
Compartment-Specific Modulation of GABAergic Synaptic Transmission by μ-Opioid Receptor in the Mouse Striatum with Green Fluorescent Protein-Expressing Dopamine Islands
Authors: Miura Masami , Saino-Saito Sachiko , Masuda Masao , Kobayashi Kazuto , Aosaki Toshihiko
Published: September 2007

The striatum is a heterogeneous mosaic of two neurochemically, developmentally, and functionally distinct compartments: the μ-opioid receptor (MOR)-enriched striosomes and the matrix. Preferential activation of the striosomes and persistent suppression of the matrix have recently been suggested to represent neural correlates of motor stereotypy. However, little is known concerning the physiological properties of the striosomes. We made patch-clamp recordings from medium spiny neurons in identified MOR-immunoreactive “dopamine islands” as striosomes in a slice preparation taken from transgenic mice expressing green fluorescent protein in tyrosine hydroxylase mRNA-containing neurons. Striosomal neurons differed electrophysiologically from cells in the matrix in having significantly less hyperpolarized resting membrane potentials and larger input resistances, suggesting developmental differences between the two types of cells. Moreover, corticostriatal EPSCs were inhibited by MOR activation to similar extents in the two compartments, although inhibition of IPSCs was observed only in the striosomes. This MOR-induced inhibition of IPSCs was presynaptically mediated, because MOR agonist invariably decreased IPSC amplitudes when postsynaptic G-protein was inactivated, significantly increased the paired-pulse ratio of the IPSCs, and decreased the frequency but not the amplitude of miniature IPSCs. These effects of MOR were mediated principally by 4-aminopyridine-sensitive K+conductance via a cAMP-dependent pathway, which was further augmented by previous blockade of the protein kinase C cascade. These findings suggest that MOR activation by endogenous and/or exogenous MOR-selective opioid substances differentially regulates the activities of the striosome and matrix compartments and thus plays an important role in motivated behavior and learning.
Transfusions in the Preterm Infant
Authors: Ohls Robin K.
Published: September 2007

Preterm infants in the neonatal intensive care unit receive a greater number of red cell transfusions than any other hospitalized patient group. During the first weeks after birth, when blood draws are frequent and phlebotomy losses are high, approximately 50% of extremely low birthweight (ELBW) infants receive their first transfusion. (1) By the end of hospitalization, approximately 85% of ELBW infants have received at least one transfusion. (2)(3)(4) Although the numbers of transfusions administered to preterm infants remains significant, they have decreased over the last 20 years, primarily due to the institution of restrictive transfusion guidelines in conjunction with the study of erythropoietin administration to preterm infants. (5)(6) This article reviews the need for administering red cell transfusions, summarizes studies evaluating the efficacy of restrictive transfusion guidelines, and provides strategies to decrease red cell transfusions in neonates, including instituting neonatal transfusion guidelines.
Flow nets and textbooks
Authors: Bromhead E. N.
Published: September 2007

Textbooks in soil mechanics for undergraduate, postgraduate and professional use have been published since 1941. Most of them cover the use of flow nets to illustrate or solve problems in seepage. A review of a number of such textbooks reveals that the examples of flow nets provided are often few in number, and greatly simplified. Many of the example illustrations contain errors that are of the ‘schoolboy howler’ kind and which have not been corrected from edition to edition of a particular textbook. Perhaps more controversially, there are cases where illustrations from one source appear to have been reproduced in different books by different authors, complete with the errors. The flow net technique predates the first comprehensive textbook on soil mechanics and so has been fully understood throughout the period covered by the review; these inconsistencies are therefore difficult to explain away as the graphical equivalent of the typographical error or as something that was not understood fully at the time of publication.
Remediating a soil-nailed excavation in Wuhan, China
Authors: Yang Y.
Published: September 2007

Soil nailing was employed to stabilise the sides of a basement excavation in an urban district of Wuhan City, China. During the course of the excavation, excessive movements were observed, and collapse occurred along one of the basement sides. A remedial earth-retaining system was developed to provide additional stability to the ground retained by the soil-nailed wall. In the revised system, the soil-nailed wall retained the upper soil while propped piles at the toe of the wall augmented the overall stability of the sides. The case study presented in this paper demonstrates the effectiveness of the earthretaining system in controlling movements.
A Genome-Wide Linkage Scan of Insulin Level–Derived Traits
Authors: Hsueh Wen-Chi , Silver Kristi D. , Pollin Toni I. , Bell Callum J. , O’Connell Jeffrey R. , Mitchell Braxton D. , Shuldiner Alan R.
Published: September 2007

OBJECTIVE—Serum insulin levels are altered in insulin resistance and insulin deficiency, states that are associated with the development of type 2 diabetes. The goal of our study was to identify chromosomal regions that are likely to harbor genetic determinants of these traits.

RESEARCH DESIGN AND METHODS—We conducted a series of genetic analyses, including genome-wide and fine-mapping linkage studies, based on insulin levels measured during an oral glucose tolerance test (OGTT) in 552 nondiabetic participants in the Amish Family Diabetes Study. Indices of insulin secretion included the insulinogenic index and insulin at 30 min postglucose load (insulin 30), while indices of insulin resistance included homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin. Insulin area under the curve, a measure of both insulin secretion and insulin resistance, was also examined.

RESULTS—All traits were modestly heritable, with heritability estimates ranging from 0.1 to 0.4 (all P < 0.05). There was significant genetic correlation between fasting insulin and HOMA-IR (ρG > 0.86, P < 0.05), as well as insulin 30 and insulinogenic index (ρG = 0.81, P < 0.0001), suggesting that common genes influence variation in these pairs of traits. Suggestive linkage signals in the genome scan were to insulin 30 on chromosome 15q23 (logarithm of odds [LOD] 2.53, P = 0.00032) and to insulinogenic index on chromosome 2p13 (LOD 2.51, P = 0.00034). Fine-mapping study further refined our signal for insulin 30 on chromosome 15 (LOD 2.38 at 68 cM).

CONCLUSIONS—These results suggest that there may be different genes influencing variation in OGTT measures of insulin secretion and insulin resistance.
High-Fat Diet–Induced Neuropathy of Pre-Diabetes and Obesity
Authors: Obrosova Irina G. , Ilnytska Olga , Lyzogubov Valeriy V. , Pavlov Ivan A. , Mashtalir Nazar , Nadler Jerry L. , Drel Viktor R.
Published: September 2007

OBJECTIVE—Subjects with dietary obesity and pre-diabetes have an increased risk for developing both nerve conduction slowing and small sensory fiber neuropathy. Animal models of this type of neuropathy have not been described. This study evaluated neuropathic changes and their amenability to dietary and pharmacological interventions in mice fed a high-fat diet (HFD), a model of pre-diabetes and alimentary obesity.

RESEARCH DESIGN AND METHODS—Female C57BL6/J mice were fed normal diets or HFDs for 16 weeks.

RESULTS—HFD-fed mice developed obesity, increased plasma FFA and insulin concentrations, and impaired glucose tolerance. They also had motor and sensory nerve conduction deficits, tactile allodynia, and thermal hypoalgesia in the absence of intraepidermal nerve fiber loss or axonal atrophy. Despite the absence of overt hyperglycemia, the mice displayed augmented sorbitol pathway activity in the peripheral nerve, as well as 4-hydroxynonenal adduct nitrotyrosine and poly(ADP-ribose) accumulation and 12/15-lipoxygenase overexpression in peripheral nerve and dorsal root ganglion neurons. A 6-week feeding with normal chow after 16 weeks on HFD alleviated tactile allodynia and essentially corrected thermal hypoalgesia and sensory nerve conduction deficit without affecting motor nerve conduction slowing. Normal chow containing the aldose reductase inhibitor fidarestat (16 mg · kg−1· day −1) corrected all functional changes of HFD-induced neuropathy.

CONCLUSIONS—Similar to human subjects with pre-diabetes and obesity, HFD-fed mice develop peripheral nerve functional, but not structural, abnormalities and, therefore, are a suitable model for evaluating dietary and pharmacological approaches to halt progression and reverse diabetic neuropathy at the earliest stage of the disease.
Essential Role for Signal Transducer and Activator of Transcription-1 in Pancreatic β-Cell Death and Autoimmune Type 1 Diabetes of Nonobese Diabetic Mice
Authors: Kim Sunshin , Kim Hun Sik , Chung Kun Wook , Oh Seung Hoon , Yun Jong Won , Im Sin-Hyeog , Lee Moon-Kyu , Kim Kwang-Won , Lee Myung-Shik
Published: September 2007

OBJECTIVE—We have reported important roles for signal transducer and activator of transcription-1 (STAT1) in pancreatic β-cell death by cytokines in vitro. However, in vivo evidence supporting the role for STAT1 in natural type 1 diabetes has not been reported. We studied whether STAT1 plays an important role in the development of natural type 1 diabetes.

RESEARCH DESIGN AND METHODS—We produced nonobese diabetic (NOD)/STAT1−/− mice by backcrossing and studied the in vivo role of STAT1 in β-cell death and type 1 diabetes.

RESULTS— STAT1 −/− islet cells were resistant to death by interferon (IFN)-γ/tumor necrosis factor (TNF)-α or IFN-γ/interleukin (IL)-1β combination. Cytochrome c translocation by IFN-γ/TNF-α was abrogated in STAT1−/− islet cells. The induction of X-linked inhibitor of apoptosis protein by TNF-α was inhibited by IFN-γ in STAT1+/− islet cells but not in STAT1−/− islet cells. Inducible nitric oxide (NO) synthase induction and NO production by IFN-γ/IL-1β were impaired in STAT1−/− islet cells. Strikingly, diabetes and insulitis were completely abrogated in NOD/STAT1−/− mice. Development of diabetes after CD4+ diabetogenic T-cell transfer was inhibited in those mice. STAT1−/− neonatal pancreata were not destroyed when grafted into diabetic NOD/BDC2.5 mice that developed CD4+ T-cell–dependent islet cell death. In NOD/STAT1−/− mice, autoreactive T-cell priming was not impaired, but Th1 differentiation was impaired. A janus kinase (JAK) 2 inhibitor upstream of STAT1 attenuated islet cell death by IFN-γ/TNF-α or IFN-γ/IL-1β and delayed diabetes onset in NOD/BDC2.5-SCID mice.

CONCLUSIONS—These data demonstrate a critical role for STAT1 in β-cell death, T-cell immunoregulation, and type 1 diabetes in vivo and suggest potential therapeutic values of STAT1 or JAK inhibitors in the treatment/prevention of type 1 diabetes.
The Transcriptional Coactivator Peroxisome Proliferator–Activated Receptor (PPAR)γ Coactivator-1α and the Nuclear Receptor PPARα Control the Expression of Glycerol Kinase and Metabolism Genes Independently of PPARγ Activation in Human White Adipocytes
Authors: Mazzucotelli Anne , Viguerie Nathalie , Tiraby Claire , Annicotte Jean-Sébastien , Mairal Aline , Klimcakova Eva , Lepin Emmanuelle , Delmar Paul , Dejean Sébastien , Tavernier Geneviève , Lefort Corinne , Hidalgo Juan , Pineau Thierry , Fajas Lluis , Clément Karine , Langin Dominique
Published: September 2007

OBJECTIVE—The purpose of this work was to determine the pattern of genes regulated by peroxisome proliferator–activated receptor (PPAR) γ coactivator 1α (PGC-1α) in human adipocytes and the involvement of PPARα and PPARγ in PGC-1α transcriptional action.

RESEARCH DESIGN AND METHODS—Primary cultures of human adipocytes were transduced with a PGC-1α adenovirus and treated with PPARγ and PPARα agonists. Variation in gene expression was assessed using pangenomic microarrays and quantitative RT-PCR. To investigate glycerol kinase (GyK), a target of PGC-1α, we measured enzymatic activity and glycerol incorporation into triglycerides. In vivo studies were performed on wild-type and PPARα−/− mice. The GyK promoter was studied using chromatin immunoprecipitation and promoter reporter gene assays.

RESULTS—Among the large number of genes regulated by PGC-1α independently of PPARγ, new targets involved in metabolism included the gene encoding GyK. The induction of GyK by PGC-1α was observed at the levels of mRNA, enzymatic activity, and glycerol incorporation into triglycerides. PPARα was also upregulated by PGC-1α. Its activation led to an increase in GyK expression and activity. PPARα was shown to bind and activate the GyK promoter. Experiments in mice confirmed the role of PGC-1α and PPARα in the regulation of GyK in vivo.

CONCLUSIONS—This work uncovers novel pathways regulated by PGC-1α and reveals that PPARα controls gene expression in human white adipocytes. The induction of GyK by PGC-1α and PPARα may promote a futile cycle of triglyceride hydrolysis and fatty acid reesterification.
Farnesoid X Receptor Modulates Renal Lipid Metabolism, Fibrosis, and Diabetic Nephropathy
Authors: Jiang Tao , Wang Xiaoxin X. , Scherzer Pnina , Wilson Paul , Tallman James , Takahashi Hideaki , Li Jinping , Iwahashi Mieko , Sutherland Eileen , Arend Lois , Levi Moshe
Published: September 2007

OBJECTIVE—Recent studies indicate an important role for nuclear receptors in regulating lipid and carbohydrate metabolism, fibrosis, and inflammation. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily. FXR is highly expressed in the liver, intestine, adrenal gland, and kidney. The primary bile acids are the highest affinity endogenous ligands for FXR. The effects of FXR agonists in diabetic kidney disease, the main cause of end-stage renal disease, however, have not been determined.

RESEARCH DESIGN AND METHODS—To identify the effect of FXR activation in modulation of diabetic nephropathy, we treated 1) C57BL/6J mice on low-fat diet or high-fat diet with FXR agonists (GW4064 or cholic acid) for 1 week; 2) C57BLKS/J-db/db mice and their lean mates with GW4064 for 1 week; and 3) C57BL/6J-db/db mice and their lean mates with cholic acid for 12 weeks.

RESULTS—We found that FXR agonists modulate renal sterol regulatory element–binding protein-1 (SREBP-1) expression and lipid metabolism and renal expression of profibrotic growth factors, proinflammatory cytokines, and oxidative stress enzymes and decrease glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. In renal mesangial cells, overexpression of FXR or treatment with GW4064 also inhibited SREBP-1c and other lipogenic genes, transforming growth factor-β, and interleukin-6, suggesting a direct role of FXR in modulating renal lipid metabolism and modulation of fibrosis and inflammation.

CONCLUSIONS—These results therefore indicate a new and important role for FXR in the kidney and provide new therapeutic avenues for the treatment of diabetic nephropathy.
The Adipokine Lipocalin 2 Is Regulated by Obesity and Promotes Insulin Resistance
Authors: Yan Qing-Wu , Yang Qin , Mody Nimesh , Graham Timothy E. , Hsu Chung-Hsin , Xu Zhao , Houstis Nicholas E. , Kahn Barbara B. , Rosen Evan D.
Published: September 2007

OBJECTIVE—We identified lipocalin 2 (Lcn2) as a gene induced by dexamethasone and tumor necrosis factor-α in cultured adipocytes. The purpose of this study was to determine how expression of Lcn2 is regulated in fat cells and to ascertain whether Lcn2 could be involved in metabolic dysregulation associated with obesity.

RESEARCH DESIGN AND METHODS—We examined Lcn2 expression in murine tissues and in 3T3-L1 adipocytes in the presence and absence of various stimuli. We used quantitative Western blotting to observe Lcn2 serum levels in lean and obese mouse models. To assess effects on insulin action, we used retroviral delivery of short hairpin RNA to reduce Lcn2 levels in 3T3-L1 adipocytes.

RESULTS— Lcn2 is highly expressed by fat cells in vivo and in vitro. Expression of Lcn2 is elevated by agents that promote insulin resistance and is reduced by thiazolidinediones. The expression of Lcn2 is induced during 3T3-L1 adipogenesis in a CCAAT/enhancer-binding protein–dependent manner. Lcn2 serum levels are elevated in multiple rodent models of obesity, and forced reduction of Lcn2 in 3T3-L1 adipocytes improves insulin action. Exogenous Lcn2 promotes insulin resistance in cultured hepatocytes.

CONCLUSIONS— Lcn2 is an adipokine with potential importance in insulin resistance associated with obesity.
Variants of the Transcription Factor 7-Like 2 (TCF7L2) Gene Are Associated With Type 2 Diabetes in an African-American Population Enriched for Nephropathy
Authors: Sale Michèle M. , Smith Shelly G. , Mychaleckyj Josyf C. , Keene Keith L. , Langefeld Carl D. , Leak Tennille S. , Hicks Pamela J. , Bowden Donald W. , Rich Stephen S. , Freedman Barry I.
Published: September 2007

OBJECTIVE—Recently, variants in the TCF7L2 gene have been reported to be associated with type 2 diabetes across multiple Europid populations, but only one small sample of African-American type 2 diabetic patients has been examined. Our objective was to investigate the importance of TCF7L2 in a larger African-American case-control population.

RESEARCH DESIGN AND METHODS—We investigated single nucleotide polymorphisms (SNPs) in six known type 2 diabetes genes in 577 African-American case subjects with type 2 diabetes enriched for nephropathy and 596 African-American control subjects. Additionally, we genotyped 70 ancestry-informative markers (AIMs) to apply adjustments for differences in ancestral proportions.

RESULTS—The most significant associations were observed with TCF7L2 intron 3 SNPs rs7903146 (additive P = 4.10 × 10−6, odds ratio [OR] 1.51; admixture-adjusted Pa = 3.77 × 10−6) and rs7901695 (P = 0.001, OR 1.30; Pa = 0.003). The 2-SNP haplotype containing these SNPs was also associated with type 2 diabetes (P = 3 × 10−5). Modest associations were also seen with TCF7L2 intron 4 SNPs rs7895340, rs11196205, and rs12255372 (0.01 < P < 0.05; 0.03 < Pa < 0.08), as well as with ATP-sensitive inwardly rectifying potassium channel subunit Kir6.2 (KCNJ11) and hepatocyte nuclear factor 4-α (HNF4A) SNPs (0.01 < P < 0.05; 0.01 < Pa < 0.41). No significant associations were detected with genotyped calpain 10 (CAPN10), peroxisome proliferator–activated receptor γ (PPARG), and transcription factor 1 (TCF1) SNPs.

CONCLUSIONS—This study indicates that variants in the TCF7L2 gene significantly contribute to diabetes susceptibility in African-American populations.
Glucose Ingestion Fails to Inhibit Hypothalamic Neuronal Activity in Patients With Type 2 Diabetes
Authors: Vidarsdottir Solrun , Smeets Paul A.M. , Eichelsheim Diane L. , van Osch Matthias J.P. , Viergever Max A. , Romijn Johannes A. , van der Grond Jeroen , Pijl Hanno
Published: September 2007

OBJECTIVE—The hypothalamus plays a critical role in the regulation of energy balance and fuel flux. Glucose ingestion inhibits hypothalamic neuronal activity in healthy humans. We hypothesized that hypothalamic neuronal activity in response to an oral glucose load would be altered in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—In this randomized, single blind, case-control study, 7 type 2 diabetic men (BMI 27.9 ± 2.0 kg/m2) and 10 age-matched healthy men (BMI 26.1 ± 3.2 kg/m2) were scanned twice for 38 min on separate days using functional magnetic resonance imaging. After 8 min, they ingested either a glucose solution (75 g in 300 ml water) or water (300 ml).

RESULTS—Glucose ingestion resulted in a prolonged significant blood oxygen level–dependent signal decrease in the upper and lower hypothalamus in healthy subjects but not in diabetic patients.

CONCLUSIONS—Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes. Failure of neural circuits to properly adapt to nutrient ingestion may contribute to metabolic imbalance in type 2 diabetic patients.
Effect of Insulin Deprivation on Muscle Mitochondrial ATP Production and Gene Transcript Levels in Type 1 Diabetic Subjects
Authors: Karakelides Helen , Asmann Yan W. , Bigelow Maureen L. , Short Kevin R. , Dhatariya Ketan , Coenen-Schimke Jill , Kahl Jane , Mukhopadhyay Debabrata , Nair K. Sreekumaran
Published: September 2007

OBJECTIVE—Muscle mitochondrial dysfunction occurs in many insulin-resistant states, such as type 2 diabetes, prompting a hypothesis that mitochondrial dysfunction may cause insulin resistance. We determined the impact of insulin deficiency on muscle mitochondrial ATP production by temporarily depriving type 1 diabetic patients of insulin treatment.

RESEARCH DESIGN AND METHODS—We withdrew insulin for 8.6 ± 0.6 h in nine C-peptide–negative type 1 diabetic subjects and measured muscle mitochondrial ATP production and gene transcript levels (gene array and real-time quantitative PCR) and compared with insulin-treated state. We also measured oxygen consumption (indirect calorimetry); plasma levels of glucagon, bicarbonate, and other substrates; and urinary nitrogen.

RESULTS—Withdrawal of insulin resulted in increased plasma glucose, branched chain amino acids, nonesterified fatty acids, β-hydroxybutyrate, and urinary nitrogen but no change in bicarbonate. Insulin deprivation decreased muscle mitochondrial ATP production rate (MAPR) despite an increase in whole-body oxygen consumption and altered expression of many muscle mitochondrial gene transcripts. Transcript levels of genes involved in oxidative phosphorylation were decreased, whereas those involved in vascular endothelial growth factor (VEGF) signaling, inflammation, cytoskeleton signaling, and integrin signaling pathways were increased.

CONCLUSIONS—Insulin deficiency and associated metabolic changes reduce muscle MAPR and expression of oxidative phosphorylation genes in type 1 diabetes despite an increase in whole-body oxygen consumption. Increase in transcript levels of genes involved in VEGF, inflammation, cytoskeleton, and integrin signaling pathways suggest that vascular factors and cell proliferation that may interact with mitochondrial changes occurred.
Association Study of the Genetic Polymorphisms of the Transcription Factor 7-Like 2 (TCF7L2) Gene and Type 2 Diabetes in the Chinese Population
Authors: Chang Yi-Cheng , Chang Tien-Jyun , Jiang Yi-Der , Kuo Shan-Shan , Lee Kuan-Ching , Chiu Ken C. , Chuang Lee-Ming
Published: September 2007

OBJECTIVE—Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene is one of the few validated genetic variants with large effects on the risk of type 2 diabetes in the populations of European ancestry. In this study, we aimed to explore the effect of the TCF7L2 polymorphisms in a Han Chinese population.

RESEARCH DESIGN AND METHODS—We genotyped 20 single nucleotide polymorphisms (SNPs) across the TCF7L2 gene in 1,520 unrelated subjects from a Han Chinese population in Taiwan. The associations of SNPs and haplotypes with type 2 diabetes and linkage disequilibrium (LD) structure of the TCF7L2 gene were analyzed.

RESULTS—The previously reported SNPs rs7903146 T- and rs12255372 T-alleles of the TCF7L2 gene were rare and were not associated with type 2 diabetes in a Chinese population, which may attribute to the low frequencies of these two SNPs. SNP rs290487 located in an LD block close to the 3′ end of the gene was associated with type 2 diabetes (allele-specific P = 0.0021; permuted P = 0.03). The odds ratio was 1.36 for the CT genotype (95% CI 1.08−1.71; P = 0.0063) and 1.51 for the CC genotype (1.10 −2.07; P = 0.0085) compared with the TT genotype, corresponding to a population attributable risk fraction of 18.7%. The haplotypes composed of rs290487 were also significantly associated with type 2 diabetes (global P = 0.012).

CONCLUSIONS—We identified a novel risk-conferring genetic variant of TCF7L2 for type 2 diabetes in a Chinese population. Our data suggested that the TCF7L2 genetic polymorphisms are major determinants for risk of type 2 diabetes in the Chinese population.
Meal Fatty Acid Uptake in Visceral Fat in Women
Authors: Votruba Susanne B. , Mattison Rebecca S. , Dumesic Daniel A. , Koutsari Christina , Jensen Michael D.
Published: September 2007

OBJECTIVE—Differential meal fat uptake into adipose tissue depots may be a determinant of body fat distribution.

RESEARCH DESIGN AND METHODS—We used the meal fat tracer/adipose tissue biopsy approach to compare the effects of meal fat content on the fat uptake into visceral and upper and lower body subcutaneous fat depots in 21 premenopausal women. [3H]triolein was used to trace the fate of fatty acids from a normal-fat or high-fat meal.

RESULTS—The proportion of dietary fat uptake into the three depots did not differ between meals; visceral fat accounted for only ∼5% of meal fat disposal irrespective of visceral fat mass. For the women consuming the normal-fat meal, the uptake of meal fatty acid into femoral fat (milligrams meal fat per gram lipid) increased as a function of leg fat mass (r = 0.68, P < 0.05), which we interpret as increased efficiency of uptake. The opposite pattern was seen in omental fat with the normal-fat meal and in all depots after the high-fat meal. For both meals, ∼40% of meal fat was oxidized (3H2O production) after 24 h.

CONCLUSIONS—We conclude that greater thigh adipose tissue in women is associated with greater efficiency of meal fat storage under conditions of energy balance, whereas the opposite is seen with visceral fat. These findings imply that different mechanisms may regulate fatty acid uptake in different depots, which may in turn impact on body fat distribution.
Protein Kinase C-ζ Activation Markedly Enhances β-Cell Proliferation
Authors: Vasavada Rupangi C. , Wang Lin , Fujinaka Yuichi , Takane Karen K. , Rosa Taylor C. , Mellado-Gil Jose M.D. , Friedman Peter A. , Garcia-Ocaña Adolfo
Published: September 2007

OBJECTIVE— Diabetes results from a deficiency of functional β-cells. Previous studies have identified hepatocyte growth factor (HGF) and parathyroid hormone–related protein (PTHrP) as two potent β-cell mitogens. The objective of this study is to determine 1) whether HGF and PTHrP have additive/synergistic effects on β-cell growth and proliferation; 2) the signaling pathways through which these growth factors mediate β-cell mitogenesis; and 3) whether activation of this/these signaling pathway(s) enhances human β-cell replication.

RESEARCH DESIGN AND METHODS— We generated and phenotypically analyzed doubly transgenic mice overexpressing PTHrP and HGF in the β-cell. INS-1 and primary mouse and human islet cells were used to identify mitogenic signaling pathways activated by HGF and/or PTHrP.

RESULTS— Combined overexpression of HGF and PTHrP in the β-cell of doubly transgenic mice did not result in additive/synergistic effects on β-cell growth and proliferation, suggesting potential cross-talk between signaling pathways activated by both growth factors. Examination of these signaling pathways in INS-1 cells revealed atypical protein kinase C (PKC) as a novel intracellular target activated by both HGF and PTHrP in β-cells. Knockdown of PKCζ, but not PKCι/λ, expression using specific small-interfering RNAs blocked growth factor–induced INS-1 cell proliferation. Furthermore, adenovirus-mediated delivery of kinase-dead PKCζ completely inhibited β-cell proliferation in primary islet cells overexpressing PTHrP and/or HGF. Finally, adenovirus-mediated delivery of constitutively active PKCζ in mouse and human primary islet cells significantly enhanced β-cell proliferation.

CONCLUSIONS— PKCζ is essential for PTHrP- and HGF-induced β-cell proliferation. PKCζ activation could be useful in therapeutic strategies for expanding β-cell mass in vitro and in vivo.
Mitochondrial Energetics in the Heart in Obesity-Related Diabetes
Authors: Boudina Sihem , Sena Sandra , Theobald Heather , Sheng Xiaoming , Wright Jordan J. , Hu Xia Xuan , Aziz Salwa , Johnson Josie I. , Bugger Heiko , Zaha Vlad G. , Abel E. Dale
Published: September 2007

OBJECTIVE—In obesity and diabetes, myocardial fatty acid utilization and myocardial oxygen consumption (MVo2) are increased, and cardiac efficiency is reduced. Mitochondrial uncoupling has been proposed to contribute to these metabolic abnormalities but has not been directly demonstrated.

RESEARCH DESIGN AND METHODS—Oxygen consumption and cardiac function were determined in db/db hearts perfused with glucose or glucose and palmitate. Mitochondrial function was determined in saponin-permeabilized fibers and proton leak kinetics and H2O2 generation determined in isolated mitochondria.

RESULTS— db/db hearts exhibited reduced cardiac function and increased MVo2. Mitochondrial reactive oxygen species (ROS) generation and lipid and protein peroxidation products were increased. Mitochondrial proliferation was increased in db/db hearts, oxidative phosphorylation capacity was impaired, but H2O2 production was increased. Mitochondria from db/db mice exhibited fatty acid–induced mitochondrial uncoupling that is inhibitable by GDP, suggesting that these changes are mediated by uncoupling proteins (UCPs). Mitochondrial uncoupling was not associated with an increase in UCP content, but fatty acid oxidation genes and expression of electron transfer flavoproteins were increased, whereas the content of the F1 α-subunit of ATP synthase was reduced.

CONCLUSIONS—These data demonstrate that mitochondrial uncoupling in the heart in obesity and diabetes is mediated by activation of UCPs independently of changes in expression levels. This likely occurs on the basis of increased delivery of reducing equivalents from β-oxidation to the electron transport chain, which coupled with decreased oxidative phosphorylation capacity increases ROS production and lipid peroxidation.
FGFR4 Prevents Hyperlipidemia and Insulin Resistance but Underlies High-Fat Diet–Induced Fatty Liver
Authors: Huang Xinqiang , Yang Chaofeng , Luo Yongde , Jin Chengliu , Wang Fen , McKeehan Wallace L.
Published: September 2007

OBJECTIVE—Fibroblast growth factor (FGF) family signaling largely controls cellular homeostasis through short-range intercell paracrine communication. Recently FGF15/19, 21, and 23 have been implicated in endocrine control of metabolic homeostasis. The identity and location of the FGF receptor isotypes that mediate these effects are unclear. The objective was to determine the role of FGFR4, an isotype that has been proposed to mediate an ileal FGF15/19 to hepatocyte FGFR4 axis in cholesterol homeostasis, in metabolic homeostasis in vivo.

RESEARCH DESIGN AND METHODS—FGFR4−/− mice—mice overexpressing constitutively active hepatic FGFR4—and FGFR4−/− with constitutively active hepatic FGFR4 restored in the liver were subjected to a normal and a chronic high-fat diet sufficient to result in obesity. Systemic and liver-specific metabolic phenotypes were then characterized.

RESULTS—FGFR4-deficient mice on a normal diet exhibited features of metabolic syndrome that include increased mass of white adipose tissue, hyperlipidemia, glucose intolerance, and insulin resistance, in addition to hypercholesterolemia. Surprisingly, the FGFR4 deficiency alleviated high-fat diet–induced fatty liver in obese mice, which is also a correlate of metabolic syndrome. Restoration of FGFR4, specifically in hepatocytes of FGFR4-deficient mice, decreased plasma lipid levels and restored the high-fat diet–induced fatty liver but failed to restore glucose tolerance and sensitivity to insulin.

CONCLUSIONS—FGFR4 plays essential roles in systemic lipid and glucose homeostasis. FGFR4 activity in hepatocytes that normally serves to prevent systemic hyperlipidemia paradoxically underlies the fatty liver disease associated with chronic high-fat intake and obesity.
Association of the Vitamin D Metabolism Gene CYP27B1 With Type 1 Diabetes
Authors: Bailey Rebecca , Cooper Jason D. , Zeitels Lauren , Smyth Deborah J. , Yang Jennie H.M. , Walker Neil M. , Hyppönen Elina , Dunger David B. , Ramos-Lopez Elizabeth , Badenhoop Klaus , Nejentsev Sergey , Todd John A.
Published: September 2007

OBJECTIVE—Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1α,25-dihydroxyvitamin D (1α,25(OH)2D) could protect from immune destruction of the pancreatic β-cells. 1α,25(OH)2D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1α-hydroxylase encoded by the CYP27B1 gene and is inactivated by 24-hydroxylase encoded by the CYP24A1 gene. Our aim was to study the association between the CYP27B1 and CYP24A1 gene polymorphisms and type 1 diabetes.

RESEARCH DESIGN AND METHODS—We studied 7,854 patients with type 1 diabetes, 8,758 control subjects from the U.K., and 2,774 affected families. We studied four CYP27B1 variants, including common polymorphisms −1260C>A (rs10877012) and +2838T>C (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene.

RESULTS—We found evidence of association with type 1 diabetes for CYP27B1 −1260 and +2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 −1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P = 9.6 × 10−4) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P = 3.9 × 10−3). The combined P value for an association with type 1 diabetes was 3.8 × 10−6. For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P = 0.23).

CONCLUSIONS—The present data provide evidence that common inherited variation in the vitamin D metabolism affects susceptibility to type 1 diabetes.
Glucagon, in Concert With Insulin, Supports the Postabsorptive Plasma Glucose Concentration in Humans
Authors: Breckenridge Suzanne M. , Cooperberg Benjamin A. , Arbelaez Ana Maria , Patterson Bruce W. , Cryer Philip E.
Published: September 2007

OBJECTIVE—Given the interest in glucagon antagonism as a potential treatment of diabetes, we tested the hypothesis that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans.

RESEARCH DESIGN AND METHODS—Following preliminary studies that indicated that a peripheral intravenous insulin dose of 0.1 mU · kg−1 · min−1 (lower than those used previously) provides basal insulin replacement and that a glucagon dose of 1.0 ng · kg−1 · min−1 underreplaces basal glucagon, we infused the somatostatin analog octreotide (30 ng · kg−1 · min−1) (with growth hormone replacement) over 4 h in 14 healthy adults on four separate occasions to produce endogenous insulin and glucagon deficiency with 1) saline (combined insulin and glucagon deficiency), 2) insulin replacement (isolated glucagon deficiency), 3) partial glucagon replacement (insulin and partial glucagon deficiency), and 4) insulin and partial glucagon replacement (partial glucagon deficiency).

RESULTS—During combined insulin and glucagon deficiency, glucose production decreased and then increased, and mean (±SE) plasma glucose decreased from 83 ± 1 to 63 ± 2 mg/dl at 60 min and then increased to 89 ± 3 mg/dl at 240 min. During isolated glucagon deficiency, plasma glucose decreased to hypoglycemic levels and was 55 ± 2 mg/dl at 240 min (P < 0.0001 vs. combined insulin and glucagon deficiency). Partial glucagon replacement raised plasma glucose to higher levels (P = 0.0469) during insulin deficiency and to higher levels (P = 0.0090) during insulin replacement.

CONCLUSIONS—These three findings provide direct evidence that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans.
Noninvasive Magnetic Resonance Imaging of Microvascular Changes in Type 1 Diabetes
Authors: Medarova Zdravka , Castillo Gerardo , Dai Guangping , Bolotin Elijah , Bogdanov Alexei , Moore Anna
Published: September 2007

OBJECTIVE— The pathogenesis of type 1 diabetes involves autoimmune lymphocytic destruction of insulin-producing β-cells and metabolic dysregulation. An early biomarker of pancreatic islet damage is islet microvascular dysfunction, and alterations in vascular volume, flow, and permeability have been reported in numerous models of type 1 diabetes. Consequently, the ability to noninvasively monitor the dynamics of the pancreatic microvasculature would aid in early diagnosis and permit the assessment, design, and optimization of individualized therapeutic intervention strategies.

RESEARCH DESIGN AND METHODS— Here, we used the long circulating paramagnetic contrast agent, protected graft copolymer (PGC) covalently linked to gadolinium-diethylenetriaminepentaacetic acid residues (GdDTPAs) labeled with fluorescein isothiocyanate (PGC-GdDTPA-F), for the noninvasive semiquantitative evaluation of vascular changes in a streptozotocin (STZ)-induced mouse model of type 1 diabetes. Diabetic animals and nondiabetic controls were monitored by magnetic resonance imaging (MRI) after injection of PGC-GdDTPA-F.

RESULTS— Our findings demonstrated a significantly greater accumulation of PGC-GdDTPA-F in the pancreata of diabetic animals compared with controls. MRI permitted the in vivo semiquantitative assessment and direct visualization of the differential distribution of PGC-GdDTPA-F in diabetic and control pancreata. Ex vivo histology revealed extensive distribution of PGC-GdDTPA-F within the vascular compartment of the pancreas, as well as considerable leakage of the probe into the islet interstitium. By contrast, in nondiabetic controls, PGC-GdDTPA-F was largely restricted to the pancreatic vasculature at the islet periphery.

CONCLUSIONS— Based on these observations, we conclude that in the STZ model of type 1 diabetes, changes in vascular volume and permeability associated with early stages of the disease can be monitored noninvasively and semiquantitatively by MRI.