bluuebunny/crossref_metadata_2025 huggingface dataset:
Mice expressing HLA-DQ6α8β transgenes develop polychondritis spontaneously
Authors: Lamoureux Jennifer L , Buckner Jane Hoyt , David Chella S , Bradley David S
Published: July 2006

Relapsing polychondritis (RP) is a human autoimmune disease of unknown etiology in which cartilaginous sites are destroyed by cyclic inflammatory episodes beginning, most commonly, during the fourth or fifth decade of life. We have previously described collagen-induced polychondritis that closely mirrors RP occurring in young (6–8 weeks old) HLA-DQ6αβ8αβ transgenic Aβ0 mice, following immunization with heterologous type II collagen (CII).

We present evidence here that transgenic strains expressing the DQ6α8β transgene develop spontaneous polychondritis (SP) at the mouse equivalent of human middle age (4.5–6 months and 40–50 years old, respectively) and display polyarthritis, auricular chondritis and nasal chondritis – three of the most common sites affected in RP. Auricular chondritis in SP, like RP but unlike CII-induced polychondritis, exhibited a relapsing/remitting phenotype, requiring several inflammatory cycles before the cartilage is destroyed. Elevated serum levels of total IgG corresponded with the onset of disease in SP, as in RP and CII-induced polychondritis. No CII-specific immune response was detected in SP, however – more closely mirroring RP, in which as few as 30% of RP patients have been reported to have CII-specific IgG. CII-induced polychondritis displays a strong CII-specific immune response. SP also demonstrated a strong female preponderance, as some workers have reported in RP but has not observed in CII-induced polychondritis. These characteristics of SP allow for the examination of the immunopathogenesis of polychondritis in the absence of an overwhelming CII-specific immune response and the strong adjuvant-induced immunostimulatory influence in CII-induced polychondritis.

This spontaneous model of polychondritis provides a new and unique tool to investigate both the initiatory events as well as the immunopathogenic mechanisms occurring at cartilaginous sites during the cyclic inflammatory assaults of polychondritis.
Holocene palaeoclimate reconstructions at Vanndalsvatnet, western Norway, with particular reference to the 8200 cal. yr BP event
Authors: Nesje Atle , Bjune Anne E. , Bakke Jostein , Dahl Svein Olaf , Lie Øyvind , Birks H. J.B.
Published: July 2006

Analyses of organic content, magnetic susceptibility, grain size and pollen in sediments from the proglacial lake Vanndalsvatnet in western Norway provide a high-resolution terrestrial record and pollen-based quantitative estimates of mean July and January temperatures and annual precipitation across the ∼ 8200 cal. yr BP event. Glaciers in the catchment melted away at approximately 8600 cal. yr BP. Immediately following deglaciation, a series of thin minerogenic layers indicate several abrupt, short-lived glacial episodes peaking at ∼ 8550, 8450, 8350, 8250, 8200, 7900, 7300 and 7150 cal. yr BP. A single, mid-Holocene glacial episode occurred at 4900-4800 cal. yr BP. Between 2000 and 1400 cal. yr BP, six short-lived glacial episodes occurred ∼ 2000, 1900, 1800, 1700, 1600, and 1500 cal. yr BP. The part of Spørteggbreen that drains to Vanndalsvatnet has existed continuously since ∼ 1400 cal. yr BP. Just prior to a first loss-on-ignition minimum reflecting a glacial episode centred at 8200 cal. yr BP, pollen-inferred July temperatures were relatively high, January temperatures were low, and annual precipitation was relatively low. During the period 8200-7900 cal. yr BP, July temperatures showed a falling trend. Both January temperature and annual precipitation, however, were relatively high. After 7900 cal. yr BP, July temperatures increased, but both January temperatures and annual precipitation were lower than in the preceding period. The pollen analytical and sedimentary data suggest that the glacial advance during the Finse event seems not to have been a response to cooler summers, but to milder winters and increasing precipitation (similar to a positive North Atlantic Oscillation weather mode).
The macroscopic charcoal record in forested boreal peatlands in southeast Norway
Authors: Ohlson Mikael , Korbøl Auen , Økland Rune H.
Published: July 2006

We present a spatial and quantitative analysis of the macroscopic charcoal record in 11 forested peat basins in a boreal forest landscape in southeast Norway. The areas of the basins ranged from 200 to 6400 m2 and our study is based on 247 peat sequences that were sampled from randomly selected positions. In total we found 1228 charcoal layers in these peat sequences, which altogether had a length of 551 m. The number of charcoal layers per sequence ranged from 0 to 31 and the average number of charcoal layers per sequence was 3.99±0.3 SE, giving a mean fire frequency of one per 475 years. The average charcoal layer contained 170 charcoal particles > 0.28 mm per 10 cm2, of which 30 were > 1 mm. Peat sequences that totally lacked macroscopic charcoal were found at all sites. Nonetheless, all sites have burned recurrently during the Holocene, since at least one sequence from each site had seven or more charcoal layers. Neither the number of layers nor particle size decreased with increasing distance to the surrounding forests, indicating an in situ charcoal production and deposition. The charcoal record was characterized by a striking spatial variability. Geostatistical analyses revealed a strong spatial structuring on fine scales, ie, c. 0.25-1.5 m, but there was no evidence for spatial structuring at between-site scales, demonstrating that the sites have idiosyncratic fire histories. The rate of charcoal deposition was greater for the period prior to establishment of Picea abies than for the post-establishment period.
Holocene development of the fauna of Lake Boeckella, northern Antarctic Peninsula
Authors: Gibson John A.E. , Zale Rolf
Published: July 2006

The origins of the freshwater fauna that inhabits Antarctic lakes are poorly known. The species present today could be relict species that have survived Quaternary glaciations on the continent, or Holocene migrants from more temperate regions. One approach to investigating these questions is to study faunal microfossils in lake sediment. This approach was applied to a 293 cm sediment core from Lake Boeckella, located at the northern tip of the Antarctic Peninsula. The microfossils indicated that most of the metazoan species that occur in the lake today have been present since soon after the lake’s formation c. 5.5 ka ago. In particular, the centropagid copepod Boeckella poppei (Mrázek) has been present throughout the lake’s history, suggesting a local source for this species. The development of biodiversity in the lake with time was in general more consistent with local (Antarctic) rather than distant (South American) sources, though an alternative explanation is that dispersal to Antarctica was more efficient in the mid-Holocene. Evidence of dispersal from extra-continental sites comes from the scattered occurrence throughout the core of Eubosmina chilensis (Daday), a South American species that does not reach the Antarctic or the sub-Antarctic islands at present, and which failed to establish a permanent population in the lake.
A late-Holocene record of loess deposition in ice-wedge polygons reflecting wind activity and ground moisture conditions, Bylot Island, eastern Canadian Arctic
Authors: Fortier Daniel , Allard Michel , Pivot Frédérique
Published: July 2006

On Bylot Island, a field of tundra polygons at the margin of a glacial outwash plain contains a well-preserved syngenetic permafrost sequence of ground ice and alternating loess and organic layers that was accumulated during the late Holocene. Periods of increased deposition of loess alternated with periods of growth of bryophytes during the last 3500 years. These shifts in soil accretion regime are interpreted in terms of significant shifts of the summer surface wind conditions and active layer moisture regime (Precipitation-Evaporation or P-E), in response to regional climatic variations and recurrent changes of atmospheric circulation. There was a high level of variability and large amplitude of the P-E regime and summer surface wind conditions on a decennial and secular timescale in general. However, according to the Greenland GISP2 bi-decennial oxygen isotopes data, there was a low variability and amplitude (by a few degrees centigrade or less) of the regional mean annual air temperature. From 2950 to 2750 cal. BP, the summer climate was warmer and had the strongest and most frequent northwesterly surface winds of the late Holocene. Shifts to a weaker northwesterly summer surface wind activity preceded the dryer episodes that occurred from 2750 to 2450 and around 1850 cal. BP. Major wetter episodes occurred from 2450 to 2350, around 2050, from 1750 to 1550, from 1350 to 1150 and from 550 to 250 cal. BP. There is no clear relationship between P-E or summer surface wind regimes and air temperatures. Shifts of late Holocene summer aeolian regime can probably be better explained by the recurrence of particular synoptic circulation types in response to changes in the position of the atmospheric eastern Canadian Polar Trough.
The late-Holocene origin of the modern Murray River course, southeastern Australia
Authors: Stone Tim
Published: July 2006

The modern course of the Murray River flows south around the Cadell Tilt Block in southeastern Australia. The avulsion that took the river in this direction formed the Barmah Choke, a reach with an unusually straight planform. This morphology has been used to argue Holocene inertia of the modern river system. The avulsion was initially placed at ∼ 10 ka on the basis of a single charcoal age. Optically stimulated luminescence (OSL) and AMS14C dating of deposits along the Barmah Choke demonstrates that the Murray has not been inert during this period. A digitate delta deposited on the floor of a palaeolake by the avulsion is only ∼ 550 years old. Point bar deposition along the Choke also began around this time. The Murray River probably followed the course of Bullatale Creek for most of the Holocene. It formed large, inset meander scrolls of Pleistocene ‘Kotupna-type’ along this creek course but without source-bordering dunes. The persistence of Kotupna-type bedload along this course suggests that there was no simple switch to suspended load channels at the Pleistocene/Holocene transition. The Barmah Choke avulsion trebled the discharge of the Goulburn River causing morphological adjustment and formation of new reaches downstream. The extensive Barmah and Gunbower-Koondrook red gum forests probably arose from the increased flood flows. Pollen and spores from lacustrine sediments beneath the Choke show that the vegetation ∼ 4000 years ago was very different. The lake and hinterland began to dry from this time and the lake became a swamp. A pedogenic interval shows that the swamp was dry for lengthy periods prior to deposition of the digitate delta.
FGF signaling is required for β-catenin-mediated induction of the zebrafish organizer
Authors: Maegawa Shingo , Varga Máté , Weinberg Eric S.
Published: July 2006

We have used the maternal effect mutant ichabod, which is deficient in maternal β-catenin signaling, to test for the epistatic relationship between β-catenin activation, FGF signaling and bozozok,squint and chordin expression. Injection of β-catenin RNA into ichabod embryos can completely rescue normal development. By contrast, when FGF signaling is inhibited, β-catenin did not induce goosecoid and chordin, repress bmp4 expression or induce a dorsal axis. These results demonstrate that FGF signaling is necessary for β-catenin induction of the zebrafish organizer. We show that FGFs function downstream of squint and bozozok to turn on chordin expression. Full rescue of ichabod by Squint is dependent on FGF signaling, and partial rescue by FGFs is completely dependent on chordin. By contrast, Bozozok can rescue the complete anteroposterior axis, but not notochord, in embryos blocked in FGF signaling. Surprisingly, accumulation of bozozok transcript in β-catenin RNA-injected ichabod embryos is also dependent on FGF signaling,indicating a role of FGFs in maintenance of bozozok RNA. These experiments show that FGF-dependent organizer function operates through both bozozok RNA accumulation and a pathway consisting ofβ-catenin→Squint→FGF→Chordin, in which each component is sufficient for expression of the downstream factors of the pathway, and in which Nodal signaling is required for FGF gene expression and FGF signaling is required for Squint induction of chordin.
Virus Transport in Saturated and Unsaturated Sand Columns
Authors: Torkzaban S. , Hassanizadeh S. M. , Schijven J. F. , de Bruin H. A. M. , de Roda Husman A. M.
Published: July 2006

The transport of viruses in unsaturated porous media has been a subject of great interest in recent years because of the enhanced removal of these microorganisms compared with saturated conditions. We studied the transport of bacteriophages MS2 and ϕX174, used as surrogate pathogenic viruses, at various water contents and solution chemistries in terms of pH and ionic strength (IS). The objective was to explore the interaction of viruses with the solid–water interfaces (SWI) and air–water interfaces (AWI) for a range of conditions. The experimental data were fitted with a transport model to determine the adsorption (attachment and detachment rate) parameters. Our results show that the retention of viruses in the soil column increases as water saturation decreases when the chemical conditions are favorable for adsorption (pH 7 and relatively high IS). Our analysis indicates that the enhanced retention of ϕX174 viruses at lower water contents is caused by increased attachment to the SWI and that retention by the AWI is not significant. Results obtained from a first series of experiments (pH 9 and low IS) showed insignificant attachment of MS2 viruses to both the SWI and the AWI. The MS2 breakthrough data for a second series of experiments (pH 7 and high IS) did not allow us to separate out the role of the AWI. Although attachment of MS2 viruses to the AWI cannot be ruled out in our experiments, we suspect that the increased retention of this phage under unsaturated condition was also due to enhanced attachment to the SWI. Increased attachment to the SWI under unsaturated conditions is attributed to increased mass transfer of viruses to the SWI due to a reduced diffusion length at lower water contents. Our results demonstrate that if there is any attachment to the AWI, it is reversible. When unfavorable conditions occur for attachment to the SWI, the attached viruses may be detached by moving solid–water–air contact lines (SWA).
The Relationship between Psychometric and Self-Estimated Intelligence, Creativity, Personality and Academic Achievement
Authors: Furnham Adrian , Zhang Jane , Chamorro-Premuzic Tomas
Published: July 2006

This longitudinal study aimed to explore the nature of the relationships between personality Big Five as measured by the (NEO PI-R), psychometric and self-estimated intelligence (Ravens, Wonderlic and Baddeley Tests) and creativity (Barron Welsh Test). A model was developed which proposed that both self-estimated intelligence (SEI) and creativity (SEC) as well as the Big Five personality traits, predicted both psychometric intelligence and creativity which in turn predicted academic performance. Results showed that Openness was significantly correlated with, and predicted, fluid intelligence (Ravens) as well as psychometric Creativity (Barron Welsh). SEI was found to be predictive of intelligence scores on all three IQ tests. Openness to Experience (positively) and Conscientiousness (negatively) was found to predict psychometric Creativity. Males gave consistently higher estimates than females in SEI and SEC. Academic performance was found to be predicted by trait Conscientiousness, and also by Baddeley (fluid intelligence). Implications of this study are discussed.
Failure Imagery Reduces Self-Reflectivity in Individuals High in Activity Inhibition
Authors: Langens Thomas A.
Published: July 2006

The present research tested the effects of failure imagery on the structure of conscious thought. Based on prior research which shows that (a) individuals high in activity inhibition (as measured by the picture-story exercise) tend to suppress negative mood-relevant thought and (b) suppression can be accomplished by shifting to a low level of thinking, it was assumed that failure imagery induces a shift toward low-level thinking in individuals high in activity inhibition. Participants had to imagine either successfully achieving two important goals they were currently pursuing or failing to do so. After the imagination task, they were asked to work on a stream-of-consciousness writing task. Protocols were analyzed for self-reflectivity (operationalized as the frequency of using the pronoun “I”) and awareness of emotions. The lowest level of self-reflectivity was found among individuals high in activity inhibition who imagined a failure of goal pursuit. This result is discussed with respect to the long-term consequences of suppressing negative mood-relevant thought.
Association Studies of Variants in the Genes Involved in Pancreatic β-Cell Function in Type 2 Diabetes in Japanese Subjects
Authors: Yokoi Norihide , Kanamori Masao , Horikawa Yukio , Takeda Jun , Sanke Tokio , Furuta Hiroto , Nanjo Kishio , Mori Hiroyuki , Kasuga Masato , Hara Kazuo , Kadowaki Takashi , Tanizawa Yukio , Oka Yoshitomo , Iwami Yukiko , Ohgawara Hisako , Yamada Yuichiro , Seino Yutaka , Yano Hideki , Cox Nancy J. , Seino Susumu
Published: July 2006

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic β-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2–2, NKX6–1, and NEUROD1) and genes encoding the ATP-sensitive K+ channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 −3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97–1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.
A Conditional Model Reveals That Induction of Hepatocyte Nuclear Factor-1α inHnf1α-Null Mutant β-Cells Can Activate Silenced Genes Postnatally, Whereas Overexpression Is Deleterious
Authors: Luco Reini F. , Maestro Miguel A. , del Pozo Natalia , Philbrick William M. , de la Ossa Pablo Perez , Ferrer Jorge
Published: July 2006

Humans with heterozygous loss-of-function mutations in the hepatocyte nuclear factor-1α (HNF1α) gene develop β-cell–deficient diabetes (maturity-onset diabetes of the young type 3), indicating that HNF1α gene dosage is critical in β-cells. However, whether increased HNF1α expression might be beneficial or deleterious for β-cells is unknown. Furthermore, although it is clear that HNF1α is required for β-cell function, it is not known whether this role is cell autonomous or whether there is a restricted developmental time frame for HNF1α to elicit gene activation in β-cells. To address this, we generated a tetracycline-inducible mouse model that transcribes HNF1α selectively in β-cells in either wild-type or Hnf1α-null backgrounds. Short-term induction of HNF1α in islets from adult Hnf1α−/− mice that did not express HNF1α throughout development resulted in the activation of target genes, indicating that HNF1α has β-cell–autonomous functions that can be rescued postnatally. However, transgenic induction throughout development, which inevitably resulted in supraphysiological levels of HNF1α, strikingly caused a severe reduction of cellular proliferation, increased apoptosis, and consequently β-cell depletion and diabetes. Thus, HNF1α is sensitive to both reduced and excessive concentrations in β-cells. This finding illustrates the paramount importance of using the correct concentration of a β-cell transcription factor in both gene therapy and artificial differentiation strategies.
Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Convertase PC2 Leads to Amyloid Formation and Cell Death
Authors: Marzban Lucy , Rhodes Christopher J. , Steiner Donald F. , Haataja Leena , Halban Philippe A. , Verchere C. Bruce
Published: July 2006

Islet amyloid, formed by aggregation of islet amyloid polypeptide (IAPP; amylin), is a pathological characteristic of the pancreas in type 2 diabetes and may contribute to the progressive loss of β-cells in this disease. We tested the hypothesis that impaired processing of the IAPP precursor proIAPP contributes to amyloid formation and cell death. GH3 cells lacking the prohormone convertase 1/3 (PC1/3) and IAPP and with very low levels of prohormone convertase 2 (PC2) were transduced with adenovirus (Ad) expressing human or rat (control) proIAPP linked to green fluorescent protein, with or without Ad-PC2 or Ad-PC1/3. Expression of human proIAPP increased the number of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells 96 h after transduction (+hIAPP 8.7 ± 0.4% vs. control 3.0 ± 0.4%; P < 0.05). COOH-terminal processing of human proIAPP by PC1/3 increased (hIAPP+PC1/3 10.4 ± 0.7%; P < 0.05), whereas NH2-terminal processing of proIAPP by addition of PC2 markedly decreased (hIAPP+PC2 5.5 ± 0.5%; P < 0.05) the number of apoptotic GH3 cells. Islets from mice lacking PC2 and with β-cell expression of human proIAPP (hIAPP+/+/PC2−/−) developed amyloid associated with β-cell death during 2-week culture. Rescue of PC2 expression by ex vivo transduction with Ad-PC2 restored NH2-terminal processing to mature IAPP and decreased both the extent of amyloid formation and the number of TUNEL-positive cells (−PC2 26.5 ± 4.1% vs. +PC2 16.1 ± 4.3%; P < 0.05). These findings suggest that impaired NH2-terminal processing of proIAPP leads to amyloid formation and cell death and that accumulation of the NH2-terminally extended human proIAPP intermediate may be a critical initiating step in amyloid formation.
Insulin Resistance Is Associated With Increased Serum Concentration of IGF-Binding Protein–Related Protein 1 (IGFBP-rP1/MAC25)
Authors: López-Bermejo Abel , Khosravi Javad , Fernández-Real José Manuel , Hwa Vivian , Pratt Katherine L. , Casamitjana Roser , Garcia-Gil Maria M. , Rosenfeld Ron G. , Ricart Wifredo
Published: July 2006

IGF-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-rP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [Si] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [KITT] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-rP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-rP1 exhibited decreased Si and adiponectin (both P < 0.01) as well as increased CRP and sTNFR2 (both P < 0.05). Circulating IGFBP-rP1 was also found to be increased in previously undiagnosed type 2 diabetic patients (P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-rP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-rP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-rP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, Si, sTNFR2, and age stood as independent predictive variables of IGFBP-rP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-rP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans.
Effects of Recombinant Human IGF-I/IGF-Binding Protein-3 Complex on Glucose and Glycerol Metabolism in Type 1 Diabetes
Authors: Saukkonen Tero , Shojaee-Moradie Fariba , Williams Rachel M. , Amin Rakesh , Yuen Kevin C. , Watts Angie , Acerini Carlo L. , Umpleby A. Margot , Dunger David B.
Published: July 2006

Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13–24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1–0.8 mg · kg−1 · day −1) was given subcutaneously at 6:00 p.m. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU · kg−1 · min −1) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/IGFBP-3 dose-dependently reduced endogenous glucose production rate (Ra) (P = 0.004), while peripheral glucose uptake (Rd) was not different from placebo. The increase in glucose Rd during hyperinsulinemic clamp was greater following rhIGF-I/IGFBP-3 than placebo, both during the first (P = 0.008) and second step (P = 0.008) of the clamp. No significant differences were found in glycerol Ra, a measure of lipolysis, between rhIGF-I/IGFBP-3 and placebo. In conclusion, rhIGF-I/IGFBP-3 enhances glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake.
Intrahepatic Transplanted Islets in Humans Secrete Insulin in a Coordinate Pulsatile Manner Directly Into the Liver
Authors: Meier Juris J. , Hong-McAtee Irene , Galasso Ryan , Veldhuis Johannes D. , Moran Antoinette , Hering Bernhard J. , Butler Peter C.
Published: July 2006

Intrahepatic islet transplantation is an experimental therapy for type 1 diabetes. In the present studies, we sought to address the following questions: 1) In humans, do intrahepatic transplanted islets reestablish coordinated puslatile insulin secretion? and 2) To what extent is insulin secreted by intrahepatic transplanted islets delivered to the hepatic sinusoids (therefore effectively restoring a portal mode of insulin delivery) versus delivered to the hepatic central vein (therefore effectively providing a systemic form of insulin delivery)? To address the first question, we examined insulin concentration profiles in the overnight fasting state and during a hyperglycemic clamp (∼150 mg/dl) in 10 recipients of islet transplants and 10 control subjects. To address the second question, we measured first-pass hepatic insulin clearance in two recipients of islet autografts after pancreatectomy for pancreatitis versus five control subjects by direct catheterization of the hepatic vein. We report that coordinate pulsatile insulin secretion is reestablished in islet transplant recipients and that glucose-mediated stimulation of insulin secretion is accomplished by amplification of insulin pulse mass. Direct hepatic catheterization studies revealed that intrahepatic islets in humans do deliver insulin directly to the hepatic sinusoid because ∼80% of the insulin is extracted during first pass. In conclusion, intrahepatic islet transplantation effectively restores the liver to pulsatile insulin delivery.
Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations
Authors: Salehi Albert , Vieira Elaine , Gylfe Erik
Published: July 2006

Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25–30 mmol/l and In-R1-G9 cells at 12–20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the α-cells. Studies of isolated mouse α-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca2+ concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion. A U-shaped dose-response relationship for glucose-regulated glucagon secretion may explain why diabetic patients with pronounced hyperglycemia display paradoxical hyperglucagonemia.
α-Lipoic Acid Prevents the Increase in Atherosclerosis Induced by Diabetes in Apolipoprotein E–Deficient Mice Fed High-Fat/Low-Cholesterol Diet
Authors: Yi Xianwen , Maeda Nobuyo
Published: July 2006

Considerable evidence indicates that hyperglycemia increases oxidative stress and contributes to the increased incidence of atherosclerosis and cardiovascular complications in diabetic patients. To examine the effect of α-lipoic acid, a potent natural antioxidant, on atherosclerosis in diabetic mice, 3-month-old apolipoprotein (apo) E-deficient (apoE−/−) mice were made diabetic by administering streptozotocin (STZ). At 4 weeks after starting the STZ administration, a high-fat diet with or without α-lipoic acid (1.65 g/kg) was given to the mice and to nondiabetic apoE−/− controls. At 20 weeks, markers of oxidative stress were significantly lower in both the diabetic apoE−/− mice and their nondiabetic apoE−/− controls with α-lipoic acid supplement than in those without it. Remarkably, α-lipoic acid completely prevented the increase in plasma total cholesterol, atherosclerotic lesions, and the general deterioration of health caused by diabetes. These protective effects of α-lipoic acid were accompanied by a reduction of plasma glucose and an accelerated recovery of insulin-producing cells in the pancreas, suggesting that part of its effects are attributable to protecting pancreatic β-cells from damage. Our results suggest that dietary α-lipoic acid is a promising protective agent for reducing cardiovascular complications of diabetes.
Noninvasive Analysis of Hepatic Glycogen Kinetics Before and After Breakfast with Deuterated Water and Acetaminophen
Authors: Jones John G. , Fagulha Ana , Barosa Cristina , Bastos Margarida , Barros Luisa , Baptista Carla , Caldeira M. Madalena , Carvalheiro Manuela
Published: July 2006

The contributions of hepatic glycogenolysis to fasting glucose production and direct pathway to hepatic glycogen synthesis were quantified in eight type 1 diabetic patients and nine healthy control subjects by ingestion of 2H2O and acetaminophen before breakfast followed by analysis of urinary water and acetaminophen glucuronide. After overnight fasting, enrichment of glucuronide position 5 relative to body water (G5/body water) was significantly higher in type 1 diabetic patients compared with control subjects, indicating a reduced contribution of glycogenolysis to glucose production (38 ± 3 vs. 46 ± 2%). Following breakfast, G5/body water was significantly higher in type 1 diabetic patients, indicating a smaller direct pathway contribution to glycogen synthesis (47 ± 2 vs. 59 ± 2%). Glucuronide hydrogen 2 enrichment (G2) was equivalent to body water during fasting (G2/body water 0.94 ± 0.03 and 1.02 ± 0.06 for control and type 1 diabetic subjects, respectively) but was significantly lower after breakfast (G2/body water 0.78 ± 0.03 and 0.82 ± 0.05 for control and type 1 diabetic subjects, respectively). The reduced postprandial G2 levels reflect incomplete glucose-6-phosphate–fructose-6-phosphate exchange or glycogen synthesis from dietary galactose. Unlike current measurements of human hepatic glycogen metabolism, the 2H2O/acetaminophen assay does not require specialized on-site clinical equipment or personnel.
Benfotiamine Counteracts Glucose Toxicity Effects on Endothelial Progenitor Cell Differentiation via Akt/FoxO Signaling
Authors: Marchetti Valentina , Menghini Rossella , Rizza Stefano , Vivanti Alessia , Feccia Tiziana , Lauro Davide , Fukamizu Akiyoshi , Lauro Renato , Federici Massimo
Published: July 2006

Dysfunction of mature endothelial cells is thought to play a major role in both micro- and macrovascular complications of diabetes. However, recent advances in biology of endothelial progenitor cells (EPCs) have highlighted their involvement in diabetes complications. To determine the effect of glucotoxicity on EPCs, human EPCs have been isolated from peripheral blood mononuclear cells of healthy donors and cultured in the presence or absence of high glucose (33 mmol/l) or high glucose plus benfotiamine to scavenge glucotoxicity. Morphological analysis revealed that high glucose significantly affected the number of endothelial cell colony forming units, uptake and binding of acLDL and Lectin-1, and the ability to differentiate into CD31- and vascular endothelial growth factor receptor 2–positive cells. Functional analysis outlined a reduced EPC involvement in de novo tube formation, when cocultured with mature endothelial cells (human umbilical vein endothelial cells) on matrigel. To explain the observed phenotypes, we have investigated the signal transduction pathways known to be involved in EPC growth and differentiation. Our results indicate that hyperglycemia impairs EPC differentiation and that the process can be restored by benfotiamine administration, via the modulation of Akt/FoxO1 activity.
Impact of Chromosome 2 Obesity Loci on Cardiovascular Complications of Insulin Resistance in LDL Receptor–Deficient C57BL/6 Mice
Authors: Estrada-Smith Daria , Collins Alan R. , Wang Xuping , Crockett Craig , Castellani Lawrence , Lusis Aldons J. , Davis Richard C.
Published: July 2006

Previous characterization of mouse chromosome 2 identified genomic intervals that influence obesity, insulin resistance, and dyslipidemia. For this, resistant CAST/Ei (CAST) alleles were introgressed onto a susceptible C57BL/6J background to generate congenic strains with CAST alleles encompassing 67–162 Mb (multigenic obesity 6 [MOB6]) and 84–180 Mb (MOB5) from mouse chromosome 2. To examine the effects of each congenic locus on atherosclerosis and glucose disposal, we bred each strain onto a sensitizing LDL receptor–null (LDLR−/−) C57BL/6J background to predispose them to hypercholesterolemia and insulin resistance. LDLR−/− congenics and controls were characterized for measures of atherogenesis, insulin sensitivity, and obesity. We identified a genomic interval unique to the MOB6 congenic (72–84 Mb) that dramatically decreased atherosclerosis by approximately threefold and decreased insulin resistance. This region also reduced adiposity twofold. Conversely, the congenic region unique to MOB5 (162–180 Mb) increased insulin resistance but had little effect on atherosclerosis and adiposity. The MOB congenic intervals are concordant to human and rat quantitative trait loci influencing diabetes and atherosclerosis traits. Thus, our results define a strategy for studying the poorly understood interactions between diabetes and atherosclerosis and for identifying genes underlying the cardiovascular complications of insulin resistance.
Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α
Authors: Draznin Boris
Published: July 2006

Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible for insulin resistance in the majority of patients lies at the postreceptor level of insulin signaling. Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. However, the nature of the triggering event(s) remains largely enigmatic. Two separate, but likely, complementary mechanisms have recently emerged as a potential explanation. First, it became apparent that serine phosphorylation of IRS proteins can reduce their ability to attract PI 3-kinase, thereby minimizing its activation. A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. Additionally, mitochondrial dysfunction has been suggested to trigger activation of several serine kinases, leading to a serine phosphorylation of IRS-1. Second, a distinct mechanism involving increased expression of p85α has also been found to play an important role in the pathogenesis of insulin resistance. Conceivably, a combination of both increased expression of p85α and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance.
Intensive Insulin Therapy in the Intensive Care Unit
Authors: De Block Christophe , Manuel-y-Keenoy Begoña , Van Gaal Luc , Rogiers Peter
Published: July 2006

OBJECTIVE—Hyperglycemia occurs in most critically ill patients. Using continuous glucose monitoring (CGM), we investigated whether intensive insulin therapy based on discontinuous glucose monitoring can achieve normoglycemia (80–110 mg/dl) in a medical intensive care unit (MICU).

RESEARCH DESIGN AND METHODS—Fifty adults (men/women 31/19, age 62 ± 16 years, nondiabetic/diabetic 30/20, intravenous/subcutaneous insulin 22/28, and Acute Physiology and Chronic Health Evaluation II score 22 ± 7) were prospectively recruited. Forty-eight–hour CGM was performed using a subcutaneous glucose sensor (GlucoDay) and compared with arterial glycemia. Main outcome measures were percent of time in normoglycemia and accuracy/applicability of CGM.

RESULTS—During 48-h CGM, glycemia reached target (80–110 mg/dl) in only 22 ± 18%, was >140 mg/dl in 39 ± 27%, and was <60 mg/dl in 5 ± 10% of the time. Patients on subcutaneous versus intravenous insulin had more glycemia readings >110 mg/dl (P = 0.016). Glycemia was higher in diabetic patients (170 ± 77 vs. 129 ± 35 mg/dl, P = 0.013). BMI was an independent determinant for bad glycemic control (β = 0.73, P < 0.0001). Diabetic state (β = 0.47, P < 0.0001), septic shock (β = 0.22, P = 0.045), sequential organ failure assessment score (β = 0.40, P = 0.001), and use of corticoids (β = 0.28, P = 0.014) and inotropics (β = −0.24, P = 0.035) were independent determinants of insulin dose. GlucoDay values and arterial glycemia correlated well (r = 0.85, P < 0.0001, n = 555 after six-point calibration), with 97% of data falling in regions A and B of error grid analysis. There were no adverse events using GlucoDay.

CONCLUSIONS—GlucoDay, a well-tolerated 48-h CGM system, revealed that normoglycemia was only achieved 22% of the time in MICU patients. Further studies should investigate whether application of CGM to titrate insulin therapy can improve patient outcome.
Clinical Effectiveness of First and Repeat Influenza Vaccination in Adult and Elderly Diabetic Patients
Authors: Looijmans-Van den Akker Ingrid , Verheij Theo J.M. , Buskens Erik , Nichol Kristin L. , Rutten Guy E.H.M. , Hak Eelko
Published: July 2006

OBJECTIVE—Influenza vaccine uptake remains low among the high-risk group of patients with diabetes, partly because of conflicting evidence regarding its potential benefits. We assessed the clinical effectiveness of influenza vaccination in adults with diabetes and specifically examined potential modification of effect by age and prior influenza vaccine uptake.

RESEARCH DESIGN AND METHODS—The study was part of the Prevention of Influenza, Surveillance and Management (PRISMA) study, a nested case-control study conducted during the 1999–2000 influenza A epidemic, among 75,235 patients from primary care of any age recommended for vaccination. Among 9,238 adult patients with diabetes, 131 cases arose who were either hospitalized for diabetes dysregulation, acute respiratory disease, or cardiovascular disease and 61 cases who died, and we compared them with 1,561 control subjects. We evaluated the effect of (prior) influenza vaccination by means of logistic regression analysis controlling for age, sex, health insurance coverage, prior health care use, medication use, and comorbid conditions.

RESULTS—Vaccination was associated with a 56% reduction in any complication (95% CI 36–70%), a 54% reduction in hospitalizations (26–71%), and 58% reduction in deaths (13–80%). Among study subjects aged 18–64 years, we observed somewhat higher reductions in the occurrence of any complication than among those aged >65 years (72 vs. 39%). In first-time vaccinated subjects, the primary end point was reduced by 47% (0.2–72%), and in those who received vaccination in the year before, the reduction was 58% (4–81%).

CONCLUSIONS—Adults with type 2 diabetes, like other individuals from recognized risk groups, benefit considerably from influenza vaccination, and no difference in vaccine effectiveness was observed between first-time and repeat vaccination.
Systematic Evaluation of the Quality of Randomized Controlled Trials in Diabetes
Authors: Montori Victor M. , Wang Yaqian Grace , Alonso-Coello Pablo , Bhagra Sumit
Published: July 2006

OBJECTIVE—We sought to systematically ascertain the quality of randomized controlled trials (RCTs) in diabetes.

RESEARCH DESIGN AND METHODS—We identified the 10 most recently published trials as of 31 October 2003 in each of six general medical, five diabetes, and five metabolism and nutrition journals and further enriched our sample with 10 additional RCTs from each of five journals that published the most eligible RCTs in a year. We explored the association between trial characteristics and reporting quality using univariate analyses and a preplanned multivariate regression model.

RESULTS—After excluding redundant reports of included trials and one trial that measured outcomes on the health system and not on patients, we included 199 RCTs: 119 assessed physiological and other laboratory outcomes, 42 assessed patient-important outcomes (e.g., morbidity and mortality, quality of life), and 38 assessed surrogate outcomes (e.g., disease progression or regression, HbA1c, cholesterol). Fifty-three percent were of low methodological quality, as were one-third (36–40%) of trials reporting patient-important or surrogate outcomes and two-thirds (64%) of laboratory investigations. Independent predictors of low quality were nonprofit funding source (odds ratio 3.1 [95% CI 1.5–6.2]), measure of physiological and laboratory outcomes (2.3 [1.2–4.4]), and cross-over design (2.3 [1.1–4.8]), all characteristics of laboratory clinical investigations.

CONCLUSIONS—There is ample room for improving the quality of diabetes trials. To enhance the practice of evidence-based diabetes care, trialists need to pay closer attention to the rigorous implementation and reporting of important methodological safeguards against bias in randomized trials.
Effects of Traditional and Western Environments on Prevalence of Type 2 Diabetes in Pima Indians in Mexico and the U.S.
Authors: Schulz Leslie O. , Bennett Peter H. , Ravussin Eric , Kidd Judith R. , Kidd Kenneth K. , Esparza Julian , Valencia Mauro E.
Published: July 2006

OBJECTIVE—Type 2 diabetes and obesity have genetic and environmental determinants. We studied the effects of different environments on these diseases in Pima Indians in Mexico and the U.S.

RESEARCH DESIGN AND METHODS—Adult Pima-Indian and non-Pima populations in the Sierra Madre mountains of Mexico were examined using oral glucose tolerance tests and assessments for obesity, physical activity, and other risk factors. Results were compared with those from Pima Indians in Arizona. Both Pima populations were typed for DNA polymorphisms to establish their genetic similarity.

RESULTS—The age- and sex-adjusted prevalence of type 2 diabetes in the Mexican Pima Indians (6.9%) was less than one-fifth that in the U.S. Pima Indians (38%) and similar to that of non-Pima Mexicans (2.6%). The prevalence of obesity was similar in the Mexican Pima Indians (7% in men and 20% in women) and non-Pima Mexicans (9% in men and 27% in women) but was much lower than in the U.S. Pima Indians. Levels of physical activity were much higher in both Mexican groups than in the U.S. Pima Indians. The two Pima groups share considerable genetic similarity relative to other Native Americans.

CONCLUSIONS—The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. This study provides compelling evidence that changes in lifestyle associated with Westernization play a major role in the global epidemic of type 2 diabetes.