bluuebunny/crossref_metadata_2025 huggingface dataset:
Peroxisome proliferator-activated receptor α deficiency modifies glucose handling by isolated mouse adipocytes
Authors: Walker C G , Sugden M C , Gibbons G F , Holness M J
Published: March 2007

Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates enzymes involved in fatty acid (FA) utilisation. PPARα null mice have recently been demonstrated to have increased whole-body glucose turnover in vivo. This has been attributed to increased glucose uptake by adipose tissue, but the impact of PPARα deficiency on the characteristics of glucose handling by isolated adipocytes ex vivo is unknown. To determine directly the impact of PPARα deficiency on adipocyte glucose handling, thereby excluding any influence of humoral/neuronal factors, we examined total glucose metabolism as well as glucose disposition towards alternative fates in epididymal adipocytes isolated from wild-type and PPARαnull mice. Total glucose metabolism (oxidation, incorporation into FA and glycerol moieties of triglyceride (TAG) and conversion to lactate) was measured under basal conditions (low glucose) and ‘stimulated lipogenic’ conditions (high glucose + insulin). Adipocytes from PPARα null mice had higher rates of glucose metabolism under both basal and stimulated lipogenic conditions, with increased glucose utilisation both for oxidation and entry into the synthesis of the FA and glycerol components of lipid. In particular, the capacity of adipocytes from PPARα-deficient mice to utilise glucose for synthesis of the glycerol backbone of TAG was greatly enhanced under stimulated (high glucose + insulin) conditions. The increased use of glucose for the glycerol moiety of adipocyte TAG may therefore contribute to, and provide explanation for, enhanced glucose turnover in PPARα null mice.
Strength, ductility and stiffness of fibre-reinforced shotcrete
Authors: Malmgren L.
Published: March 2007

In mining flexible linings are preferred because large displacements of underground openings are often allowed. This often results in extensive cracking of the shotcrete. Therefore, ductility of shotcrete is very important. In an investigation comprising 45 beam tests and 33 panel tests, Young's modulus, residual flexural strength and absorbed energy were determined for shotcrete reinforced by polypropylene fibres, steel fibres and steel mesh. The residual flexural strength was determined as the average strength over the displacement range 0–4 mm. Beams reinforced with steel fibres had higher residual flexural strength than beams reinforced with polypropylene fibres or steel mesh. The shotcrete reinforced with steel fibres and the best polypropylene fibres had almost the same energy absorption in the panel tests (0–25 mm displacement range) as well as in the beam tests (0–20 mm displacement range). Young's modulus of reinforced shotcrete determined by beam tests was lower than that derived from compression tests of cast concrete
Seismic deformation capacity indices for concrete columns: model estimates and experimental results
Authors: Inel M. , Aschheim M. A. , Pantazopoulou S. J.
Published: March 2007

The transition to displacement-controlled methods for seismic design relies on explicit measures of deformation capacity. Although conceptually clearly defined, the various alternative indices such as displacement ductility, drift and plastic rotation capacity calculated with the available analytical tools in the literature are marked by excessive scatter when tested with well-controlled experimental results, indicating that the validity of the underlying physical models is questionable. This problem is explored systematically in the current paper, by evaluating the parametric performance of the analytical models, as well as through comparison with the experimental trends. An important result of the present study is that well-confined members designed as per the ATC-32 requirements have large dependable deformation capacities regardless of the axial load ratio, a finding with significant implications in practical bridge seismic design.
Changes in Socioeconomic Inequalities in Cancer Mortality Rates Among French Men Between 1968 and 1996
Authors: Menvielle Gwenn , Leclerc Annette , Chastang Jean-François , Melchior Maria , Luce Danièle
Published: March 2007

Objectives. We investigated changes in socioeconomic inequalities in cancer mortality rates among men in France between 1968 and 1996.

Methods. We used a representative sample of 1% of the French population and studied 4 periods (1968–1974, 1975–1981, 1982–1988, and 1990–1996). Causes of death were obtained by direct linkage with the French national death registry. The socioeconomic position of men aged 35 to 59 years was measured by using the occupational class reported at the time of the census at the beginning of each period. Analyses were conducted for all cancers and specifically for lung, upper aerodigestive tract, esophageal, colorectal, and other cancers.

Results. In all analyses, we observed socioeconomic inequalities during the 4 periods considered; the inequalities increased between the first and the last period. Most of the total increase occurred between 1968 and 1981, and inequalities remained stable thereafter. Inequalities were larger when men out of the labor force were included in the analysis. The strongest increase in socioeconomic inequalities over time was observed for upper aerodigestive tract cancer.

Conclusions. Although cancer mortality rates have decreased, substantial socioeconomic inequalities in cancer mortality among men remain.
A toast to our health: our journey toward safe water
Authors: Rose J.B. , Masago Y.
Published: March 2007

Human beings have been struggling against epidemics for centuries but the first recorded epidemic in Egypt goes back to 3180 BC. Historically, it was not recognized that many of these “plagues” were waterborne. Advancements in medicine and microbiological sciences which identified and isolated the pathogens were needed before “safer” water could be achieved through advances in engineering. Disinfection of drinking water, introduced at the end of 19th century, considerably reduced the spread of cholera and typhoid fever. However, despite these innovations, waterborne disease epidemics continue even in the 20th century. We contend that this is partly because little attention has been paid to sewage practices and these are directly related to our health as the source of contamination, while much attention has been focused on drinking water. We propose that to achieve “safe water” and an improvement in global health worldwide in the 21st century, we must address wastewater problems learning from the past and we must use new advances such as molecular microbiology for pathogen discovery, and characterization and control of emerging and re-emerging waterborne diseases.
Soil as a wastewater treatment system: historical development
Authors: Tzanakakis V.E. , Paranychianaki N.V. , Angelakis A.N.
Published: March 2007

“Land treatment” refers to the application of wastewater to the soil to achieve treatment and to meet irrigation needs of the vegetation. Application of wastewater to the land was the first practice used to protect public health and control environmental pollution. This technology has gone through different stages of development with time but it was not until 1840s when the basic principles of this technology started to establish. The use of land treatment for wastewater treatment declined after the development of conventional treatment plants but a renewed interested occurred after the passage of Clean Water Act and especially, during the last two decades. Currently, its application has been expanded in the management of various types of wastewaters including dairy, meat, industrial effluents as well as and polluted water sources. It is recognized as the ideal technology for rural communities, clusters of homes and small industrial units due to low energy demands and low operation and maintenance costs. Furthermore, in conjunction with biomass production can contribute in the control of climate change. A brief historical overview along with an introduction to the fundamental processes the current trends and the future prospects are provided in this section.
Water management in Minoan Crete, Greece: the two cisterns of one Middle Bronze Age settlement
Authors: Cadogan G.
Published: March 2007

The two earliest structures of Minoan Crete that may be considered as large cisterns were both built in the first half of the second millennium BC (the time of the first Minoan palaces) at Myrtos-Pyrgos (Ierapetra). A considerable feat of engineering and social management, they remain a most unusual attribute of a Minoan settlement, all the more so since the Myrtos river is/was available to supply water at the foot of the hill of Pyrgos. This paper presents these cisterns, briefly, in terms of geology and technology, the history of their use and re-use, and their relevance to understanding the culture and society (at local and regional levels) of Crete in the time of the Old Palaces, as well as their possible contribution to the political and military history of the period. I then review possible precursors of, and architectural parallels to, the Pyrgos cisterns at Knossos, Malia and Phaistos (none of which has been proved to be a cistern), and the later history of cisterns in Bronze Age Crete. Since only three others are known (at Archanes, Zakro and Tylissos, of Late Bronze Age date), the two cisterns of Myrtos-Pyrgos are an important addition to our still rudimentary knowledge of how the Bronze Age Cretans managed their water supplies.
Water supply of ancient Greek cities
Authors: Tassios T.P.
Published: March 2007

This is a short presentation of some typical cases of water supply schemes of ancient Greek cities. Mycenaean spring chambers and access tunnels are first briefly mentioned. Subsequently, the Peisistratos Aqueduct of Ancient Athens is described, together with the water reservoir of Theagenes in Megara. Finally, the long aqueducts of the Greek cities in Asia Minor during the Hellenistic period are mentioned, and the specific case of ancient city of Pergamos is presented. Its 3 km long siphon is discussed, and details about its lead pipes are given.
Irrigation in the Indus basin: A history of unsustainability?
Authors: Alam U. , Sahota P. , Jeffrey P.
Published: March 2007

The Indus basin civilization (3000–1500 BC) is thought to have collapsed due to the Indus river shifting its course, and unchecked salinization of the irrigated land. Though modern irrigation practices in the Indus basin do not have to worry about the river shifting its course, a priority concern should be the basin's salt profile. Despite attempts to deal with the problem since the 1960 s, the net result is still an increasing salt balance which threatens the system's sustainability. This paper explores what it means to manage risk, and then applies these insights to a narrative history of the Indus basin. Particular focus is placed on the basin's current management since it will shape how irrigation is managed in the future. A key lesson to derive is that given the short-term nature of decision-making in the basin, any significant change has to address the political reality whereby politicians exert influence over water allocations in order to safeguard their political lives.
Minimal Impact of a De Novo–Expressed β-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice
Authors: Martinic Marianne M. , Juedes Amy E. , Bresson Damien , Homann Dirk , Skak Kresten , Huber Christoph , Ling Eleanor , Ejrnaes Mette , Wolfe Tom , Togher Lisa , Christen Urs , von Herrath Matthias G.
Published: March 2007

During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such “antigenic spreading” can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic β-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo–expressed β-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.
Phenotype and Functional Characteristics of Islet-Infiltrating B-Cells Suggest the Existence of Immune Regulatory Mechanisms in Islet Milieu
Authors: Puertas Maria Carmen , Carrillo Jorge , Pastor Xavier , Ampudia Rosa Maria , Alba Aurora , Planas Raquel , Pujol-Borrell Ricardo , Vives-Pi Marta , Verdaguer Joan
Published: March 2007

B-cells participate in the autoimmune response that precedes the onset of type 1 diabetes, but how these cells contribute to disease progression is unclear. In this study, we analyzed the phenotype and functional characteristics of islet-infiltrating B-cells in the diabetes-prone NOD mouse and in the insulitis-prone but diabetes-resistant (NOD×NOR)F1 mouse. The results indicate that B-cells accumulate in the islets of both mice influenced by sex traits. Phenotypically and functionally, these B-cells are highly affected by the islet inflammatory milieu, which may keep them in a silenced status. Moreover, although islet-infiltrating B-cells seem to be antigen experienced, they can only induce islet-infiltrating T-cell proliferation when they act as accessory cells. Thus, these results strongly suggest that islet-infiltrating B-cells do not activate islet-infiltrating T-cells in situ, although they may affect the progression of the disease otherwise.
Insulin-Expressing Colonies Developed From Murine Embryonic Stem Cell–Derived Progenitors
Authors: Ku Hsun Teresa , Chai Jing , Kim Yoon-Jung , White Peter , Purohit-Ghelani Sheetal , Kaestner Klaus H. , Bromberg Jonathan S.
Published: March 2007

Previous studies describe a unique culture method for the commitment of murine embryonic stem cells to early endocrine pancreata. In this report, early pancreatic-like β-cell progenitors were enriched and a colony assay devised to allow these progenitors to differentiate into insulin-expressing colonies in vitro. An embryonic stem cell line with enhanced green fluorescent protein (EGFP) inserted into one allele of neurogenin 3 (Ngn3), a marker for pancreatic endocrine progenitors, was differentiated. During the late stage of culture, 20–30% of cells were Ngn3-EGFP+. Gene expression profiling using the PancChip microarray platform demonstrated that Ngn3-EGFP+ cells differentially express endocrine-related genes. A novel semisolid culture method was developed to support the formation of individual insulin/C-peptide–expressing colonies from dissociated single cells. Approximately 0.1–0.6% of Ngn3-EGFP+ cells gave rise to insulin-expressing colonies, a three- to fivefold enrichment of β-cell–like progenitors, or insulin-expressing colony-forming units (ICFUs), compared with nonsorted cells. All of the single colonies expressed insulin II, while 69% coexpressed insulin I and 44% coexpressed glucagon. Some single colonies expressed insulin I, insulin II, and Pdx-1 (pancreatic duodenal homeobox–1), but not glucagon. In other colonies, glucagon expression overlapped with C-peptide II in double immunostaining analysis, suggesting heterogeneity among the ICFUs and their resulting colonies. Together, these results demonstrate that progenitors that have the potential to give rise to insulin-expressing cells can be derived from murine embryonic stem cells.
Chronic Treatment With Sildenafil Improves Energy Balance and Insulin Action in High Fat–Fed Conscious Mice
Authors: Ayala Julio E. , Bracy Deanna P. , Julien Brianna M. , Rottman Jeffrey N. , Fueger Patrick T. , Wasserman David H.
Published: March 2007

Stimulation of nitric oxide–cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat–fed mice treated with sildenafil plus l-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus l-arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without l-arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperinsulinemic (4 mU · kg−1 · min−1)–euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat–fed mice with sildenafil plus l-arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance.
Factors Associated With Diabetes Onset During Metformin Versus Placebo Therapy in the Diabetes Prevention Program
Authors: Lachin John M. , Christophi Costas A. , Edelstein Sharon L. , Ehrmann David A. , Hamman Richard F. , Kahn Steven E. , Knowler William C. , Nathan David M. ,   on behalf of the DPP Research Group
Published: March 2007

In the Diabetes Prevention Program, treatment of subjects with impaired glucose tolerance with metformin >3.2 years reduced the risk of developing type 2 diabetes by 30% compared with placebo. This study describes the mechanisms of this effect. In proportional hazards regression models with 2,155 subjects, changes in weight, the insulinogenic index (IGR), fasting insulin, and proinsulin were predictive of diabetes, though to different degrees within each group. The mean change in weight, fasting insulin, and proinsulin, but not IGR, differed between groups during the study. The 1.7-kg weight loss with metformin versus a 0.3-kg gain with placebo alone explained 64% of the beneficial metformin effect on diabetes risk. Adjustment for weight, fasting insulin, proinsulin, and other metabolic factors combined explained 81% of the beneficial metformin effect, but it remained nominally significant (P = 0.034). After the addition of changes in fasting glucose, 99% of the group effect was explained and is no longer significant. Treatment of high-risk subjects with metformin results in modest weight loss and favorable changes in insulin sensitivity and proinsulin, which contribute to a reduction in the risk of diabetes apart from the associated reductions in fasting glucose.
Identification of PVT1 as a Candidate Gene for End-Stage Renal Disease in Type 2 Diabetes Using a Pooling-Based Genome-Wide Single Nucleotide Polymorphism Association Study
Authors: Hanson Robert L. , Craig David W. , Millis Meredith P. , Yeatts Kimberly A. , Kobes Sayuko , Pearson John V. , Lee Anne M. , Knowler William C. , Nelson Robert G. , Wolford Johanna K.
Published: March 2007

To identify genetic variants contributing to end-stage renal disease (ESRD) in type 2 diabetes, we performed a genome-wide analysis of 115,352 single nucleotide polymorphisms (SNPs) in pools of 105 unrelated case subjects with ESRD and 102 unrelated control subjects who have had type 2 diabetes for ≥10 years without macroalbuminuria. Using a sliding window statistic of ranked SNPs, we identified a 200-kb region on 8q24 harboring three SNPs showing substantial differences in allelic frequency between case and control pools. These SNPs were genotyped in individuals comprising each pool, and strong evidence for association was found with rs2720709 (P = 0.000021; odds ratio 2.57 [95% CI 1.66–3.96]), which is located in the plasmacytoma variant translocation gene PVT1. We sequenced all exons, exon-intron boundaries, and the promoter of PVT1 and identified 47 variants, 11 of which represented nonredundant markers with minor allele frequency ≥0.05. We subsequently genotyped these 11 variants and an additional 87 SNPs identified through public databases in 319-kb flanking rs2720709 (∼1 SNP/3.5 kb); 23 markers were associated with ESRD at P < 0.01. The strongest evidence for association was found for rs2648875 (P = 0.0000018; 2.97 [1.90–4.65]), which maps to intron 8 of PVT1. Together, these results suggest that PVT1 may contribute to ESRD susceptibility in diabetes.
ATP-Sensitive K+ Channels Regulate the Release of GABA in the Ventromedial Hypothalamus During Hypoglycemia
Authors: Chan Owen , Lawson Marcus , Zhu Wanling , Beverly Joseph Lee , Sherwin Robert S.
Published: March 2007

OBJECTIVE—To determine whether alterations in counterregulatory responses to hypoglycemia through the modulation of ATP-sensitive K+ channels (KATP channels) in the ventromedial hypothalamus (VMH) are mediated by changes in GABAergic inhibitory tone in the VMH, we examined whether opening and closing KATP channels in the VMH alter local GABA levels and whether the effects of modulating KATP channel activity within the VMH can be reversed by local modulation of GABA receptors.

RESEARCH DESIGN AND METHODS—Rats were cannulated and bilateral guide cannulas inserted to the level of the VMH. Eight days later, the rats received a VMH microinjection of either 1) vehicle, 2) the KATP channel opener diazoxide, 3) the KATP channel closer glybenclamide, 4) diazoxide plus the GABAA receptor agonist muscimol, or 5) glybenclamide plus the GABAA receptor antagonist bicuculline methiodide (BIC) before performance of a hypoglycemic clamp. Throughout, VMH GABA levels were measured using microdialysis.

RESULTS—As expected, diazoxide suppressed glucose infusion rates and increased glucagon and epinephrine responses, whereas glybenclamide raised glucose infusion rates in conjunction with reduced glucagon and epinephrine responses. These effects of KATP modulators were reversed by GABAA receptor agonism and antagonism, respectively. Microdialysis revealed that VMH GABA levels decreased 22% with the onset of hypoglycemia in controls. Diazoxide caused a twofold greater decrease in GABA levels, and glybenclamide increased VMH GABA levels by 57%.

CONCLUSIONS—Our data suggests that KATP channels within the VMH may modulate the magnitude of counterregulatory responses by altering release of GABA within that region.
Ubiquitinated-Protein Aggregates Form in Pancreatic β-Cells During Diabetes-Induced Oxidative Stress and Are Regulated by Autophagy
Authors: Kaniuk Natalia A. , Kiraly Michael , Bates Holly , Vranic Mladen , Volchuk Allen , Brumell John H.
Published: March 2007

Diabetes-induced oxidative stress can lead to protein misfolding and degradation by the ubiquitin-proteasome system. This study examined protein ubiquitination in pancreatic sections from Zucker diabetic fatty rats. We observed large aggregates of ubiquitinated proteins (Ub-proteins) in insulin-expressing β-cells and surrounding acinar cells. The formation of these aggregates was also observed in INS1 832/13 β-cells after exposure to high glucose (30 mmol/l) for 8–72 h, allowing us to further characterize this phenotype. Oxidative stress induced by aminotriazole (ATZ) was sufficient to stimulate Ub-protein aggregate formation. Furthermore, the addition of the antioxidants N-acetyl cysteine (NAC) and taurine resulted in a significant decrease in formation of Ub-protein aggregates in high glucose. Puromycin, which induces defective ribosomal product (DRiP) formation was sufficient to induce Ub-protein aggregates in INS1 832/13 cells. However, cycloheximide (which blocks translation) did not impair Ub-protein aggregate formation at high glucose levels, suggesting that long-lived proteins are targeted to these structures. Clearance of Ub-protein aggregates was observed during recovery in normal medium (11 mmol/l glucose). Despite the fact that 20S proteasome was localized to Ub-protein aggregates, epoxomicin treatment did not affect clearance, indicating that the proteasome does not degrade proteins localized to these structures. The autophagy inhibitor 3MA blocked aggregate clearance during recovery and was sufficient to induce their formation in normal medium. Together, these findings demonstrate that diabetes-induced oxidative stress induces ubiquitination and storage of proteins into cytoplasmic aggregates that do not colocalize with insulin. Autophagy, not the proteasome, plays a key role in regulating their formation and degradation. To our knowledge, this is the first demonstration that autophagy acts as a defense to cellular damage incurred during diabetes.
Serial Metabolic Measurements and Conversion to Type 2 Diabetes in the West of Scotland Coronary Prevention Study
Authors: Sattar Naveed , McConnachie Alex , Ford Ian , Gaw Allan , Cleland Stephen J. , Forouhi Nita G. , McFarlane Peter , Shepherd James , Cobbe Stuart , Packard Chris
Published: March 2007

To examine metabolic changes (lipids, liver enzymes, blood pressure, and weight) potentially associated with conversion to diabetes, we analyzed serial glucose and other metabolic measures obtained every 6 months within the West of Scotland Coronary Prevention Study trial. Changes in parameters for 86 men who converted to new-onset diabetes (“converters”: two consecutive glucose levels ≥7 mmol/l) were compared with 860 “nonconverters” matched for age and treatment allocation. Eighteen months before the diagnosis, converters to diabetes had elevated (P < 0.01) fasting glucose, weight, triglyceride, alanine aminotransferase (ALT), blood pressure, and white cell count and lower HDL cholesterol compared with nonconverters. The mean (SD) increase in fasting glucose over 18 months in converters was 1.80 (1.52) mmol/l, compared with 0.10 (0.57) in nonconverters. Of parameters measured, only ALT (P = 0.0005) and triglyceride (P = 0.030) increased significantly more over the 18 months in converters compared with nonconverters, but neither parameter increased significantly in nonconverters with high baseline glucose concentrations (>6.1 mmol/l). Finally, only sustained increases in ALT predicted a higher risk for diabetes. We conclude that a relatively rapid rise in fasting glucose levels is frequent in converters to diabetes and that associated increases over time in ALT and potentially triglyceride suggest hepatic fat accumulation as a contributing factor for conversion to diabetes in men at risk.
Effects of Nonglucose Nutrients on Insulin Secretion and Action in People With Pre-Diabetes
Authors: Bock Gerlies , Dalla Man Chiara , Campioni Marco , Chittilapilly Elizabeth , Basu Rita , Toffolo Gianna , Cobelli Claudio , Rizza Robert
Published: March 2007

To determine whether nonglucose nutrient–induced insulin secretion is impaired in pre-diabetes, subjects with impaired or normal fasting glucose were studied after ingesting either a mixed meal containing 75 g glucose or 75 g glucose alone. Despite comparable glucose areas above basal, glucose-induced insulin secretion was higher (P < 0.05) and insulin action lower (P < 0.05) during the meal than the oral glucose tolerance test (OGTT) in all subgroups regardless of whether they had abnormal or normal glucose tolerance (NGT). However, the nutrient-induced δ (meal minus OGTT) in insulin secretion and glucagon concentrations did not differ among groups. Furthermore, the decrease in insulin action after meal ingestion was compensated in all groups by an appropriate increase in insulin secretion resulting in disposition indexes during meals that were equal to or greater than those present during the OGTT. In contrast, disposition indexes were reduced (P < 0.01) during the OGTT in the impaired glucose tolerance groups, indicating that reduced glucose induced insulin secretion. We conclude that, whereas glucose-induced insulin secretion is impaired in people with abnormal glucose tolerance, nonglucose nutrient–induced secretion is intact, suggesting that a glucose-specific defect in the insulin secretory pathway is an early event in the evolution of type 2 diabetes.
GPR40 Is Necessary but Not Sufficient for Fatty Acid Stimulation of Insulin Secretion In Vivo
Authors: Latour Martin G. , Alquier Thierry , Oseid Elizabeth , Tremblay Caroline , Jetton Thomas L. , Luo Jian , Lin Daniel C.-H. , Poitout Vincent
Published: March 2007

Long-chain fatty acids amplify insulin secretion from the pancreatic β-cell. The G-protein–coupled receptor GPR40 is specifically expressed in β-cells and is activated by fatty acids; however, its role in acute regulation of insulin secretion in vivo remains unclear. To this aim, we generated GPR40 knockout (KO) mice and examined glucose homeostasis, insulin secretion in response to glucose and Intralipid in vivo, and insulin secretion in vitro after short- and long-term exposure to fatty acids. Our results show that GPR40 KO mice have essentially normal glucose tolerance and insulin secretion in response to glucose. Insulin secretion in response to Intralipid was reduced by ∼50%. In isolated islets, insulin secretion in response to glucose and other secretagogues was unaltered, but fatty acid potentiation of insulin release was markedly reduced. The Gαq/11 inhibitor YM-254890 dose-dependently reduced palmitate potentiation of glucose-induced insulin secretion. Islets from GPR40 KO mice were as sensitive to fatty acid inhibition of insulin secretion upon prolonged exposure as islets from wild-type animals. We conclude that GPR40 contributes approximately half of the full acute insulin secretory response to fatty acids in mice but does not play a role in the mechanisms by which fatty acids chronically impair insulin secretion.
Does Patient Behavior or Access Factors Have the Largest Influence on Screening in Type 1 Diabetes?
Authors: Dorsey Rashida , Songer Thomas , Zgibor Janice , Kelsey Sheryl , Ibrahim Said , Orchard Trevor
Published: March 2007

OBJECTIVE—Successful disease management is heavily influenced by access to care issues and patient behavior. Screening tests to detect chronic complications are part of diabetes management and may be influenced by access to care or patient decisions. The objective of this research was to examine how strongly access to care and patient behavior predict screening practices.

RESEARCH DESIGN AND METHODS—Information on screening practices, access to care, and diabetes management were identified from the Pittsburgh Epidemiology of Diabetes Complications Study at two time points: 1998–2001 and 2002–2006. Information on access to care and patient behavior identified in 1998–2001 were examined relative to screening practices observed in 2002–2006.

RESULTS—Access-to-care issues positively predicted subsequent screening practices. Specifically, specialist care visits, number of doctor visits, and intensive insulin therapy were all strong predictors for screening use. Receipt of the recommended level of screening tests was also positively associated with the patient behavior of daily blood glucose testing.

CONCLUSIONS—The findings of this study show that access to care, in general, and access to quality diabetes care, in specific, play a key role in the use of recommended screening tests in type 1 diabetic patients. These data suggest that future efforts to improve screening practices in the type 1 diabetic population should address issues related to access to care.
Sex Differences in the Prediction of Type 2 Diabetes by Inflammatory Markers
Authors: Thorand Barbara , Baumert Jens , Kolb Hubert , Meisinger Christa , Chambless Lloyd , Koenig Wolfgang , Herder Christian
Published: March 2007

OBJECTIVE—Although sex differences have been reported for associations between obesity and inflammation, the question of whether there is an effect modification by sex in the association between inflammation and type 2 diabetes has not been investigated in detail. Therefore, the aim of this study was to compare associations of markers of inflammation with type 2 diabetes risk between men and women.

RESEARCH DESIGN AND METHODS—Following a case-cohort design, cases of incident type 2 diabetes were identified from 7,936 subjects aged 35–74 years at baseline who participated in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) studies conducted between 1984 and 2002. Concentrations of C-reactive protein (CRP) and interleukin (IL)-6 were measured in 527 cases of incident type 2 diabetes (305 men and 222 women) and 1,698 noncases (889 men and 809 women).

RESULTS—After adjustment for age and survey and lifestyle factors including smoking, alcohol intake, and physical activity, elevated concentrations of CRP showed a considerably stronger association with risk of type 2 diabetes in women (hazard ratio comparing tertile extremes 7.60 [95% CI 4.43–13.04]) than in men (1.84 [1.27–2.67]). The P value for the sex interaction was <0.001. Further adjustment for metabolic risk factors considerably attenuated these associations, and they became nonsignificant in men but remained significant in women. IL-6 was also more strongly associated with type 2 diabetes in women, but there was no significant sex interaction.

CONCLUSIONS—Our data suggest that inflammatory processes may be of particular importance in the pathogenesis of type 2 diabetes in women.
Fasting Glucose in Acute Myocardial Infarction
Authors: Aronson Doron , Hammerman Haim , Kapeliovich Michael R. , Suleiman Abeer , Agmon Yoram , Beyar Rafael , Markiewicz Walter , Suleiman Mahmoud
Published: March 2007

OBJECTIVE—Elevation of blood glucose is a common metabolic disorder among patients with acute myocardial infarction (AMI) and is associated with adverse prognosis. However, few data are available concerning the long-term prognostic value of elevated fasting glucose during the acute phase of infarction.

RESEARCH DESIGN AND METHODS—We prospectively studied the relationship between fasting glucose and long-term mortality in patients with AMI. Fasting glucose was determined after an ≥8 h fast within 24 h of admission. The median duration of follow-up was 24 months (range 6–48). All multivariable Cox models were adjusted for the Global Registry of Acute Coronary Events (GRACE) risk score.

RESULTS—In nondiabetic patients (n = 1,101), compared with patients with normal fasting glucose (<100 mg/dl), the adjusted hazard ratio for mortality progressively increased with higher tertiles of elevated fasting glucose (first tertile 1.5 [95% CI 0.8–2.9], P = 0.19; second tertile 3.2 [1.9–5.5], P < 0.0001; third tertile 5.7 [3.5–9.3], P < 0.0001). The c statistic of the model containing the GRACE risk score increased when fasting glucose data were added (0.8 ± 0.02–0.85 ± 0.02, P = 0.004). Fasting glucose remained an independent predictor of mortality after further adjustment for ejection fraction. Elevated fasting glucose did not predict mortality in patients with diabetes (n = 462).

CONCLUSIONS—Fasting glucose is a simple robust tool for predicting long-term mortality in nondiabetic patients with AMI. Fasting glucose provides incremental prognostic information when added to the GRACE risk score and left ventricular ejection fraction. Fasting glucose is not a useful prognostic marker in patients with diabetes.
Efficacy of Sertraline in Prevention of Depression Recurrence in Older Versus Younger Adults With Diabetes
Authors: Williams Monique M. , Clouse Ray E. , Nix Billy D. , Rubin Eugene H. , Sayuk Gregory S. , McGill Janet B. , Gelenberg Alan J. , Ciechanowski Paul S. , Hirsch Irl B. , Lustman Patrick J.
Published: March 2007

OBJECTIVE—Sertraline maintenance therapy effectively delays recurrence of major depressive disorder in adult diabetic patients when data are examined across all age-groups. A secondary analysis was performed to assess this effect in younger and older subsets of patients.

RESEARCH DESIGN AND METHODS—Younger (aged <55 years, n = 85) and older (aged ≥55 years, n = 67) subsets were identified from a multicenter, double-blind, placebo-controlled, maintenance treatment trial of sertraline in diabetic participants who achieved depression recovery with open-label sertraline treatment. Cox proportional hazards models were used to determine differences in time to depression recurrence between treatment arms (sertraline or placebo) for each age subset and between age subsets for each treatment.

RESULTS—In younger subjects, sertraline conferred significantly greater prophylaxis against depression recurrence than placebo (hazard ratio 0.37 [95% CI 0.20–0.71]; P = 0.003). Benefits of sertraline maintenance therapy were lost in older participants (0.94 [0.39–2.29]; P = 0.89). There was no difference in time to recurrence for sertraline-treated subjects between age subsets (P = 0.65), but older subjects had a significantly longer time to recurrence on placebo than younger subjects (P = 0.03).

CONCLUSIONS—While sertraline significantly increased the time to depression recurrence in the younger diabetic participants, there was no treatment effect in those aged ≥55 years because of a high placebo response rate. Further research is necessary to determine the mechanisms responsible for this effect and whether depression maintenance strategies specific for older patients with diabetes should be developed.
Depressive Symptoms and Stressful Life Events Predict Metabolic Syndrome Among Middle-Aged Women
Authors: Räikkönen Katri , Matthews Karen A. , Kuller Lewis H.
Published: March 2007

OBJECTIVE—We evaluated whether psychosocial factors that are related to cardiovascular disease and type 2 diabetes predict prospectively the risk for the metabolic syndrome using the different clinical criteria available for defining the syndrome.

RESEARCH DESIGN AND METHODS—Women were enrolled in a population-based prospective cohort study called the Healthy Women Study and were followed for an average of 15 years after baseline. Metabolic syndrome was defined via the World Health Organization, the National Cholesterol Education Program Adult Treatment Panel III, and the International Diabetes Foundation clinical criteria.

RESULTS—Among women who did not have the metabolic syndrome at the baseline, the risk for the metabolic syndrome defined in multiple ways varied from 1.21- to 2.12-fold ([95% CI 1.00–4.25], P < 0.05) for more severe depressive symptoms or very stressful life event(s). These associations were largely the same, regardless of the clinical criteria used to define the metabolic syndrome. Those who at the baseline reported feeling frequently and intensely angry, tense, or stressed also had an increased risk for developing the metabolic syndrome at least by one definition (relative risk 1.19–1.66 [1.00–2.39]).

CONCLUSIONS—These are the first data to demonstrate that psychosocial factors predict the risk for developing the metabolic syndrome by multiple definitions. Psychosocial factors may play a causal role in the chain of events leading to the metabolic syndrome.
The 2005 Dietary Guidelines for Americans and Insulin Resistance in the Framingham Offspring Cohort
Authors: Fogli-Cawley Jeanene J. , Dwyer Johanna T. , Saltzman Edward , McCullough Marjorie L. , Troy Lisa M. , Meigs James B. , Jacques Paul F.
Published: March 2007

OBJECTIVE—The aim of this study was to examine the relationship between a diet consistent with the 2005 Dietary Guidelines for Americans (DGA), as assessed by the 2005 Dietary Guidelines for Americans Adherence Index (DGAI), and measures of insulin resistance in the Framingham Heart Study Offspring Cohort.

RESEARCH DESIGN AND METHODS—We examined cross-sectional associations between DGAI score and degree of insulin resistance as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin in 3,082 participants in the Framingham Offspring Cohort fifth examination (January 1991–June 1995).

RESULTS—Participants in the highest quintile category of the DGAI score had significantly lower HOMA-IR than those in the lowest quintile category after adjusting for age, sex, and waist circumference (6.4 compared with 6.7, P = 0.04). We observed a significant interaction between DGAI score and sex, and upon stratification, the association appeared to be largely confined to women (5.9 compared with 6.6, P < 0.001). No association was apparent in men (7.2 compared with 7.1, P = 0.30). Similar associations were evident between the DGAI score and fasting insulin.

CONCLUSIONS—Consumption of a diet consistent with the 2005 DGA may be an effective means to limit insulin resistance in women.
Trends in Outpatient Prescription Drug Costs in Diabetic Patients in Germany, 1994–2004
Authors: Rathmann Wolfgang , Haastert Burkhard , Icks Andrea , Giani Guido
Published: March 2007

OBJECTIVE—New antidiabetic medications have been introduced during the last decade, but their impact on health care cost is largely unknown. Prescription costs in diabetic patients in primary care in Germany were evaluated (1994–2004).

RESEARCH DESIGN AND METHODS—A total of 46,017 diabetic patients and 46,017 age- and sex-matched control subjects in 400 nationwide practices (2004) were compared with 29,956 diabetic patients and 13,226 control subjects (361 practices) in 1994 (data from IMS HEALTH). Inflation-adjusted age- and sex-standardized costs (ex-manufacturer prices) were calculated.

RESULTS—Mean annual total prescription costs per diabetic patient were €559 in 2004 (€372 in 1994), equaling a 60% (standardized) increase (P < 0.01). Average costs for antidiabetic medication were €172 in 2004, a 100% increase (P < 0.01). The major antidiabetic cost factor was insulin and analogs, which accounted for 22% of total drug costs in diabetic patients in 2004 (17% in 1994). All oral antidiabetic drugs together accounted for 8% of total costs (6% in 1994). New drugs (glitazones, glinides, and insulins) accounted for 15% of total costs (40% of antidiabetic drugs) in 2004. A 40% increase (€387 vs. 286) in all non–diabetes-related drugs was due mainly to cardiovascular and lipid-lowering drugs. In nondiabetic patients, only a 30% cost increase was found (€210 vs. 147; P < 0.01).

CONCLUSIONS—Prescription drug costs among diabetic patients increased 60% during the last decade, which was twofold higher than the increase in nondiabetic patients. New types of antidiabetic drugs accounted for a substantial cost share of the overproportional increase for diabetes treatment. Progress in pharmacological therapy is a key driver of drug expenditure growth in diabetes treatment.
Type 2 Diabetes and the Risk of Parkinson's Disease
Authors: Hu Gang , Jousilahti Pekka , Bidel Siamak , Antikainen Riitta , Tuomilehto Jaakko
Published: March 2007

OBJECTIVE—To evaluate whether type 2 diabetes at baseline is a risk factor for Parkinson's disease.

RESEARCH DESIGN AND METHODS—We prospectively followed 51,552 Finnish men and women 25–74 years of age without a history of Parkinson's disease at baseline. History of diabetes and other study parameters were determined at baseline using standardized measurements. Ascertainment of the Parkinson's disease status was based on the nationwide Social Insurance Institution's drug register data. Hazard ratios of incident Parkinson's disease associated with the history of type 2 diabetes were estimated.

RESULTS—During a mean follow-up period of 18.0 years, 324 men and 309 women developed incident Parkinson's disease. Age- and study year–adjusted hazard ratios of incident Parkinson's disease among subjects with type 2 diabetes, compared with those without it, were 1.80 (95% CI 1.03–3.15) in men, 1.93 (1.05–3.53) in women, and 1.85 (1.23–2.80) in men and women combined (adjusted also for sex). Further adjustment for BMI, systolic blood pressure, total cholesterol, education, leisure-time physical activity, smoking, alcohol drinking, and coffee and tea consumption affected the results only slightly. The multivariate adjusted association between type 2 diabetes and the risk of Parkinson's disease was also confirmed in stratified subgroup analysis.

CONCLUSIONS—These data suggest that type 2 diabetes is associated with an increased risk of Parkinson's disease. Surveillance bias might account for higher rates in diabetes. The mechanism behind this association between diabetes and Parkinson's disease is not known.
Relationship Between Patient Medication Adherence and Subsequent Clinical Inertia in Type 2 Diabetes Glycemic Management
Authors: Grant Richard , Adams Alyce S. , Trinacty Connie Mah , Zhang Fang , Kleinman Ken , Soumerai Stephen B. , Meigs James B. , Ross-Degnan Dennis
Published: March 2007

OBJECTIVE—Clinical inertia has been identified as a critical barrier to glycemic control in type 2 diabetes. We assessed the relationship between patients' initial medication adherence and subsequent regimen intensification among patients with persistently elevated A1C levels.

RESEARCH DESIGN AND METHODS—We analyzed an inception cohort of 2,065 insured patients with type 2 diabetes who were newly started on hypoglycemic therapy and were followed for at least 3 years between 1992 and 2001. Medication adherence was assessed by taking the ratio of medication days dispensed (from pharmacy records) to medication days prescribed (as documented in the medical record) for the first prescribed hypoglycemic drug. Adherence was measured for the period between medication initiation and the next elevated A1C result measured at least 3 months later; intensification was defined as a dose increase or the addition of a second hypoglycemic agent.

RESULTS—Patients were aged (mean ± SD) 55.4 ± 12.2 years; 53% were men, and 19% were black. Baseline medication adherence was 79.8 ± 19.3%. Patients in the lowest quartile of adherence were significantly less likely to have their regimens increased within 12 months of their first elevated A1C compared with patients in the highest quartile (27 vs. 37%, respectively, with increased regimens if A1C is elevated, P < 0.001). In multivariate models adjusting for patient demographic and treatment factors, patients in the highest adherence quartile had 53% greater odds of medication intensification after an elevated A1C (95% CI 1.11–1.93, P = 0.01).

CONCLUSIONS—Among insured diabetic patients with elevated A1C, level of medication adherence predicted subsequent medication intensification. Poor patient self-management behavior increases therapeutic clinical inertia.
Characterization of Adrenoceptors
Authors: Bylund David B.
Published: March 2007

Norepinephrine and epinephrine are important neurotransmitters in both the peripheral and the central nervous systems. The actions of these neurotransmitters are mediated by adrenoceptors. Three major types of adrenoceptors have been identified on the basis of pharmacological data: α1, α2, and β. Within each major type, at least three receptor subtypes have been identified. Three basic types of radioligand binding experiments are provided in this unit: (1) saturation binding from which the affinity (Kd) of the radioligand for the adrenoceptor and the binding site density (Bmax) can be determined; (2) inhibition experiments from which the affinity (Ki) of a competing, unlabeled compound for the receptor can be determined; and (3) kinetic assays from which the forward and reverse rate constants of the binding process can be determined. Three support protocols are provided covering the preparation of membranes containing the receptor from tissue or cells in culture, calculation ofKdandBmaxfrom saturation experiments, and calculation ofKifrom inhibition experiments.