bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Scans for Diabetic Nephropathy and Albuminuria in Multiethnic Populations
Authors: Iyengar Sudha K. , Abboud Hanna E. , Goddard Katrina A.B. , Saad Mohammed F. , Adler Sharon G. , Arar Nedal H. , Bowden Donald W. , Duggirala Ravi , Elston Robert C. , Hanson Robert L. , Ipp Eli , Kao W.H. Linda , Kimmel Paul L. , Klag Michael J. , Knowler William C. , Meoni Lucy A. , Nelson Robert G. , Nicholas Susanne B. , Pahl Madeleine V. , Parekh Rulan S. , Quade Shannon R.E. , Rich Stephen S. , Rotter Jerome I. , Scavini Marina , Schelling Jeffrey R. , Sedor John R. , Sehgal Ashwini R. , Shah Vallabh O. , Smith Michael W. , Taylor Kent D. , Winkler Cheryl A. , Zager Philip G. , Freedman Barry I. ,   on behalf of the Family Investigation of Nephropathy and Diabetes Research Group
Published: May 2007

The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy. A total of 11 centers participated under a single collection protocol to recruit large numbers of diabetic sibling pairs concordant and discordant for diabetic nephropathy. We report the findings from the first-phase genetic analyses in 1,227 participants from 378 pedigrees of European-American, African-American, Mexican-American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for diabetic nephropathy in 397 sibling pairs, as well as the quantitative trait urinary albumin-to-creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the diabetic nephropathy trait was on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. In ACR (883 diabetic sibling pairs), the strongest linkage signals were on chromosomes 2q14.1, 7q21.1, and 15q26.3. These results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likely to accelerate the identification of genes causing diabetic nephropathy, a life-threatening complication of diabetes.
PPARα Agonists Suppress Osteopontin Expression in Macrophages and Decrease Plasma Levels in Patients With Type 2 Diabetes
Authors: Nakamachi Takafumi , Nomiyama Takashi , Gizard Florence , Heywood Elizabeth B. , Jones Karrie L. , Zhao Yue , Fuentes Lucia , Takebayashi Kohzo , Aso Yoshimasa , Staels Bart , Inukai Toshihiko , Bruemmer Dennis
Published: May 2007

Osteopontin (OPN) is a proinflammatory cytokine implicated in the chemoattraction of monocytes and the development of atherosclerosis. Peroxisome proliferator–activated receptor (PPAR)α, a ligand-activated transcription factor with pleiotropic anti-inflammatory effects in macrophages, is the molecular target for fibrates, which are frequently used to treat dyslipidemia in patients with type 2 diabetes at high risk for cardiovascular disease. In the present study, we examined the regulation of OPN by PPARα agonists in macrophages and determined the effect of fibrate treatment on OPN plasma levels in patients with type 2 diabetes. Treatment of human macrophages with the PPARα ligands bezafibrate or WY14643 inhibited OPN expression. PPARα ligands suppressed OPN promoter activity, and an activator protein (AP)-1 consensus site conferred this repression. Overexpression of c-Fos and c-Jun reversed the inhibitory effect of PPARα ligands on OPN transcription, and, in chromatin immunoprecipitation assays, PPARα ligands inhibited c-Fos and phospho–c-Jun binding to the OPN promoter. Moreover, c-Fos and phospho–c-Jun protein expression was inhibited by PPARα agonists, indicating that PPARα ligands suppress OPN expression through negative cross talk with AP-1–dependent transactivation of the OPN promoter. This inhibitory effect of PPARα ligands on OPN expression was absent in PPARα-deficient macrophages, suggesting a receptor-mediated mechanism of OPN suppression. Finally, treatment of type 2 diabetic patients with bezafibrate significantly decreased OPN plasma levels. These results demonstrate a novel mechanism whereby PPARα ligands may impact macrophage inflammatory responses and decrease early proinflammatory markers for cardiovascular disease.
Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis
Authors: Lee Young-Sun , Shin Seungjin , Shigihara Toshikatsu , Hahm Eunsil , Liu Meng-Ju , Han Jaeseok , Yoon Ji-Won , Jun Hee-Sook
Published: May 2007

Long-term treatment with glucagon-like peptide (GLP)-1 or its analog can improve insulin sensitivity. However, continuous administration is required due to its short half-life. We hypothesized that continuous production of therapeutic levels of GLP-1 in vivo by a gene therapy strategy may remit hyperglycemia and maintain prolonged normoglycemia. We produced a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) under the cytomegalovirus promoter, intravenously injected it into diabetic ob/ob mice, and investigated the effect of this treatment on remission of diabetes, as well as the mechanisms involved. rAd-GLP-1–treated diabetic ob/ob mice became normoglycemic 4 days after treatment, remained normoglycemic over 60 days, and had reduced body weight gain. Glucose tolerance tests found that exogenous glucose was cleared normally. rAd-GLP-1–treated diabetic ob/ob mice showed improved β-cell function, evidenced by glucose-responsive insulin release, and increased insulin sensitivity, evidenced by improved insulin tolerance and increased insulin-stimulated glucose uptake in adipocytes. rAd-GLP-1 treatment increased basal levels of insulin receptor substrate (IRS)-1 in the liver and activation of IRS-1 and protein kinase C by insulin in liver and muscle; increased Akt activation was only observed in muscle. rAd-GLP-1 treatment reduced hepatic glucose production and hepatic expression of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fatty acid synthase in ob/ob mice. Taken together, these results show that a single administration of rAd-GLP-1 results in the long-term remission of diabetes in ob/ob mice by improving insulin sensitivity through restoration of insulin signaling and reducing hepatic gluconeogenesis.
Implantation Site–Dependent Dysfunction of Transplanted Pancreatic Islets
Authors: Lau Joey , Mattsson Göran , Carlsson Carina , Nyqvist Daniel , Köhler Martin , Berggren Per-Olof , Jansson Leif , Carlsson Per-Ola
Published: May 2007

OBJECTIVE—Clinical islet transplantations are performed through infusion of islets via the portal vein into the liver. This study aimed at characterizing the influence of the implantation microenvironment on islet graft metabolism and function.

RESEARCH DESIGN AND METHODS—Islets were transplanted into their normal environment, i.e., the pancreas, or intraportally into the liver of mice. One month posttransplantation, the transplanted islets were retrieved and investigated for changes in function and gene expression.

RESULTS—Insulin content, glucose-stimulated insulin release, (pro)insulin biosynthesis, and glucose oxidation rate were markedly decreased in islets retrieved from the liver, both when compared with islets transplanted into the pancreas and endogenous islets. Islets transplanted into the pancreas showed normal insulin content, (pro)insulin biosynthesis, and glucose oxidation rate but increased basal insulin secretion and impaired glucose stimulation index. Gene expression data for retrieved islets showed downregulation of pancreatic and duodenal homeobox gene-1, GLUT-2, glucokinase, mitochondrial glycerol-phosphate dehydrogenase, and pyruvate carboxylase, preferentially in intraportally transplanted islets.

CONCLUSIONS—Islets transplanted into their normal microenvironment, i.e., the pancreas, display gene expression changes when compared with endogenous islets but only moderate changes in metabolic functions. In contrast, site-specific properties of the liver markedly impaired the metabolic functions of intraportally transplanted islets.
Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes
Authors: Ramos Khara M. , Jiang Yun , Svensson Camilla I. , Calcutt Nigel A.
Published: May 2007

Hyperalgesia to noxious stimuli is accompanied by increased spinal cyclooxygenase (COX)-2 protein in diabetic rats. The present studies were initiated to establish causality between increased spinal COX-2 activity and hyperalgesia during diabetes and to assess the potential involvement of polyol pathway activity in the pathogenesis of spinally mediated hyperalgesia. Rats with 1, 2, or 4 weeks of streptozotocin-induced diabetes exhibited significantly increased levels of spinal COX-2 protein and activity, along with exaggerated paw flinching in response to 0.5% paw formalin injection. Increased flinching of diabetic rats was attenuated by intrathecal pretreatment with a selective COX-2 inhibitor immediately before formalin injection, confirming the involvement of COX-2 activity in diabetic hyperalgesia. Chronic treatment with insulin or ICI222155, an aldose reductase inhibitor (ARI) previously shown to prevent spinal polyol accumulation and formalin-evoked hyperalgesia in diabetic rats, prevented elevated spinal COX-2 protein and activity in diabetic rats. In contrast, the ARI IDD676 had no effect on spinal polyol accumulation, elevated spinal COX-2, or hyperalgesia to paw formalin injection. In the spinal cord, aldose reductase immunoreactivity was present solely in oligodendrocytes, which also contained COX-2 immunoreactivity. Polyol pathway flux in spinal oligodendrocytes provides a pathogenic mechanism linking hyperglycemia to hyperalgesia in diabetic rats.
The STAT5A-Mediated Induction of Pyruvate Dehydrogenase Kinase 4 Expression by Prolactin or Growth Hormone in Adipocytes
Authors: White Ursula A. , Coulter Ann A. , Miles Tiffany K. , Stephens Jacqueline M.
Published: May 2007

The purpose of this study was to determine whether pyruvate dehydrogenase kinase (PDK)4 was expressed in adipocytes and whether PDK4 expression was hormonally regulated in fat cells. Both Northern blot and Western blot analyses were conducted on samples isolated from 3T3-L1 adipocytes after various treatments with prolactin (PRL), growth hormone (GH), and/or insulin. Transfection of PDK4 promoter reporter constructs was performed. In addition, glucose uptake measurements were conducted. Our studies demonstrate that PRL and porcine GH can induce the expression of PDK4 in 3T3-L1 adipocytes. Our studies also show that insulin pretreatment can attenuate the ability of these hormones to induce PDK4 mRNA expression. In addition, we identified a hormone-responsive region in the murine PDK4 promoter and characterized a STAT5 binding site in this region that mediates the PRL (sheep) and GH (porcine) induction in PDK4 expression in 3T3-L1 adipocytes. PDK4 is a STAT5A target gene. PRL is a potent inducer of PDK4 protein levels, results in an inhibition of insulin-stimulated glucose transport in fat cells, and likely contributes to PRL-induced insulin resistance.
Quantitative Trait Loci for Fasting Glucose in Young Europeans Replicate Previous Findings for Type 2 Diabetes in 2q23–24 and Other Locations
Authors: Fradin Delphine , Heath Simon , Lathrop Mark , Bougnères Pierre
Published: May 2007

Long before reaching diagnostic cutoff levels for type 2 diabetes, fasting glucose can be a powerful risk marker for this disease. We conducted a genome-wide search for fasting glucose as a quantitative trait in 412 young European sib-pairs including obese children, with adjustment for sex, age, and BMI. We identified more quantitative trait loci specific to fasting glucose and more significant than would be found by simple chance estimated by permutation tests. The strongest linkage was on chromosome 2q (logarithm of odds [LOD] = 3.00) in a region previously linked to type 2 diabetes as a disease. We also found linkage signals of fasting glucose with 7q (LOD = 2.03), 8q (1.28), 17p (2.12), 17q (1.4), and 11p (1.33). These findings suggest that the quantitative genetics of fasting glucose could contribute to the search for type 2 diabetes genes.
Global Assessment of Regulation of Phosphorylation of Insulin Receptor Substrate-1 by Insulin In Vivo in Human Muscle
Authors: Yi Zhengping , Langlais Paul , De Filippis Elena A. , Luo Moulun , Flynn Charles R. , Schroeder Stefanie , Weintraub Susan T. , Mapes Rebekka , Mandarino Lawrence J.
Published: May 2007

OBJECTIVE—Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Of 1,242 amino acids in IRS-1, 242 are serine/threonine. Serine/threonine phosphorylation of IRS-1 is affected by many factors, including insulin. The purpose of this study was to perform global assessment of phosphorylation of serine/threonine residues in IRS-1 in vivo in humans.

RESEARCH DESIGN AND METHODS—In this study, we describe our use of capillary high-performance liquid chromotography electrospray tandem mass spectrometry to identify/quantify site-specific phosphorylation of IRS-1 in human vastus lateralis muscle obtained by needle biopsy basally and after insulin infusion in four healthy volunteers.

RESULTS—Twenty-two serine/threonine phosphorylation sites were identified; 15 were quantified. Three sites had not been previously identified (Thr495, Ser527, and S1005). Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 (2.6 ± 0.4, 2.9 ± 0.8, 2.1 ± 0.3, 1.6 ± 0.1, 1.3 ± 0.1, and 1.3 ± 0.1–fold, respectively, compared with basal; P < 0.05); phosphorylation of Ser348, Thr446, Thr495, and Ser1005 decreased (0.4 ± 0.1, 0.2 ± 0.1, 0.1 ± 0.1, and 0.3 ± 0.2–fold, respectively; P < 0.05).

CONCLUSIONS—These results provide an assessment of IRS-1 phosphorylation in vivo and show that insulin has profound effects on IRS-1 serine/threonine phosphorylation in healthy humans.
Resistance Exercise and Insulin Regulate AS160 and Interaction With 14-3-3 in Human Skeletal Muscle
Authors: Howlett Kirsten F. , Sakamoto Kei , Garnham Andrew , Cameron-Smith David , Hargreaves Mark
Published: May 2007

A single bout of aerobic exercise can enhance insulin action, but whether a similar effect occurs after resistance exercise is unknown. Hyperinsulinemic-euglycemic clamps were performed on eight male subjects at rest and after a single bout and three repeated bouts of resistance exercise over 7 days. Skeletal muscle biopsies were taken before and after the clamp and immediately after a single exercise bout. Whole-body insulin action measured by glucose infusion rate decreased (P < 0.05) after a single exercise bout, whereas in response to repeated bouts of resistance exercise, the glucose infusion rate was similar to the rest trial. In skeletal muscle, Akt substrate of 160 kDa (AS160) phosphorylation, an Akt substrate implicated in the regulation of GLUT4 translocation, and its interaction with 14-3-3 was decreased (P < 0.05) only after a single exercise bout. Insulin increased (P < 0.05) phosphorylation of AS160 and its interaction with 14-3-3, but the insulin response was not influenced by resistance exercise. Phosphorylation of insulin receptor substrate-1 and Akt were similar to changes in AS160 phosphorylation after exercise and/or insulin. In conclusion, a single bout of resistance exercise impairs whole-body insulin action. Regulation of AS160 and interaction with 14-3-3 in skeletal muscle are influenced by resistance exercise and insulin but do not fully explain the effect of resistance exercise on whole-body insulin action.
Variations in Adiponectin Receptor Genes and Susceptibility to Type 2 Diabetes in Women
Authors: Qi Lu , Doria Alessandro , Giorgi Elena , Hu Frank B.
Published: May 2007

Adiponectin has been associated with low diabetes risk. The metabolic effects of adiponectin are mediated by adiponectin receptors 1 (ADIPOR1) and 2 (ADIPOR2). We conducted a prospective, nested case-control study of 714 cases of type 2 diabetes and 1,120 control subjects. Six polymorphisms in ADIPOR1 and 16 polymorphisms in ADIPOR2 were determined. Haplotypes inferred from ADIPOR1 polymorphisms were significantly associated with diabetes risk (overall test, −2log-likelihood = 15.1 on 5 df; P = 0.0098). A single copy of haplotype 001100 (0, common allele; and 1, minor allele) was associated with 24% decreased risk (odds ratio [OR] 0.76 [95% CI 0.61–0.96], P = 0.02) compared with the most common haplotype, 110000, adjusting for age, BMI, and other covariates. A 3′ untranslated region (UTR) polymorphism, rs1139646, showed the strongest and nominally significant association with greater diabetes risk (unadjusted OR 1.26 [1.03–1.53] and adjusted OR 1.36 [1.10–1.70]). However, such an association became marginal after controlling for multiple comparisons by permutation test (P = 0.08 on the basis of 10,000 permutations). There were not significant associations between ADIPOR2 polymorphisms, individually or in haplotypes, and the risk of type 2 diabetes. In conclusion, our data indicate significant associations between ADIPOR1 haplotypes and diabetes risk but do not support a relation between ADIPOR2 variability and the disease.
Omentin Plasma Levels and Gene Expression Are Decreased in Obesity
Authors: de Souza Batista Celia M. , Yang Rong-Ze , Lee Mi-Jeong , Glynn Nicole M. , Yu Dao-Zhan , Pray Jessica , Ndubuizu Kelechi , Patil Susheel , Schwartz Alan , Kligman Mark , Fried Susan K. , Gong Da-Wei , Shuldiner Alan R. , Pollin Toni I. , McLenithan John C.
Published: May 2007

Central obesity and the accumulation of visceral fat are risk factors for the development of type 2 diabetes and cardiovascular disease. Omentin is a protein expressed and secreted from visceral but not subcutaneous adipose tissue that increases insulin sensitivity in human adipocytes. To determine the impact of obesity-dependent insulin resistance on the regulation of two omentin isoforms, gene expression and plasma levels were measured in lean, overweight, and obese subjects. Omentin 1 was shown to be the major circulating isoform in human plasma. Lean subjects had significantly higher plasma omentin 1 levels than obese and overweight subjects. In addition, higher plasma omentin 1 levels were detected in women compared with men. Plasma omentin 1 levels were inversely correlated with BMI, waist circumference, leptin levels, and insulin resistance as measured by homeostasis model assessment and positively correlated with adiponectin and HDL levels. Both omentin 1 and omentin 2 gene expression were decreased with obesity and were highly correlated with each other in visceral adipose tissue. In summary, decreased omentin levels are associated with increasing obesity and insulin resistance. Therefore, omentin levels may be predictive of the metabolic consequences or co-morbidities associated with obesity.
Aerobic Exercise Overcomes the Age-Related Insulin Resistance of Muscle Protein Metabolism by Improving Endothelial Function and Akt/Mammalian Target of Rapamycin Signaling
Authors: Fujita Satoshi , Rasmussen Blake B. , Cadenas Jerson G. , Drummond Micah J. , Glynn Erin L. , Sattler Fred R. , Volpi Elena
Published: May 2007

Muscle protein metabolism is resistant to insulin's anabolic effect in healthy older subjects. This is associated with reduced insulin vasodilation. We hypothesized that aerobic exercise restores muscle protein anabolism in response to insulin by improving vasodilation in older subjects. We measured blood flow, endothelin-1, Akt/mammalian target of rapamycin (mTOR) signaling, and muscle protein kinetics in response to physiological local hyperinsulinemia in two groups of older subjects following a bout of aerobic exercise (EX group: aged 70 ± 2 years; 45-min treadmill walk, 70% heart rate max) or rest (CTRL group: aged 68 ± 1 years). Baseline endothelin-1 was lower and blood flow tended to be higher in the EX group, but protein kinetics was not different between groups. Insulin decreased endothelin-1 (P < 0.05) in both groups, but endothelin-1 remained higher in the CTRL group (P < 0.05) and blood flow increased only in the EX group (EX group: 3.8 ± 0.7 to 5.3 ± 0.8; CTRL group: 2.5 ± 0.2 to 2.6 ± 0.2 ml · min−1 · 100 ml leg−1). Insulin improved Akt phosphorylation in the EX group and increased mTOR/S6 kinase 1 phosphorylation and muscle protein synthesis (EX group: 49 ± 11 to 89 ± 23; CTRL group: 58 ± 8 to 57 ± 12 nmol · min−1 · 100 ml leg−1) in the EX group only (P < 0.05). Because breakdown did not change, net muscle protein balance became positive only in the EX group (P < 0.05). In conclusion, a bout of aerobic exercise restores the anabolic response of muscle proteins to insulin by improving endothelial function and Akt/mTOR signaling in older subjects.
Reduction in Microalbuminuria as an Integrated Indicator for Renal and Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
Authors: Araki Shin-ichi , Haneda Masakazu , Koya Daisuke , Hidaka Hideki , Sugimoto Toshiro , Isono Motohide , Isshiki Keiji , Chin-Kanasaki Masami , Uzu Takashi , Kashiwagi Atsunori
Published: May 2007

OBJECTIVE—Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study.

RESEARCH DESIGN AND METHODS—We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a reduction <50% from the initial level of microalbuminuria. The association between reducing microalbuminuria and first occurrence of a renal or cardiovascular event and annual decline rate of estimated glomerular filtration rate (eGFR) was evaluated.

RESULTS—Twelve events occurred in 93 patients who attained a 50% reduction of microalbuminuria during the follow-up versus 35 events in 123 patients without a 50% reduction. The cumulative incidence rate of events was significantly lower in patients with a 50% reduction. A pooled logistic regression analysis revealed that the adjusted risk for events in subjects after a 50% reduction was 0.41 (95% CI 0.15–0.96). In addition, the annual decline rate of eGFR in patients with a 50% reduction was significantly slower than in those without such a reduction. The same results were also found in the analysis regarding whether remission occurred.

CONCLUSIONS—The present study provides clinical evidence implying that a reduction of microalbuminuria in type 2 diabetic patients is an integrated indicator for renal and cardiovascular risk reduction.
Paradoxical Elevation of High–Molecular Weight Adiponectin in Acquired Extreme Insulin Resistance Due to Insulin Receptor Antibodies
Authors: Semple Robert K. , Halberg Nils H. , Burling Keith , Soos Maria A. , Schraw Todd , Luan Jian'an , Cochran Elaine K. , Dunger David B. , Wareham Nicholas J. , Scherer Philipp E. , Gorden Phillip , O'Rahilly Stephen
Published: May 2007

Total plasma adiponectin and high–molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. However, we have recently reported paradoxical hyperadiponectinemia in patients with severe insulin resistance due to genetically defective insulin receptors. This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12–54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3–54.2] vs. 8.9 mg/l [1.5–28.5 for BMI <25 kg/m2]), which was accounted for largely by HMW polymers. Hyperadiponectinemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated.
GAD Autoantibody Affinity and Epitope Specificity Identify Distinct Immunization Profiles in Children at Risk for Type 1 Diabetes
Authors: Mayr Anja , Schlosser Michael , Grober Natalie , Kenk Heidrun , Ziegler Anette G. , Bonifacio Ezio , Achenbach Peter
Published: May 2007

OBJECTIVE—Autoantibodies to insulin and GAD are features of preclinical type 1 diabetes in children. For insulin autoantibodies, the antibody affinity and epitope specificity predict which children progress to diabetes. We asked whether autoantibodies to GAD (GADAs) are heterogeneous in affinity and epitope recognition and whether diabetes-related GADA are restricted to high-affinity responses.

RESEARCH DESIGN AND METHODS—GADA affinity was measured by competitive binding experiments with [125I]-labeled and -unlabeled recombinant human GAD65 in the first GADA-positive sample from 95 children with a type 1 diabetes family history who were prospectively followed from birth and in follow-up samples from 65 of these children.

RESULTS—At first GADA appearance, affinity ranged from 107 to 1010 l/mol. Affinity was higher in multiple islet autoantibody-positive children (P < 0.0001) and in HLA DR3–positive children (P = 0.006). GADA affinities were >109 l/mol in 52 of 53 multiple autoantibody-positive children. In contrast, children who were single GADA positive often had lower affinity GADA and/or GADA with specificities that were restricted to minor NH2-terminal GAD65 epitopes. At follow-up, affinity increased from low to high in 3 of 65 children. All 24 children who developed diabetes had high-affinity GADAs before diabetes onset.

CONCLUSIONS—Children develop discrete, heterogeneous antibody responses to GAD that could arise from distinct immunization events, only some of which are diabetes relevant. Subtyping the GADA responses using affinity measurement will improve type 1 diabetes risk assessment.
Transient Upregulation of Indoleamine 2,3-Dioxygenase in Dendritic Cells by Human Chorionic Gonadotropin Downregulates Autoimmune Diabetes
Authors: Ueno Aito , Cho Suzanne , Cheng Lu , Wang Jianxiong , Hou Sheng , Nakano Hiroko , Santamaria Pere , Yang Yang
Published: May 2007

OBJECTIVE—Pregnancy induces a state of immunological tolerance that aims at suppressing immune responses against the fetus and has been linked to temporal remission of preexisting autoimmune disorders. To understand the mechanisms of this reversible immune regulation, we investigated the role of a key pregnancy hormone, human chorionic gonadotropin (hCG), in immune tolerance against autoimmune type 1 diabetes in nonobese diabetic (NOD) mice.

RESEARCH DESIGN AND METHODS—We injected hCG into cytokine gene–deficient NOD mice and evaluated the effects of hCG administration on T-cells and dendritic cells (DCs).

RESULTS—We show that administration of hCG to NOD mice inhibits both the activation of diabetogenic CD4+ and CD8+ T-cells, in vitro and in vivo, and the progression of type 1 diabetes by upregulating the expression of indoleamine 2,3-dioxygenase (IDO) in DCs. IDO upregulation is transient and declined shortly after hCG withdrawal. DC depletion restores the diabetetogenic activity of splenic T-cells from hCG-treated mice, and inhibition of IDO activity by 1-methyl-tryptophan abrogates the hCG-induced T-cell suppression and resistance to type 1 diabetes.

CONCLUSIONS—We propose that hCG-induced upregulation of IDO in DCs plays a major role in pregnancy-associated resistance to autoimmunity.
Interleukin-6 Directly Increases Glucose Metabolism in Resting Human Skeletal Muscle
Authors: Glund Stephan , Deshmukh Atul , Long Yun Chau , Moller Theodore , Koistinen Heikki A. , Caidahl Kenneth , Zierath Juleen R. , Krook Anna
Published: May 2007

Interleukin (IL)-6 is a proinflammatory cytokine shown to modify insulin sensitivity. Elevated plasma levels of IL-6 are observed in insulin-resistant states. Interestingly, plasma IL-6 levels also increase during exercise, with skeletal muscle being the predominant source. Thus, IL-6 has also been suggested to promote insulin-mediated glucose utilization. In this study, we determined the direct effects of IL-6 on glucose transport and signal transduction in human skeletal muscle. Skeletal muscle strips were prepared from vastus lateralis biopsies obtained from 22 healthy men. Muscle strips were incubated with or without IL-6 (120 ng/ml). We found that IL-6 increased glucose transport in human skeletal muscle 1.3-fold (P < 0.05). A 30-min pre-exposure to IL-6 did not affect insulin-stimulated glucose transport. IL-6 also increased skeletal muscle glucose incorporation into glycogen, as well as glucose oxidation (1.5- and 1.3-fold, respectively; P < 0.05). IL-6 increased phosphorylation of STAT3 (signal transducer and activator of transcription 3; P < 0.05), AMP-activated protein kinase (P = 0.063), and p38 mitogen-activated protein kinase (P < 0.05) and reduced phosphorylation of S6 ribosomal protein (P < 0.05). In contrast, phosphorylation of protein kinase B/Akt, AS160 (Akt substrate of 160 kDa), and GSK3α/β (glycogen synthase kinase 3α/β) as well as insulin receptor substrate 1–associated phosphatidylinositol 3-kinase activity remained unaltered. In conclusion, acute IL-6 exposure increases glucose metabolism in resting human skeletal muscle. Insulin-stimulated glucose transport and insulin signaling were unchanged after IL-6 exposure.
Adipogenesis in Obesity Requires Close Interplay Between Differentiating Adipocytes, Stromal Cells, and Blood Vessels
Authors: Nishimura Satoshi , Manabe Ichiro , Nagasaki Mika , Hosoya Yumiko , Yamashita Hiroshi , Fujita Hideo , Ohsugi Mitsuru , Tobe Kazuyuki , Kadowaki Takashi , Nagai Ryozo , Sugiura Seiryo
Published: May 2007

OBJECTIVE—The expansion of adipose tissue mass seen in obesity involves both hyperplasia and hypertrophy of adipocytes. However, little is known about how adipocytes, adipocyte precursors, blood vessels, and stromal cells interact with one another to achieve adipogenesis.

RESEARCH DESIGN AND METHODS—We have developed a confocal microscopy-based method of three-dimensional visualization of intact living adipose tissue that enabled us to simultaneously evaluate angiogenesis and adipogenesis in db/db mice.

RESULTS—We found that adipocyte differentiation takes place within cell clusters (which we designated adipogenic/angiogenic cell clusters) that contain multiple cell types, including endothelial cells and stromal cells that express CD34 and CD68 and bind lectin. There were close spatial and temporal interrelationships between blood vessel formation and adipogenesis, and the sprouting of new blood vessels from preexisting vasculature was coupled to adipocyte differentiation. CD34+ CD68+ lectin-binding cells could clearly be distinguished from CD34− CD68+ macrophages, which were scattered in the stroma and did not bind lectin. Adipogenic/angiogenic cell clusters can morphologically and immunohistochemically be distinguished from crown-like structures frequently seen in the late stages of adipose tissue obesity. Administration of anti–vascular endothelial growth factor (VEGF) antibodies inhibited not only angiogenesis but also the formation of adipogenic/angiogenic cell clusters, indicating that the coupling of adipogenesis and angiogenesis is essential for differentiation of adipocytes in obesity and that VEGF is a key mediator of that process.

CONCLUSIONS—Living tissue imaging techniques provide novel evidence of the dynamic interactions between differentiating adipocytes, stromal cells, and angiogenesis in living obese adipose tissue.
Contribution of Hepatic and Extrahepatic Insulin Resistance to the Pathogenesis of Impaired Fasting Glucose
Authors: Bock Gerlies , Chittilapilly Elizabeth , Basu Rita , Toffolo Gianna , Cobelli Claudio , Chandramouli Visvanathan , Landau Bernard R. , Rizza Robert A.
Published: May 2007

OBJECTIVE—To determine the contribution of hepatic insulin resistance to the pathogenesis of impaired fasting glucose (IFG).

RESEARCH DESIGN AND METHODS—Endogenous glucose production (EGP) and glucose disposal were measured in 31 subjects with IFG and 28 subjects with normal fasting glucose (NFG) after an overnight fast and during a clamp when endogenous secretion was inhibited with somatostatin and insulin infused at rates that approximated portal insulin concentrations present in IFG subjects after an overnight fast (∼80 pmol/l, “preprandial”) or within 30 min of eating (∼300 pmol/l, “prandial”).

RESULTS—Despite higher (P < 0.001) insulin and C-peptide concentrations and visceral fat (P < 0.05), fasting EGP and glucose disposal did not differ between IFG and NFG subjects, implying hepatic and extrahepatic insulin resistance. This was confirmed during preprandial insulin infusion when glucose disposal was lower (P < 0.05) and EGP higher (P < 0.05) in IFG than in NFG subjects. Higher EGP was due to increased (P < 0.05) rates of gluconeogenesis in IFG. EGP was comparably suppressed in IFG and NFG groups during prandial insulin infusion, indicating that hepatic insulin resistance was mild. Glucose disposal remained lower (P < 0.01) in IFG than in NFG subjects.

CONCLUSIONS—Hepatic and extrahepatic insulin resistance contribute to fasting hyperglycemia in IFG with the former being due at least in part to impaired insulin-induced suppression of gluconeogenesis. However, since hepatic insulin resistance is mild and near-maximal suppression of EGP occurs at portal insulin concentrations typically present in IFG subjects within 30 min of eating, extrahepatic (but not hepatic) insulin resistance coupled with accompanying defects in insulin secretion is the primary cause of postprandial hyperglycemia.
A Novel Susceptibility Locus on Rat Chromosome 8 Affects Spontaneous but Not Experimentally Induced Type 1 Diabetes
Authors: Wallis Robert H. , Wang KeSheng , Dabrowski Dominika , Marandi Leili , Ning Terri , Hsieh Eugene , Paterson Andrew D. , Mordes John P. , Blankenhorn Elisabeth P. , Poussier Philippe
Published: May 2007

OBJECTIVE—The biobreeding diabetes-prone (BBDP) rat spontaneously develops type 1 diabetes. Two of the genetic factors contributing to this syndrome are the major histocompatibility complex (Iddm1) and a Gimap5 mutation (Iddm2) responsible for a T-lymphopenia. Susceptibility to experimentally induced type 1 diabetes is widespread among nonlymphopenic (wild-type Iddm2) rat strains provided they share the BBDP Iddm1 allele. The question follows as to whether spontaneous and experimentally induced type 1 diabetes share susceptibility loci besides Iddm1. Our objectives were to map a novel, serendipitously discovered Iddm locus, confirm its effects by developing congenic sublines, and assess its differential contribution to spontaneous and experimentally induced type 1 diabetes.

RESEARCH DESIGN AND METHODS—An unexpected reduction in spontaneous type 1 diabetes incidence (86 to 31%, P < 0.0001) was observed in a BBDP line congenic for a Wistar Furth–derived allotypic marker, RT7 (chromosome 13). Genome-wide analysis revealed that, besides the RT7 locus, a Wistar Furth chromosome 8 fragment had also been introduced. The contribution of these intervals to diabetes resistance was assessed through linkage analysis using 134 F2 (BBDP × double congenic line) animals and a panel of congenic sublines. One of these sublines, resistant to spontaneous type 1 diabetes, was tested for susceptibility to experimentally induced type 1 diabetes.

RESULTS—Both linkage analysis and congenic sublines mapped a novel locus (Iddm24) to the telomeric 10.34 Mb of chromosome 8, influencing cumulative incidence and age of onset of spontaneous type 1 diabetes but not insulitis nor experimentally induced type 1 diabetes.

CONCLUSIONS—This study has identified a type 1 diabetes susceptibility locus that appears to act after the development of insulitis and that regulates spontaneous type 1 diabetes exclusively.
Body Size and Shape Changes and the Risk of Diabetes in the Diabetes Prevention Program
Authors: Fujimoto Wilfred Y. , Jablonski Kathleen A. , Bray George A. , Kriska Andrea , Barrett-Connor Elizabeth , Haffner Steven , Hanson Robert , Hill James O. , Hubbard Van , Stamm E. , Pi-Sunyer F. Xavier ,   for the Diabetes Prevention Program Research Group
Published: May 2007

The researchers conducted this study to test the hypothesis that risk of type 2 diabetes is less following reductions in body size and central adiposity. The Diabetes Prevention Program (DPP) recruited and randomized individuals with impaired glucose tolerance to treatment with placebo, metformin, or lifestyle modification. Height, weight, waist circumference, and subcutaneous and visceral fat at L2-L3 and L4-L5 by computed tomography were measured at baseline and at 1 year. Cox proportional hazards models assessed by sex the effect of change in these variables over the 1st year of intervention upon development of diabetes over subsequent follow-up in a subset of 758 participants. Lifestyle reduced visceral fat at L2-L3 (men −24.3%, women −18.2%) and at L4-L5 (men −22.4%, women −17.8%), subcutaneous fat at L2-L3 (men −15.7%, women −11.4%) and at L4-L5 (men −16.7%, women −11.9%), weight (men −8.2%, women −7.8%), BMI (men −8.2%, women −7.8%), and waist circumference (men −7.5%, women −6.1%). Metformin reduced weight (−2.9%) and BMI (−2.9%) in men and subcutaneous fat (−3.6% at L2-L3 and −4.7% at L4-L5), weight (−3.3%), BMI (−3.3%), and waist circumference (−2.8%) in women. Decreased diabetes risk by lifestyle intervention was associated with reductions of body weight, BMI, and central body fat distribution after adjustment for age and self-reported ethnicity. Reduced diabetes risk with lifestyle intervention may have been through effects upon both overall body fat and central body fat but with metformin appeared to be independent of body fat.
Glucose-Dependent Modulation of Insulin Secretion and Intracellular Calcium Ions by GKA50, a Glucokinase Activator
Authors: Johnson Daniel , Shepherd Ruth M. , Gill Debra , Gorman Tracy , Smith David M. , Dunne Mark J.
Published: May 2007

Because glucokinase is a metabolic sensor involved in the regulated release of insulin, we have investigated the acute actions of novel glucokinase activator compound 50 (GKA50) on islet function. Insulin secretion was determined by enzyme-linked immunosorbent assay, and microfluorimetry with fura-2 was used to examine intracellular Ca2+ homeostasis ([Ca2+]i) in isolated mouse, rat, and human islets of Langerhans and in the MIN6 insulin-secreting mouse cell line. In rodent islets and MIN6 cells, 1 μmol/l GKA50 was found to stimulate insulin secretion and raise [Ca2+]i in the presence of glucose (2–10 mmol/l). Similar effects on insulin release were also seen in isolated human islets. GKA50 (1 μmol/l) caused a leftward shift in the glucose-concentration response profiles, and the half-maximal effective concentration (EC50) values for glucose were shifted by 3 mmol/l in rat islets and ∼10 mmol/l in MIN6 cells. There was no significant effect of GKA50 on the maximal rates of glucose-stimulated insulin secretion. In the absence of glucose, GKA50 failed to elevate [Ca2+]i (1 μmol/l GKA50) or to stimulate insulin release (30 nmol/l–10 μmol/l GKA50). At 5 mmol/l glucose, the EC50 for GKA50 in MIN6 cells was ∼0.3 μmol/l. Inhibition of glucokinase with mannoheptulose or 5-thioglucose selectively inhibited the action of GKA50 on insulin release but not the effects of tolbutamide. Similarly, 3-methoxyglucose prevented GKA50-induced rises in [Ca2+]i but not the actions of tolbutamide. Finally, the ATP-sensitive K+ channel agonist diazoxide (200 μmol/l) inhibited GKA50-induced insulin release and its elevation of [Ca2+]i. We show that GKA50 is a glucose-like activator of β-cell metabolism in rodent and human islets and a Ca2+-dependent modulator of insulin secretion.
Prevalence and Prognostic Impact of Subclinical Cardiovascular Disease in Individuals With the Metabolic Syndrome and Diabetes
Authors: Ingelsson Erik , Sullivan Lisa M. , Murabito Joanne M. , Fox Caroline S. , Benjamin Emelia J. , Polak Joseph F. , Meigs James B. , Keyes Michelle J. , O'Donnell Christopher J. , Wang Thomas J. , D'Agostino Ralph B. , Wolf Philip A. , Vasan Ramachandran S.
Published: May 2007

Data are limited regarding prevalence and prognostic significance of subclinical cardiovascular disease (CVD) in individuals with metabolic syndrome (MetS). We investigated prevalence of subclinical CVD in 1,945 Framingham Offspring Study participants (mean age 58 years; 59% women) using electrocardiography, echocardiography, carotid ultrasound, ankle-brachial blood pressure, and urinary albumin excretion. We prospectively evaluated the incidence of CVD associated with MetS and diabetes according to presence versus absence of subclinical disease. Cross-sectionally, 51% of 581 participants with MetS had subclinical disease in at least one test, a frequency higher than individuals without MetS (multivariable-adjusted odds ratio 2.06 [95% CI 1.67–2.55]; P < 0.0001). On follow-up (mean 7.2 years), 139 individuals developed overt CVD, including 59 with MetS (10.2%). Overall, MetS was associated with increased CVD risk (multivariable-adjusted hazards ratio [HR] 1.61 [95% CI 1.12–2.33]). Participants with MetS and subclinical disease experienced increased risk of overt CVD (2.67 [1.62–4.41] compared with those without MetS, diabetes, or subclinical disease), whereas the association of MetS with CVD risk was attenuated in absence of subclinical disease (HR 1.59 [95% CI 0.87–2.90]). A similar attenuation of CVD risk in absence of subclinical disease was observed also for diabetes. Subclinical disease was a significant predictor of overt CVD in participants without MetS or diabetes (1.93 [1.15–3.24]). In our community-based sample, individuals with MetS have a high prevalence of subclinical atherosclerosis that likely contributes to the increased risk of overt CVD associated with the condition.
Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms
Authors: Zhang Yiying , Guo Kaiying , LeBlanc Robert E. , Loh Daniella , Schwartz Gary J. , Yu Yi-Hao
Published: May 2007

Leucine, as an essential amino acid and activator of mTOR (mammalian target of rapamycin), promotes protein synthesis and suppresses protein catabolism. However, the effect of leucine on overall glucose and energy metabolism remains unclear, and whether leucine has beneficial effects as a long-term dietary supplement has not been examined. In the present study, we doubled dietary leucine intake via leucine-containing drinking water in mice with free excess to either a rodent chow or a high-fat diet (HFD). While it produced no major metabolic effects in chow-fed mice, increasing leucine intake resulted in up to 32% reduction of weight gain (P < 0.05) and a 25% decrease in adiposity (P < 0.01) in HFD-fed mice. The reduction of adiposity resulted from increased resting energy expenditure associated with increased expression of uncoupling protein 3 in brown and white adipose tissues and in skeletal muscle, while food intake was not decreased. Increasing leucine intake also prevented HFD-induced hyperglycemia, which was associated with improved insulin sensitivity, decreased plasma concentrations of glucagon and glucogenic amino acids, and downregulation of hepatic glucose-6-phosphatase. Additionally, plasma levels of total and LDL cholesterol were decreased by 27% (P < 0.001) and 53% (P < 0.001), respectively, in leucine supplemented HFD-fed mice compared with the control mice fed the same diet. The reduction in cholesterol levels was largely independent of leucine-induced changes in adiposity. In conclusion, increases in dietary leucine intake substantially decrease diet-induced obesity, hyperglycemia, and hypercholesterolemia in mice with ad libitum consumption of HFD likely via multiple mechanisms.
8:01 AM, 20,000 people, and 450 kilograms of explosives
Authors: van der Hoorn Mélanie
Published: May 2007

The demolition of undesired buildings is often an ambiguous event: it can be seen as a brutal attack by some people, whereas others consider it necessary to construct something new. What needs to be accomplished is not a simple physical act, but principally the acceptance of disposal as something needed and wanted, rather than unnecessary wastage. Here resides the controversial and ambivalent character of many acts of disposal. Detonation, therefore, is a passage that acquires its relevance thanks to a careful orchestration of the event in which an unwanted piece of architecture is thrown into the public spotlight, proffering a glimpse of a multiplicity of possibilities, while simultaneously providing a remarkably powerful dual experience of the durability and ephemerality of man-made structures. The biography of the Kaiserbau in Troisdorf illustrates these issues: once a would-be mega-hotel between Köln and Bonn, the concrete structure was dynamited on 13 May 2001—a spectacle attended by no less than 20,000 people, despite the ungodly hour at which it took place.
'Greater good' in transit
Authors: Boholm Åsa
Published: May 2007

Large-scale technological projects are born as visions among politicians and leaders of industry. For such visions to become real, they must be transformed from a virtual existence in the minds of their creators to a reality that can be accepted, even welcomed, by the public, not least by the communities who will become neighbors to those projects. Democracy implies that political decisions over the expenditure of public funds should answer not merely to the partial interests of stakeholders but should be accountable to the 'greater good' of society at large. Since a technological project materializes in what Latour calls a 'variable ontology-world', the greater good associated with it can be expected to be dynamic and shifting. The Hallandsås railway tunnel in southwestern Sweden illustrates how the very premises of the project's organizational logic have changed over time, the discourse of the greater good moving from an economical focus to an environmental one.
"On the correct handling of contradictions"
Authors: Steur Luisa
Published: May 2007

Ronald Niezen, The origins of indigenism: human rights and the politics of identity. Berkeley: University of California Press, 2003, 272 pp., ISBN 0520-23554-1 (hb), 0520-23556-8 (pb).