bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin Signaling in the Central Nervous System Is Critical for the Normal Sympathoadrenal Response to Hypoglycemia
Authors: Fisher Simon J. , Brüning Jens C. , Lannon Scott , Kahn C. Ronald
Published: March 2007

Hypoglycemia, hypoglycemia unawareness, and impaired counterregulation are major challenges to the intensive management of type 1 diabetes. While the counterregulatory response to hypoglycemia is predominantly determined by the degree and duration of hypoglycemia, there is now evidence that insulin per se may influence the counterregulatory response to hypoglycemia. To define the role of insulin action in the central nervous system in regulating the counterregulatory response to hypoglycemia, mice with a brain/neuron-specific insulin receptor knockout (NIRKO) and littermate controls were subjected to 90-min hyperinsulinemic (20 mU · kg−1 · min−1) -hypoglycemic (∼1.5 mmol/l) clamps. In response to hypoglycemia, epinephrine levels rose 5.7-fold in controls but only 3.5-fold in NIRKO mice. Similarly, in response to hypoglycemia, norepinephrine levels rose threefold in controls, but this response was almost completely absent in NIRKO mice. In contrast, glucagon and corticosterone responses to hypoglycemia were similar in both groups. Thus, insulin action in the brain is critical for full activation of the sympathoadrenal response to hypoglycemia, and altered neural insulin signaling could contribute to defective glucose counterregulation in diabetes.
Demonstration of a Hyperglycemia-Driven Pathogenic Abnormality of Copper Homeostasis in Diabetes and Its Reversibility by Selective Chelation
Authors: Cooper Garth J.S. , Chan Yih-Kai , Dissanayake Ajith M. , Leahy Fiona E. , Keogh Geraldine F. , Frampton Chris M. , Gamble Gregory D. , Brunton Dianne H. , Baker John R. , Poppitt Sally D.
Published: March 2007

We recently showed that treatment with the CuII-selective chelator, trientine, alleviates heart failure in diabetic rats, improves left ventricular hypertrophy in humans with type 2 diabetes, and increases urinary Cu excretion in both diabetic rats and humans compared with nondiabetic control subjects. In this study, we characterized the homeostasis of Cu and eight other nutritionally essential elements in diabetes under fully residential conditions in male subjects with type 2 diabetes and age-matched control subjects. We then probed elemental balance with oral trientine in a parallel-group, placebo-controlled study in these subjects. Before treatment, there were no detectable between-group differences in the balance of any element, although urinary output of several elements was greater in diabetic subjects. Mean extracellular superoxide dismutase (EC-SOD) activity was elevated in diabetic subjects, and its activity correlated strongly with the interaction between [Cu]serum and HbA1c. Trientine caused the Cu balance to become negative in diabetic subjects through elevated urinary Cu losses and suppressed elevated EC-SOD. Basal urinary Cu predicted urinary Cu losses during treatment, which caused extraction of systemic CuII. We suggest that cardiovascular complications in diabetes might be better controlled by therapeutic strategies that focus on lowering plasma glucose and loosely bound systemic CuII.
Intensive Lifestyle Intervention or Metformin on Inflammation and Coagulation in Participants With Impaired Glucose Tolerance
Authors:   The Diabetes Prevention Program Research Group
Published: March 2007

Increases in subclinical inflammation (C-reactive protein [CRP]) and impaired coagulation have been associated with increased obesity and insulin resistance. Only a few small studies have examined the effect of lifestyle changes, such as weight loss, increased physical activity, and insulin-sensitizing intervention on inflammation and coagulation. The Diabetes Prevention Program (DPP) clinical trial studied the effect of an intensive lifestyle intervention or metformin on progression to diabetes relative to placebo in 3,234 adults with impaired glucose tolerance. The effects of these interventions on CRP and fibrinogen at 12 months are examined in this report. Metformin reduced CRP in women compared with the placebo group. In men, the median changes in CRP from baseline to 1 year were −33% in the lifestyle group, −7% in the metformin group, and +5% in the placebo group. In women, the changes in CRP from baseline to follow-up were −29% in the lifestyle group, −14% in the metformin group, and 0% in the placebo group. In the lifestyle group weight loss rather than increased physical activity seems to account for most of the changes in CRP. Only modest reductions (although significant) were seen in fibrinogen levels in the lifestyle group relative to the metformin and placebo group. Lifestyle intervention reduced levels of nontraditional cardiovascular risk factors relative to both placebo and to a lesser degree to metformin.
Subcellular Localization of ALMS1 Supports Involvement of Centrosome and Basal Body Dysfunction in the Pathogenesis of Obesity, Insulin Resistance, and Type 2 Diabetes
Authors: Hearn Tom , Spalluto Cosma , Phillips Victoria J. , Renforth Glenn L. , Copin Nane , Hanley Neil A. , Wilson David I.
Published: March 2007

Alström syndrome is a rare autosomal recessive disorder caused by mutations in a novel gene of unknown function, ALMS1. Central features of Alström syndrome include obesity, insulin resistance, and type 2 diabetes, and therefore investigating ALMS1 function stands to offer new insights into the pathogenesis of these common conditions. To begin this process, we have analyzed the subcellular localization and tissue distribution of ALMS1 by immunofluorescence. We show that ALMS1 is widely expressed and localizes to centrosomes and to the base of cilia. Fibroblasts with disrupted ALMS1 assemble primary cilia and microtubule cytoskeletons that appear normal, suggesting that the Alström syndrome phenotype results from impaired function rather than abnormal development. Coupled with recent data on the complex phenotype of Bardet-Biedl syndrome, our findings imply an unexpected central role for basal body and centrosome dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Unraveling the molecular mechanisms underlying the Alström syndrome phenotype will be important in the search for new therapeutic targets for these conditions.
OAS1 Splice Site Polymorphism Controlling Antiviral Enzyme Activity Influences Susceptibility to Type 1 Diabetes
Authors: Field L. Leigh , Bonnevie-Nielsen Vagn , Pociot Flemming , Lu Shao , Nielsen Thomas B. , Beck-Nielsen Henning
Published: March 2007

Both genetic and nongenetic factors contribute to the development of type 1 diabetes. Many investigations, including prospective studies of high-risk children, have implicated virus infections as predisposing environmental agents. We previously reported that basal activity of the key antiviral enzyme 2′5′-oligoadenylate synthetase (2′5′AS) was significantly elevated in type 1 diabetic patients compared with healthy control subjects. Recently, we showed that an A/G splice site single nucleotide polymorphism (SNP) in the OAS1 gene encoding 2′5′AS is strongly associated with basal 2′5′AS activity. Basal enzyme activity was highest in individuals with GG genotype and lowest in those with AA genotype. In the present study, we genotyped 835 type 1 diabetic and 401 healthy siblings at the OAS1 splice site polymorphism and (for comparison) at an A/C SNP of the insulin (IDDM2) locus. Results showed that OAS1 GG and GA were significantly increased in diabetic compared with healthy siblings (P = 0.0023). The strength of association was similar to that at IDDM2, where, as expected, the C/C (variable number tandem repeat class I homozygote) genotype was increased in affected compared with healthy siblings (P = 0.0025). The results suggest that host genetic response to virus infection could influence susceptibility to type 1 diabetes.
Gene Transfer of Constitutively Active Akt Markedly Improves Human Islet Transplant Outcomes in Diabetic Severe Combined Immunodeficient Mice
Authors: Rao Poornima , Roccisana Jennifer , Takane Karen K. , Bottino Rita , Zhao Allan , Trucco Massimo , García-Ocaña Adolfo
Published: March 2007

Akt is an important intracellular mediator of β-cell growth and survival in rodents. However, whether constitutive activation of Akt in human β-cells enhances the survival and function of transplanted islets is unknown. In the current study, we examined the efficacy of constitutive activation of Akt in improving human islet transplant outcomes using a marginal mass model in diabetic severe combined immunodeficient (SCID) mice. Human islets transduced with adenoviruses encoding constitutively active Akt1 (Adv-CA-Akt) displayed increased total and phosphorylated Akt and Akt kinase activity compared with control islets. Expression of CA-Akt in human islets induced a significant increase in β-cell replication and a significant decrease in β-cell death induced by serum and glucose deprivation or chronic hyperglycemia. Two control groups of islets (1,500 uninfected or adenovirus LacZ [Adv-LacZ]–transduced human islet equivalents [IEQs]) transplanted under the kidney capsule of streptozotocin-induced diabetic SCID mice were insufficient to correct hyperglycemia. Importantly and in marked contrast to these controls, 1,500 Adv-CA-Akt–transduced IEQs were capable of restoring euglycemia in diabetic SCID mice. Moreover, blood glucose normalization persisted for at least 6 months. Human plasma insulin at day 54 after transplant was 10-fold higher in Adv-CA-Akt islet recipients (2.4 ± 0.4 ng/ml) compared with those receiving Adv-LacZ islets (0.25 ± 0.08 ng/ml) (P < 0.05). In summary, expression of CA-Akt in human islets improves islet transplant outcomes in a subcapsular renal graft model in SCID mice. Akt is an attractive target for future strategies aimed at reducing the number of islets required for successful islet transplantation in humans.
Prevention of Type 1 Diabetes with Major Histocompatibility Complex–Compatible and Nonmarrow Ablative Hematopoietic Stem Cell Transplants
Authors: Beilhack Georg F. , Landa Rosa R. , Masek Marilyn A. , Shizuru Judith A.
Published: March 2007

Progression to hyperglycemia in young nonobese diabetic (NOD) mice is blocked by the transplantation of hematopoietic cells mismatched at the major histocompatibility complex (MHC). Because the NOD MHC class II allele, I-Ag7, is the primary disease susceptibility gene, it is logical to conclude that MHC-mismatched hematopoietic grafts prevent diabetes by replacement of this susceptibility allele on critical hematolymphoid populations. In this report, transplantation of MHC-matched purified hematopoietic stem cells (HSCs) pre-vented diabetes development in NOD mice, demonstrating that alleles of non-MHC background genes expressed on hematopoietic cells are sufficient to disrupt the autoaggressive process. Nonmarrow ablative conditioning was 100% protective, further showing that elimination of NOD hematopoiesis, including T-cells, was not required for the graft to block diabetes pathogenesis. The current standard clinical practice of hematopoietic cell transplantation uses donor/recipient pairs that are matched at the MHC. In our view, the principles established here using an MHC-matched engineered hematopoietic graft in conjunction with nonmarrow ablative conditioning to successfully block autoimmune diabetes sufficiently reduces the morbidity of the allogeneic transplantation procedure such that a similar approach can be translated to the treatment of human autoimmune disorders.
Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic α-Cells
Authors: Ravier Magalie A. , Rutter Guy A.
Published: March 2007

The mechanisms by which hypoglycemia stimulates glucagon release are still poorly understood. In particular, the relative importance of direct metabolic coupling versus paracrine regulation by β-cell secretory products is unresolved. Here, we compare the responses to glucose of 1) α-cells within the intact mouse islet, 2) dissociated α-cells, and 3) clonal αTC1-9 cells. Free cytosolic concentrations of ATP ([ATP]c) or Ca2+ ([Ca2+]c) were imaged using α-cell–targeted firefly luciferase or a green fluorescent protein–based Ca2+ probe (“pericam”), respectively. Consistent with a direct effect of glucose on α-cell oxidative metabolism, an increase in glucose concentration (from 0 or 3 mmol/l to 20 mmol/l) increased [ATP]c by 7–9% in α-cells within the intact islet and by ∼4% in αTC1-9 cells. Moreover, glucose also dose-dependently decreased the frequency of [Ca2+]c oscillations in both dissociated α-cells and αTC1-9 cells. Although the effects of glucose were mimicked by exogenous insulin, they were preserved when insulin signaling was blocked with wortmannin. Addition of ZnCl2 slightly increased the frequency of [Ca2+]c oscillations but failed to affect glucagon release from either islets or αTC1-9 cells under most conditions. We conclude that glucose and insulin, but not Zn2+ ions, independently suppress glucagon secretion in the mouse.
Fine-Mapping Gene-by-Diet Interactions on Chromosome 13 in a LG/J × SM/J Murine Model of Obesity
Authors: Ehrich Thomas H. , Hrbek Tomas , Kenney-Hunt Jane P. , Pletscher L. Susan , Wang Bing , Semenkovich Clay F. , Cheverud James M.
Published: March 2007

Obesity is one of the most serious threats to human health today. Although there is general agreement that environmental factors such as diet have largely caused the current obesity pandemic, the environmental changes have not affected all individuals equally. To model gene-by-environment interactions in a mouse model system, our group has generated an F16 advanced intercross line (AIL) from the SM/J and LG/J inbred strains. Half of our sample was fed a low-fat (15% energy from fat) diet while the other half was fed a high-fat (43% energy from fat) diet. The sample was assayed for a variety of obesity- and diabetes-related phenotypes such as growth rate, response to glucose challenge, organ and fat pad weights, and serum lipids and insulin. An examination in the F16 sample of eight adiposity quantitative trait loci previously identified in an F2 intercross of SM/J and LG/J mouse strains reveals locus-by-diet interactions for all previously mapped loci. Adip7, located on proximal chromosome 13, demonstrated the most interactions and therefore was selected for fine mapping with microsatellite markers. Three phenotypic traits, liver weight in male animals, serum insulin in male animals, and reproductive fat pad weight, show locus-by-diet interactions in the 127-kb region between markers D13Mit1 and D13Mit302. The phosphofructokinase (PFK) C (Pfkp) and the pitrilysin metalloprotease 1 (Pitrm1) genes are compelling positional candidate genes in this region that show coding sequence differences between the parental strains in functional domains.
“Extended” A1, B8, DR3 Haplotype Shows Remarkable Linkage Disequilibrium but Is Similar to Nonextended Haplotypes in Terms of Diabetes Risk
Authors: Ide Akane , Babu Sunanda R. , Robles David T. , Wang Tianbao , Erlich Henry A. , Bugawan Teodorica L. , Rewers Marian , Fain Pamela R. , Eisenbarth George S.
Published: March 2007

To evaluate potential differential diabetes risk of DR3 haplotypes we have evaluated class I alleles as well as two microsatellites previously associated with differential risk associated with DR3 haplotypes. We found that over one-third of patient DR3 chromosomes consisted of an extended DR3 haplotype, from DQ2 to D6S2223 (DQ2, DR3, D6S273-143, MIC-A5.1, HLA-B8, HLA-Cw7, HLA-A1, and D6S2223-177) with an identical extended haplotype in controls. The extended haplotype was present more frequently (35.1% of autoimmune-associated DR3 haplotypes, 39.4% of control DR3 haplotypes) than other haplotypes (no other haplotype >5% of DR3 haplotypes) and remarkably conserved, but it was not transmitted from parents to affected children more frequently than nonconserved DR3-bearing haplotypes. This suggests that if all alleles are truly identical for the major A1, B8, DR3 haplotype (between A1 and DR3), with different alleles on nonconserved haplotypes without differential diabetes risk, then in this region of the genome DR3-DQ2 may be the primary polymorphisms of common haplotypes contributing to diabetes risk.
Maternal Factors in a Model of Type 1 Diabetes Differentially Affect the Development of Insulitis and Overt Diabetes in Offspring
Authors: Kagohashi Yukiko , Udagawa Jun , Abiru Norio , Kobayashi Masakazu , Moriyama Kenji , Otani Hiroki
Published: March 2007

Type 1 diabetes, a multifactorial disease involving genetic and environmental factors, results from the destruction of pancreatic β-cells. The maternal environment has been suggested to be important in the development of diabetes. To assess the role of maternal factors in the development of insulitis and overt diabetes, we transplanted pre-implantation stage embryos of nonobese diabetic (NOD) mice, a model of type 1 diabetes, into the uterus of each recipient. Recipients were ICR and DBA/2J mice without diabetic genetic predisposition and NOD mice not exhibiting overt diabetes during the experiment; offspring were designated as NOD/ICR, NOD/DBA, and NOD/NOD, respectively; unmanipulated NOD offspring were also examined. NOD/ICR and NOD/DBA offspring developed insulitis significantly earlier than NOD/NOD offspring. However, overt diabetes was significantly suppressed in NOD/ICR and NOD/DBA offspring in comparison with NOD/NOD offspring. Insulin autoantibodies (IAAs) were undetectable in ICR and DBA/2J surrogate mothers and in NOD/ICR and NOD/DBA offspring at the onset of insulitis, suggesting that maternal factors other than transmitted IAAs induced the earlier onset. The present study indicates that altered maternal factors modify the immune response to islets, which in turn might affect the pathogenic course from insulitis to overt diabetes.
Identification of Naturally Processed HLA-A2—Restricted Proinsulin Epitopes by Reverse Immunology
Authors: Hassainya Yousra , Garcia-Pons Francisco , Kratzer Roland , Lindo Vivian , Greer Fiona , Lemonnier François A. , Niedermann Gabriele , van Endert Peter M.
Published: March 2007

Type 1 diabetes is thought to result from the destruction of β-cells by autoantigen-specific T-cells. Observations in the NOD mouse model suggest that CD8+ cytotoxic T-cells play an essential role in both the initial triggering of insulitis and its destructive phase. However, little is known about the epitopes derived from human β-cell autoantigens and presented by HLA class I molecules. We used a novel reverse immunology approach to identify HLA-A2−restricted, naturally processed epitopes derived from proinsulin, an autoantigen likely to play an important role in the pathogenesis of type 1 diabetes. Recombinant human proinsulin was digested with purified proteasome complexes to establish an inventory of potential COOH-terminals of HLA class I−presented epitopes. Cleavage data were then combined with epitope predictions based on the SYFPEITHI and BIMAS algorithms to select 10 candidate epitopes; 7 of these, including 3 with a sequence identical to murine proinsulin, were immunogenic in HLA-A2 transgenic mice. Moreover, six of six tested peptides were processed and presented by proinsulin-expressing cells. These results demonstrate the power of reverse immunology approaches. Moreover, the novel epitopes may be of significant interest in monitoring autoreactive T-cells in type 1 diabetes.
Hepatic Lipase Gene Variant −514C>T Is Associated With Lipoprotein and Insulin Sensitivity Response to Regular Exercise
Authors: Teran-Garcia Margarita , Santoro Nicola , Rankinen Tuomo , Bergeron Jean , Rice Treva , Leon Arthur S. , Rao D.C. , Skinner James S. , Bergman Richard N. , Després Jean-Pierre , Bouchard Claude
Published: March 2007

We investigated the associations between the hepatic lipase gene (LIPC) −514C>T polymorphism and lipases, lipoproteins, and insulin sensitivity (Si) responses to exercise training. Hepatic lipase and lipoprotein lipase activities, plasma lipoprotein levels, and Si were measured in the sedentary state and post–exercise training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study (n = 662). The LIPC −514C allele frequency was 0.516 (blacks) and 0.796 (whites). Baseline and post–exercise training hepatic lipase activities were 40% higher in CC homozygotes (P < 0.0001) in both races. Black CC homozygotes had lower baseline lipoprotein lipase activity, HDL cholesterol, HDL3, and apolipoprotein (apo)A-1 concentrations. White CC homozygotes had lower baseline HDL cholesterol, apoA-1, LDL cholesterol, and apoB levels that remained low post–exercise training. Baseline Si was not associated with the LIPC genotypes. However, training-induced improvements in Si both in blacks and whites were greater in CC homozygotes (+1.25 ± 0.2 and +0.22 ± 0.2 μU · min−1 · ml−1) than in the TT genotype (+0.27 ± 0.3 and −0.97 ± 0.3 μU · min−1 · ml−1) (P = 0.008 and P = 0.002, respectively). The LIPC −514C allele was associated with higher hepatic lipase activity in sedentary and physically active states and better Si responses to regular exercise both in black and white individuals. The benefits from an exercise program on Si are likely to be substantial in the general population given the high frequency of the LIPC −514C allele, particularly in whites.
Rosiglitazone Reduces Glucose-Stimulated Insulin Secretion Rate and Increases Insulin Clearance in Nondiabetic, Insulin-Resistant Individuals
Authors: Kim Sun H. , Abbasi Fahim , Chu James W. , McLaughlin Tracey L. , Lamendola Cindy , Polonsky Kenneth S. , Reaven Gerald M.
Published: March 2007

Compensatory hyperinsulinemia permitting insulin-resistant individuals to maintain normal glucose tolerance is associated with a left shift in the glucose-stimulated insulin secretion rate (GS-ISR) dose-response curve and decrease in the insulin metabolic clearance rate (I-MCR). To see whether these changes would reverse with improvement in insulin sensitivity, 14 nondiabetic insulin-resistant subjects received rosiglitazone for 12 weeks (4 mg daily for 4 weeks and then 8 mg daily for 8 weeks). Insulin-mediated glucose uptake was quantified by measuring the steady-state plasma glucose concentration during the insulin suppression test. GS-ISR and I-MCR were determined during a 240-min graded intravenous glucose infusion. I-MCR was also calculated during the insulin suppression test. After rosiglitazone treatment, insulin sensitivity improved with significant fall in steady-state plasma glucose (means ± SE from 13.5 ± 0.62 to 9.8 ± 1.02 mmol/l, P < 0.001). In response, the integrated GS-ISR decreased by 21% (P < 0.001), with a right shift in the dose-response curve. Calculated I-MCR increased by 34% (P = 0.008) during the insulin suppression test and by 21% (P = 0.03) during the graded glucose infusion. In conclusion, enhanced insulin sensitivity in rosiglitazone-treated nondiabetic insulin-resistant individuals was associated with a shift to the right in the GS-ISR dose-response curve and an increase in I-MCR.
A Synonymous Coding Polymorphism in the α2-Heremans-Schmid Glycoprotein Gene Is Associated With Type 2 Diabetes in French Caucasians
Authors: Siddiq Afshan , Lepretre Frederic , Hercberg Serge , Froguel Philippe , Gibson Fernando
Published: March 2007

α2-Heremans-Schmid glycoprotein (AHSG) is an abundant plasma protein synthesized predominantly in the liver. The AHSG gene, consisting of seven exons and spanning 8.2 kb of genomic DNA, is located at chromosome 3q27, a susceptibility locus for type 2 diabetes and the metabolic syndrome. AHSG is a natural inhibitor of the insulin receptor tyrosine kinase, and AHSG-null mice exhibit significantly enhanced insulin sensitivity. These observations suggested that the AHSG gene is a strong positional and biological candidate for type 2 diabetes susceptibility. Direct sequencing of the AHSG promoter region and exons identified nine common single nucleotide polymorphisms (SNPs) with a minor allele frequency ≥5%. We carried out a detailed genetic association study of the contribution of these common AHSG SNPs to genetic susceptibility of type 2 diabetes in French Caucasians. The major allele of a synonymous coding SNP in exon 7 (rs1071592) presented significant evidence of association with type 2 diabetes (P = 0.008, odds ratio 1.27 [95% CI 1.06–1.52]). Two other SNPs (rs2248690 and rs4918) in strong linkage disequilibrium with rs1071592 showed evidence approaching significance. A haplotype carrying the minor allele of SNP rs1071592 was protective against type 2 diabetes (P = 0.014). However, our analyses indicated that rs1071592 is not associated with the evidence for linkage of type 2 diabetes to 3q27.
Novel Leptin Receptor Mutation in NOD/LtJ Mice Suppresses Type 1 Diabetes Progression
Authors: Lee Chul-Ho , Reifsnyder Peter C. , Naggert Jürgen K. , Wasserfall Clive , Atkinson Mark A. , Chen Jing , Leiter Edward H.
Published: March 2007

A spontaneous single-base mutation in the leptin receptor of type 1 diabetes−prone NOD/LtJ mice (designated as Leprdb-5J) produced a glycine640valine transversion in the extracellular domain. All mutant mice became obese and hyperinsulinemic at weaning, with 70–80% developing early-onset hyperglycemia. However, these obese diabetic mice continued to gain weight without insulin therapy. Spontaneous diabetes remission was observed in all obese females and a subset of obese males. Insulitis was largely limited to islet perimeters, with intraislet insulitis infrequently observed. In 17 obese males (age 39 weeks), we observed phenotypic heterogeneity, including full remission from hyperglycemia (24%), intermediate hyperglycemia with elevated body weight (41%), and severe hyperglycemia and weight loss (35%). The remitting normoglycemic and intermediate hyperglycemic phenotypes were associated with extensive β-cell hyperplasia. Unlike the extensive intraislet insulitis present in diabetic lean NOD/Lt mice, the severe obese diabetic phenotype was associated with islet atrophy without extensive intraislet insulitis. These results indicated that the manipulation of the leptin/leptin receptor axis may provide a novel means of downregulating autoimmunity in type 1 diabetes and confirmed a role for leptin as a mediator in the development of this disease in NOD mice.
ATP and Sulfonylurea Sensitivity of Mutant ATP-Sensitive K+ Channels in Neonatal Diabetes
Authors: Koster Joseph C. , Remedi Maria S. , Dao Crystal , Nichols Colin G.
Published: March 2007

The prediction that overactivity of the pancreatic ATP-sensitive K+ channel (KATP channel) underlies reduced insulin secretion and causes a diabetic phenotype in humans has recently been borne out by genetic studies implicating “activating” mutations in the Kir6.2 subunit of KATP as causal in both permanent and transient neonatal diabetes. Here we characterize the channel properties of Kir6.2 mutations that underlie transient neonatal diabetes (I182V) or more severe forms of permanent neonatal diabetes (V59M, Q52R, and I296L). In all cases, the mutations result in a significant decrease in sensitivity to inhibitory ATP, which correlates with channel “overactivity” in intact cells. Mutations can be separated into those that directly affect ATP affinity (I182V) and those that stabilize the open conformation of the channel and indirectly reduce ATP sensitivity (V59M, Q52R, and I296L). With respect to the latter group, alterations in channel gating are also reflected in a functional “uncoupling” of sulfonylurea (SU) block: SU sensitivity of I182V is similar to that of wild-type mutants, but the SU sensitivity of all gating mutants is reduced, with the I296L mutant being resistant to block by tolbutamide (≤10 mmol/l). These results have important implications for the use of insulinotropic SU drugs as an alternative therapy to insulin injections.
Spillover of Dietary Fatty Acids and Use of Serum Nonesterified Fatty Acids for the Synthesis of VLDL-Triacylglycerol Under Two Different Feeding Regimens
Authors: Barrows Brian R. , Timlin Maureen T. , Parks Elizabeth J.
Published: March 2007

The present study quantified dietary fatty acid flux in healthy men (n = 6) who were fed a liquid formula through a duodenal feeding tube (continuous feeding group) or who consumed the same formula in meals (meal feeding group). A triacylglycerol (TAG) stable isotope was added to the formula to determine the entry of dietary fatty acids into the serum and its clearance to the liver and resecretion into serum via VLDL. The contribution of dietary fatty acids to serum nonesterified fatty acids (NEFAs) was higher with meal feeding (24.4 ± 2.6%) compared with continuous feeding (10.8 ± 2.9%, P < 0.01) and, when multiplied by the NEFA concentration, resulted in similar absolute fatty acid spillover. Diet-derived NEFAs subsequently represented 10.6 ± 1.2% and 4.7 ± 1.3% of hepatic VLDL-TAG (meal feeding vs. continuous feeding, respectively, P = 0.004). Chylomicron remnant uptake by the liver contributed 9.3 ± 1.9% of fatty acids to hepatic VLDL-TAG synthesis with meal feeding compared with continuous feeding (4.4 ± 0.8%, P < 0.03). These data suggest that the extent of dietary fatty acid recycling via serum NEFAs and VLDL-TAG is determined by the rate of delivery of dietary fat to the intestine. The inefficient removal of dietary fat from the circulation may maintain VLDL-TAG production but may also result in prolonged postprandial lipemia.
Association of Systemic Chemokine Concentrations With Impaired Glucose Tolerance and Type 2 Diabetes
Authors: Herder Christian , Haastert Burkhard , Müller-Scholze Sylvia , Koenig Wolfgang , Thorand Barbara , Holle Rolf , Wichmann H.-Erich , Scherbaum Werner A. , Martin Stephan , Kolb Hubert
Published: March 2007

Chemokines are crucial immune mediators in many physiological and pathophysiological conditions. Chemokines have been hypothesized to be involved in macrophage infiltration into adipose tissue in obesity and might therefore play an important role in the development of obesity-related disorders like type 2 diabetes. Out of 1,653 individuals aged 55–74 years participating in a population-based survey in southern Germany (the Kooperative Gesundheitsforschung in der Region Augsburg [KORA] [Cooperative Health Research in the Region of Augsburg] Survey S4, 1999–2001), 236 individuals with type 2 diabetes, 242 subjects with impaired glucose tolerance (IGT), and 244 normoglycemic control subjects were studied for circulating concentrations of interleukin (IL)-8; RANTES (regulated on activation, normal T-cell expressed, and secreted); interferon-γ–inducible protein-10 (IP-10), and eotaxin. Systemic concentrations of RANTES were higher in individuals with IGT or type 2 diabetes than in control subjects, whereas IL-8 levels were elevated in type 2 diabetic patients only (P < 0.001 for all comparisons). IP-10 and eotaxin were not significantly associated with IGT or type 2 diabetes. Adjustment for age, sex, BMI, hypertension, LDL cholesterol, HDL cholesterol, uric acid, C-reactive protein, and IL-6 did not alter these findings. Our findings indicate that RANTES and IL-8 may be involved in the development of type 2 diabetes independent of metabolic syndrome–related risk factors and of each other. There is no general upregulation of chemokine production in type 2 diabetes, but rather an association of the disease with specific members of the chemokine family.
Class III Alleles at the Insulin VNTR Polymorphism Are Associated With Regulatory T-Cell Responses to Proinsulin Epitopes in HLA-DR4, DQ8 Individuals
Authors: Durinovic-Belló Ivana , Jelinek Eva , Schlosser Michael , Eiermann Thomas , Boehm Bernhard O. , Karges Wolfram , Marchand Luc , Polychronakos Constantin
Published: March 2007

A variable number of tandem repeats (VNTR) polymorphism upstream of the insulin promoter is strongly associated with type 1 diabetes. The short class I alleles are predisposing and the long class III alleles are protective. As a possible mechanism for this effect, we previously reported a two- to threefold higher insulin transcription from class III than from class I chromosomes in thymus where insulin is expressed at low levels, presumably for the purpose of self-tolerance. In this article, we confirm this finding with independent methodology and report studies testing the hypothesis that class III alleles are associated with T-cell tolerance to (pro)insulin. Cytokine release in vitro after stimulation with 21 overlapping preproinsulin epitopes was assessed in blood mononuclear cells as well as naive and memory CD4+ T-cell subsets from 33 individuals with the high-risk DRB1*04, DQ8 haplotype (12 type 1 diabetic patients, 11 healthy control subjects, and 10 autoantibody-positive subjects). No significant differences between genotypes (24 I/I subjects versus 10 I/III or III/III subjects) were observed for γ-interferon, tumor necrosis factor-α, or interleukin (IL)-4. By contrast, the I/III + III/III group showed a significant threefold higher IL-10 release in memory T-cells for whole proinsulin and the immunodominant region. Given that IL-10 is a marker of regulatory function, our data are consistent with the hypothesis that higher insulin levels in the thymus promote the formation of regulatory T-cells, a proposed explanation for the protective effect of the class III alleles.
N,N,N′,N′,N″‐Pentamethyl‐N″‐[(trifluorosilyl)methyl] phosphoric triamide. First example of the existence of intramolecular PO→Si coordination bond in the Si‐containing phosphoric triamides
Authors: Lazareva Nataliya F. , Albanov Alexander I. , Lazarev Igor M. , Pestunovich Vadim A.
Published: March 2007

The N,N,N′,N′,N″‐pentamethyl‐N″‐(trifluorosilylmethyl)phosphoric triamide OP(NMe2)2N(Me) CH2SiF3 with intramolecular PO→Si coordination was formed by the reaction of N,N,N′,N′,N″‐pentamethyl‐N″[(triethoxysilyl)methyl]phosphoric triamide with BF3·Et2O. Copyright © 2007 John Wiley & Sons, Ltd.
Carbon nanotube synthesis using ferrocene and ferrocenyl sulfide. The effect of sulfur
Authors: Mohlala M. Sarah , Liu Xin‐Ying , Witcomb Mike J. , Coville Neil J.
Published: March 2007

Multiwalled carbon nanotubes (MWCNTs) have been synthesized by the floating catalyst method using toluene as the carbon source and mixtures of ferrocene and ferrocenyl sulfide as the catalyst. Products were characterized by both low‐resolution and high‐resolution (HR) TEM analysis. It was found that the presence of large amounts of sulfur in the reactant mixture generated only amorphous carbon while lower amounts of sulfur led to mixtures of MWCNTs and carbon fibres. The product distribution, yield and the tube diameters varied with the sulfur content. HRTEM analysis revealed that the MWCNTs were poorly graphitized. Comparison with data using other sulfur sources (S8, thiophene) suggested that the proximity of the sulfur to the Fe catalyst in the gas phase did play a role in the CNT formation and provides a method of ‘carrying’ elements to a catalytic site. Copyright © 2007 John Wiley & Sons, Ltd.
Synthesis of some aromatic aldehydes and acids by sodium ferrate in presence of copper nano‐particles adsorbed on K 10 montmorillonite using microwave irradiation
Authors: Tandon Praveen K. , Singh Santosh B. , Srivastava Manish
Published: March 2007

Excellent yields were obtained in the oxidation of benzyl alcohol, benzaldehyde, 4‐methoxy benzyl alcohol and 4‐nitro benzaldehyde with sodium ferrate in the presence of copper nano particles adsorbed on montmorillonite K 10 under microwave irradiation. Aniline, p‐toluidine, phenol, catechol, resorcinol and p‐cresol polymerize under these conditions without exposing the mixture to microwaves. The one‐pot system does not require tedious separation of ferrate and is quick and environmentally benign. Copyright © 2007 John Wiley & Sons, Ltd.
Contamination of outdoor settled dust by butyltins in Malta
Authors: Decelis Rachel , Vella Alfred J.
Published: March 2007

The presence of compounds of tributyltin (TBT), dibutyltin (DBT) and monobutyltin (MBT) was determined in outdoor settled dust collected from several sites on the island of Malta, mainly from flat rooftops of school buildings. The dust was separated into three size fractions with diameters (µm) > 250, 125–250 and < 125, and the two finer fractions were analysed for butyltins using extraction with glacial acetic acid followed by derivatization/solvent extraction with sodium tetraethylborate in the presence of iso‐octane and quantitation by gas chromatography with flame photometric detection. The presence of TBT, DBT and MBT was established in most of the samples and TBT concentrations varied from non‐detectable (<5 ng Sn g−1) to highs of 15.5 and 18.7 µg Sn g−1 in Senglea and Marsaxlokk. TBT was generally found at concentrations significantly higher than reported hitherto in house dust collected from European homes. The geographical distribution of total organotins in both dust fractions suggests that TBT originates mainly from antifouling marine paint residues which contaminate the urban environment when ships' hulls are sand‐ or hydro‐blasted during maintenance and repair at the drydocks facility in Grand Harbour. Other significant sources of TBT are located at Marsaxlokk fishing port and Wied iż‐Żurrieq creek, both hosting sizeable communities of fishermen and leisure boating. The data also suggest that the municipal solid waste landfill at Maghtab is an inland source of butyltins. We suggest that dust containing harmful butyltins could possibly be ingested to expose humans to a risk which is probably of concern especially for young children living close to the hotspots of contamination. Copyright © 2007 John Wiley & Sons, Ltd.
Spontaneous lesions in the reproductive tract and mammary gland of female non‐human primates
Authors: Cooper Timothy K. , Gabrielson Kathleen L.
Published: March 2007

Because of their close phylogenic relationship with humans, the use of non‐human primates (NHP) as experimental subjects has a long history in biomedical research. Although research topics have shifted focus and species used have changed, NHP remain vital as models in basic and applied research. While there is a wealth of information available on the spontaneous lesions of NHP, most of this information is fragmented, dated, or narrow in focus, often limited to single case reports. This review attempts to integrate this information to illustrate and enumerate the spectrum of spontaneous pathology of the reproductive tract and mammary gland of NHP. Although not the focus of this review, steroid‐related changes are inextricably linked to these tissues, and brief consideration is given to this subject as well. Birth Defects Res (Part B), 2007. © 2007 Wiley‐Liss, Inc.
The shielding tensor. Part I: Understanding its symmetry properties
Authors: Anet Frank A. L. , O'Leary Daniel J.
Published: March 2007

The shielding tensor and the chemical shift tensor are not necessarily symmetric, and in general they have both symmetric and antisymmetric parts. The antisymmetric part (not to be confused with the anisotropy of the symmetric part) does not give rise to an observable shift, even in the solid phase, but it does cause relaxation. The antisymmetric part of the shielding tensor can be considered in its corresponding axial vector form, and this allows the effect of symmetry at a nuclear site to be deduced easily. Instead of considering the complete symmetry point group at the nucleus, it is easier to consider only certain key elements of symmetry; this leads to four simple rules that determine the zero and nonzero components of the complete shielding tensor.
Product operators and coherence transfer in multiple‐pulse NMR experiments
Authors: Shriver John
Published: March 2007

A practical introduction to coherence and coherence transfer pathways in NMR is provided using the density matrix and product‐operator formalisms. The concept of coherence in NMR is first introduced using the density matrix formalism. Pictorial and quantitative representations of coherence are provided using product operators in the Cartesian basis. A simple transformation from the Cartesian basis to a spherical basis is used to follow coherence order during multiple‐pulse experiments with coherence transfer pathways. The rules are introduced for designing phase cycles to eliminate unwanted coherences and pathways. An appendix contains a computer program written in Mathematica for performing product‐operator calculations interactively.
Fat and water differentiation by nuclear magnetic resonance imaging
Authors: Kaldoudi Eleni , Williams Steve C. R.
Published: March 2007

Differentiation between fat and water is important in proton magnetic resonance imaging. The need for creating separate fat and water images is discussed, and a review is presented of current practices, including chemical‐shift and coupled‐spin imaging, as well as techniques based on relaxation time differences. The virtues and limitations of each regime are discussed, and future directions are suggested.
Optimum tip angle and relaxation delay for quantitative analysis
Authors: Traficante Daniel D.
Published: March 2007

For the quantitative analysis of NMR spectra, the relationship between the tip angle and the relaxation delay is examined. It is shown that the common procedure of using a small tip angle combined with a short delay is not the optimum. Instead, an angle of approximately 83° with a pulse‐repetition period of 4.5 multiplied by the longest T1 is the optimum procedure. However, the results obtained from this procedure are only slightly better than those obtained from the standard „90 ‐ wait 5T1,”︁ method. It is further shown that the 83° angle is independent of T1, but that the integral accuracy is relatively dependent on the estimate of T1.
Nonlinear least‐squares fitting procedure for solid‐state NMR powder patterns
Authors: Kim Ae Ja , Butler Leslie G.
Published: March 2007

A fitting procedure for the extraction of the characteristic NMR parameters from solid‐state NMR powder patterns is described at an introductory level. The Levenberg‐Marquardt nonlinear least‐squares algorithm is recoded in Matlab, a vector‐oriented programming language, so that the NMR simulation programs are more condensed than are those in traditional programming languages. Three examples of line‐shape fitting are shown: the deuterium powder pattern for the bridging deuterium site in [Et4N] [2HCr2(CO)10], the proton‐coupled 13C powder pattern for the bridging methylene site in cis‐(μ‐CH2)(μ‐CO)[FeCp(CO)]2, and the (14N, 195Pt)‐coupled 13C powder pattern for the Pt‐CN system in K2Pt(CN)4 · 3H2O. The results provide information about quadrupolar, dipolar, and chemical‐shielding tensors. In each case, the line‐shape is calculated from the spin Hamiltonian expressed in a simple, uncoupled basis set. The variables in each case are a small set of NMR parameters: the quadruple‐coupling constant and the asymmetry parameter. The effects of finite pulse‐lengths or anisotropic cross‐polarization are not included in the line‐shape simulations. The line‐shapes are powder patterns; averaging over the Euler angles, θ and x, is done either with constant angle step size or by the Conroy‐Wolfsberg tiling scheme.
Parameterized description of NMR signal reception systems part I: Impedance of transmission line and probe
Authors: Cho Shin‐Il , Sullivan Neil S.
Published: March 2007

The impedance‐matched condition and its relation to the reflection coefficient are discussed. Some important properties of transmission lines for impedance‐matching are considered. Resonance tank circuits in NMR probes are discussed with analogies to microwave cavity resonances. By analyzing reflection coefficients in terms of Q factors, the impedance‐matched condition is re‐derived in a manner that highlights practical considerations for high‐frequency applications.
Nuclear overhauser effect in coupled‐spin systems using selective perturbation
Authors: Krishnan V. V. , Kumar Anil
Published: March 2007

Interest in the nuclear Overhauser effect (NOE) has increased enormously in recent years because of its wide application to the structure determination of molecules in the liquid state, particularly large molecules, such as biomolecules. Most NOE studies are carried out in spin systems that exhibit splittings because of indirect spin‐spin (J) couplings, but the most common NMR analyses ignore I splitting. We focus attention on the presence of J coupling and particularly on selective perturbation of a transition of coupled spins. Both steady‐state and transient NOE have been calculated in closed form. There is a large multiplet effect that results from the direct pumping effect that is observed in the intensities, careful measurement of which requires the use of small‐angle pulses. The use of a 90° pulse obliterates the multiplet effect. As an extension, cross‐correlation effects in the three‐spin system and the three‐spin effect in NOE spectra also are discussed. A brief analysis of spin diffusion in a multiple‐spin system is also included.
NMR rotating‐frame relaxation measurements of conformational exchanges on the microsecond time scale. Part I: Theory
Authors: Wang Yu‐Sen
Published: March 2007

NMR rotating‐frame spin‐lattice relaxation (Tip) is a potentially powerful tool for the investigation of chemical exchange processes in the microsecond time range, a time range that is not readily examined by the usual solution NMR methods. This article deals with on‐resonance rotating‐frame‐relaxation measurements. The relaxation mechanism is analyzed to provide a theoretical basis for accurate evaluation of the contribution of chemical exchange to T1p rates. The procedure described permits T1p measurements for medium‐sued and large molecules in solution. Interpretation of the exchange contribution provides the dynamic parameters of exchange lifetime and chemical shift difference between exchange sites.
Methods of single‐ and double‐selective excitation: Theory and applications. Part I
Authors: Gaggelli Elena , Valensin Gianni
Published: March 2007

The use of selective excitation of individual multiplets or transitions in an NMR spectrum has long been suggested for spectral interpretation, observation of nuclear Overhauser effects, investigation of exchange kinetics, polarization transfer, suppression of unwanted signals, spectral editing, measurement of dipolar cross‐relaxation rates, slice and/or volume in in vivo spectroscopy, microscopy, and NMR imaging. A general view of theory and applications of selective excitation techniques are provided. The different ways of achieving the desired frequency selectivity or biselectivity (tailoring of hard pulses, shaping of soft pulses, trains of hard pulses) in the excitation profile are summarized.
Chemical shift imaging in nuclear magnetic resonance: A comparison of methods
Authors: Rumpel Helmut , Pope James M.
Published: March 2007

Chemical shift imaging techniques are magnetic resonance imaging methods that separately map the spatial distribution of individual peaks or components in a complex NMR spectrum. A range of chemical shift imaging techniques based around the commonly employed spin‐echo Fourier imaging sequences is classified and described. The performance of the methods with regard to field dependence, chemical shift selectivity, signal‐to‐noise ratio, and imaging times is compared as a guide to selecting the most appropriate technique for a particular application.
Review of MRI gradient waveform design methods with application in the study of motion
Authors: Duerk Jeffrey L. , Simonetti Orlando P.
Published: March 2007

Many design techniques for magnetic resonance gradient waveforms have aimed at controlling the phase that results from spin motion during the application of gradients. This paper discusses the evolution of gradient waveform design into the gradient‐moment‐nulling and motion‐encoding efforts common today. It also describes current design methods and technology.