bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention and Reversal of Defective Axonal Transport and Motor Nerve Conduction Velocity In Rats with Experimental Diabetes by Treatment with the Aldose Reductase Inhibitor Sorbinil
Authors: Tomlinson David R , Moriarty Richard J , Mayer J Heidi 
Published: September 2013

This investigation was designed to determine whether the aldose reductase inhibitor Sorbinil prevented the development of or reversed defects of nerve conduction and axonal transport in streptozotocin-diabetic rats. Untreated diabetes of either 3 or 6 wk duration caused a fall in sciatic motor nerve conduction velocity (MNCV) of 6–9 m/s (P &lt; 0.001) and significantly reduced the accumulation of axonally transported choline acetyltransferase activity against a 24-h sciatic nerve crush. These functional defects were associated with accumulation of sorbitol and depletion of myo-/nositol in the sciatic nerve. Treatment with Sorbinil (25 mg/kg/day, p.o.) throughout the period of diabetes prevented the development of all these abnormalities in both 3- and 6-wk diabetic groups.
In a second study, three groups of rats were subject to 3 wk untreated diabetes followed by Sorbinil treatment (as above) for 1, 2, or 3 wk to determine whether the abnormalities expected from 3 wk of untreated diabetes could be reversed. One week of treatment significantly elevated both MNCV and choline acetyltransferase accumulation (P &lt; 0.05). The longer treatments progressively ameliorated these defects such that the group that received Sorbinil for the second 3 wk of a 6-wk diabetic period gave values that were similar to controls and to diabetic rats that had been given Sorbinil throughout their diabetes. Sorbitol accumulation was markedly reduced by only 1 wk of Sorbinil treatment, but the normalization of myo-inositol levels required 2 wk of treatment. These findings indicate that Sorbinil treatment in diabetic rats prevented and reversed both Sorbitol accumulation and depletion of nerve myo-inositol in the sciatic nerve. The treatment also prevented and reversed defects of nerve conduction and orthograde axonal transport.
Inhibition of Heparin-Catalyzed Human Antithrombin III Activity by Nonenzymatic Glycosylation: Possible Role in Fibrin Deposition in Diabetes
Authors: Brownlee Michael , Vlassara Helen , Cerami Anthony 
Published: September 2013

The effect of nonenzymatic glycosylation on the biologic function of human antithrombin III was evaluated using a chromogenie thrombin substrate assay in the presence of catalytic amounts of heparin. Experimental conditions that increased the rate of nonenzymatic protein glycosylation were associated with decreases in the thrombin-inhibiting activity of antithrombin III. This glycosylation-induced inhibition of heparin-catalyzed antithrombin III activity was completely reversible by preassay incubation with excess sodium heparin.
These observations provide a biochemical explanation for the heparin-reversible, accelerated fibrinogen disappearance rate induced by hyperglycemia in diabetic patients. Defective inhibition of the coagulation cascade induced by excessive nonenzymatic glycosylation of antithrombin III in vivo could contribute to accumulation of fibrin in various diabetic tissues.
Processing of Insulin by Bovine Endothelial Cells in Culture: Internalization Without Degradation
Authors: Jialal Ishwarlal , King George L , Buchwald Sherry , Kahn C Ronald , Crettaz Marco 
Published: September 2013

Insulin binding and processing was studied in monolayer cultures of bovine aortic endothelial cells. Specific 125I-insulin binding was both time and temperature dependent. Maximum binding at 37°C occurred at 90 min, and was 3.8%/mg protein and, at 15°C, 7%/mg protein at 4 h. 125I-insulin was crosslinked to its receptor using disuccinimidyl suberate (DSS), and the structure of the receptor complex was identified by SDS-polyacrylamide gel electrophoresis and autoradiography; a major band with Mr = 145,000 was identified, which corresponds to the α-subunit of the insulin receptor reported in other tissues. Receptor-bound insulin was internalized, and both the rate and the amount of internalization were temperature dependent. The rate of internalization was slowest at 4°C, and fastest at 37°C, and the maximum amount of 125I-insulin internalized in 120 min was 16% at 4°C, 45% at 15°C, and 81% at 37°C. Despite the high rate of internalization, endothelial cells do not appear to degrade insulin significantly, as determined by gel chromatography and TCA solubility (7% at 4 h) of media-associated radioactivity. In addition, the majority of internalized insulin (75%) was released by 60 min, largely as intact insulin. Chloroquine treatment at high concentration did not exert any major effect on insulin binding or degradation within the first 60 min, but thereafter produced a marked increase in cell-associated radioactivity.
Owing to these unusual features of endothelial cells in rapidly internalizing and releasing the 125I-insulin with minimal degradation, we suggest that insulin receptors on these cells may serve to transport insulin from the intravascular space to the subendotheliai tissues.
Factors Influencing Reticulophagocytic Function in Insulin-treated Diabetes
Authors: Lawrence Susan , Charlesworth J A , Pussell B A , Campbell Lesley V , Kotowicz M A 
Published: September 2013

The splenic component of reticulophagocytic function (RPF) was examined in 29 insulin-treated diabetic subjects (13 type I and 16 type II) by measurement of clearance of altered, radiolabeled, autologous erythrocytes. Double-isotope studies were performed with cells altered by: (1) preincubation with N-ethylmaleimide (NEM) and (2) coating with IgG antibody to the Rhesus (Rh) D antigen, labeled with 99mTc and 51Cr, respectively. HLA typing for the A, B, and DR loci was performed in those patients showing a defect in the clearance of IgG-coated cells. Values for half-life (t½ were correlated with the incidence of diabetic complications, levels of HbA15 and circulating immune complexes (CIC). Two patterns of abnormal clearance were observed: first, an isolated defect of IgG-coated cell clearance in 7 patients (3 had the HLA B8/DR3 haplotype) and second, abnormal removal of both types of cell in a further 7 patients (3 had B8/DR3). There was no correlation between half-lives as measured by the two methods, although exclusion of the patients with a defect of IgG-coated cell clearance alone yielded a highly significant correlation for the remaining 15 Rh-positive patients (P &lt; 0.01). Abnormalities of IgG-coated cell clearance were more frequent in patients with HbA1 &gt; 9% (P &lt; 0.02), while t½ of NEM-altered cells was significantly greater in patients with CIC (P &lt; 0.05). There was no correlation between t½ and the incidence of peripheral complications.
The influence of splenic blood flow (as measured by organ weight and retention of injected radiolabeled microspheres) on the t½ of NEM-altered cells was examined in rabbits. The t½ correlated with both splenic weight (P &lt; 0.001) and retention of microspheres (P &lt; 0,001).
Our data emphasize the value of double-isotope studies in assessing RPF in vivo. The isolated abnormality of IgG-coated cell clearance probably resulted from a specific defect of the splenic macrophage receptor and the B8/DR3 haplotype, and blood sugar control appeared to influence this abnormality. In addition to these factors, our animal studies suggested that splenic blood flow could contribute to the dual defect seen in a further 7 patients. These factors could hinder the removal of potentially tissue damaging macromolecules from the circulation of patients with diabetes.
Effect of 2-Bromostearate on Glucose-Phosphorylating Activities and the Dynamics of Insulin Secretion in Islets of Langerhans During Fasting
Authors: Bedoya Francisco J , Ramírez Remedios , Arilla Eduardo , Goberna Raimundo 
Published: September 2013

Glucose-phosphorylating activity and insulin secretion were measured in homogenates of isolated rat islets and of perfused rat pancreas, respectively. Fasting for 96 h produced a significant decrease of both low-and high-Km glucose-phosphorylating activities and blocked the insulin secretory response to glucose. In the presence of glucose, 0.25 mM 2-bromostearate, a known inhibitor of fatty acid oxidation, partially restored the insulin response to glucose that was lost during fasting. This effect paralleled the restoration of glucose-phosphorylation activities (primarily the high–Km component) seen when islets isolated from 96-h-fasted rats were preincubated with 0.25 mM 2-bromostearate.
It is concluded that fasting-induced adaptations of glucose-phosphorylating enzymes could account, at least in part, for the reduced insulin secretory response to glucose. 2-Bromostearate, an inhibitor of fatty acid oxidation, is able to restore both insulin secretory response and glucose-phosphorylating activities, suggesting possible interrelations among the correlated impairment in insulin secretion, islet glucose-phosphorylating activity, islet glucose metabolism, and the oxidation of fatty acids in the B-cell during fasting.
The Effect of Maternal Diabetes on Trace Element Status and Fetal Development in the Rat
Authors: Uriu-Hare Janet Y , Stern Judith'S , Reaven Gerald M , Keen Carl L 
Published: September 2013

Despite improvements in prenatal care, there is a high incidence of congenital malformations in diabetic pregnancies. Not only is the diabetic patient characterized by a disorder of total fuel metabolism, but abnormal trace element metabolism occurs as well. In the present study, maternal and fetal zinc (Zn), copper (Cu), manganese (Mn), iron (Fe), magnesium (Mg), and calcium (Ca) status has been studied in Sprague-Dawley (SD) and Wistar rats. In addition, the effect of maternal diabetes on fetal development was also investigated. Rats were injected 27 days before mating with streptozocin (STZ, 45 mg/kg) in citrate buffer. On day 20 of gestation, litters were taken by cesarean section. Fetuses from diabetic dams weighed less, and had shorter crown-rump lengths and larger placentas than fetuses from controls. Evaluation of fetal skeletal development revealed fewer calcified sternal sites, anterior phalanges and caudal vertebrae, and an increased frequency of malformations in fetuses of diabetic dams. In dams, diabetics had larger adrenals, kidneys, and liver, and smaller thymus.
Abnormal trace element metabolism was evident in diabetic dams and their fetuses. Mn was elevated in maternal liver, kidney and placenta of diabetic animals as well as in fetal liver of pups from diabetic dams. Maternal Cu and Zn levels were also higher in the liver and kidney of diabetic rats. In contrast, fetal liver Zn from fetuses of diabetic mothers was significantly decreased when compared with controls. These results suggest that diabetes may have induced fetal Zn deficiency. If this deficiency is present during embryogenesis/organogenesis, this could be one of the mechanisms of the teratogenicity of the diabetic state.
The Influence of Body Fat Distribution on the Incidence of Diabetes Mellitus: 13.5 Years of Follow-up of the Participants in the Study of Men Born in 1913
Authors: Ohlson L -O , Larsson B , Svärdsudd K , Welin L , Eriksson H , Wilhelmsen L , Björntorp P , Tibblin G 
Published: September 2013

In a prospective study of risk factors for ischemic heart disease, 792 54-yr-old men selected by year of birth (1913) and residence in Göteborg, Sweden, agreed to attend for questioning and a number of anthropometric and other measurements in 1967. Thirteen and one-half years later, these baseline findings were reviewed in relation to the number of men who had subsequently developed diabetes mellitus.
This analysis focused on the importance of abdominal adipose tissue distribution, measured as the waistto- hip circumference ratio, as a predictor for development of diabetes. Even when the confounding effect of body mass index, as a measure of the total body fat mass, was accounted for, the waist-to-hip ratio was positively and significantly associated with the risk for diabetes.
These results from a prospective study strongly support previous cross-sectional findings indicating that not only the degree of obesity but also the localization of fat is a risk factor for diabetes.
Insulin Antibodies Retard and Insulin Accelerates Growth and Differentiation in Early Embryos
Authors: Pablo Flora De , Girbau Matias , Gomez Juan A , Hernandez Eleuterio , Roth Jesse 
Published: September 2013

The physiologic function of insulin in early embryonic life is unknown. We have shown that insulin is present in unfertilized eggs and in chick embryos at 2–3 days of development, even before the emergence of the endocrine pancreas. To define insulin's role, we exposed 2-day-old chick embryos to anti-insulin antibodies and followed their development up to day 5. Antibodytreated embryos had a higher rate of growth retardation and death by days 3–5 of embryogenesis, compared with controls. Among the survivors, biochemical maturation was delayed at days 4 and 5; weight, protein, total creatine kinase activity, and creatine kinase-MB were decreased in antibody-treated embryos.
By contrast, insulin (50 ng/embryo) administered to 2-day-old embryos yielded nearly symmetrical stimulatory results. These findings suggest that endogenous insulin plays a probable physiologic role regulating growth and differentiation in early embryos. In addition, the findings provide some clues to a possible function for insulin produced outside the organism's own beta cells.
Interferon-γ Enhances the Expression of the Major Histocompatibility Class I Antigens on Mouse Pancreatic Beta Cells
Authors: Campbell Iain L , Wong Grace H W , Schrader John W , Harrison Leonard C 
Published: September 2013

Cell surface antigens of the major histocompatibility complex (MHC) play a crucial role in the initiation of immune reactions. To investigate whether the expression of MHC antigens on pancreatic islet cells could be altered, we have cultured mouse islets in the presence of interferon-γ (IFN-γ) and subsequently examined the levels of MHC antigen by indirect immunofluorescence using monoclonal antibodies. IFN-γ induced a 10-fold increase in H-2K antigen expression on islet cells, the percentage of cells with detectable H-2K expression increasing from 24% to 98%. The effects of IFN-γ on H-2D and la antigen expression were less marked, with only a twofold increase in mean fluorescence levels, the percentage of cells with detectable levels ofexpression increasing from 10% to 48% and 5% to 16%, respectively. Using double-indirect immunofluorescence, it was demonstrated that IFN-γ enhanced expression of H-2K and H-2D antigens on β-cells. However la-positive-cells were undetectable in the presence or absence of IFN-γ.
The ability of IFN-γ to induce increased expression of H-2 antigens on β-cells may represent a mechanism for targeting immune (cytotoxic) reactions to β-cells, e.g., in autoimmune insulitis or allograft rejection.
Elevation of Factor VIII Coagulant Activity Over Factor VIII Coagulant Antigen in Diabetic Children Without Vascular Disease: A Sign of Activation of the Factor Coagulant Moiety During Poor Diabetes Control
Authors: Muntean Wolfgang E , Borkenstein Martin H , Haas Josef 
Published: September 2013

To investigate whether the elevation of factor VIII coagulant activity observed in children with poor control of diabetes is due to increased levels of the factor VIII coagulant moiety of the factor VIII complex or reflects activation of the factor VIII coagulant moiety, factor VIII coagulant activity (VIII C), factor VIII coagulant antigen (VIM C:Ag), and factor VIII-related antigen (VIII R:Ag) were determined in 75 insulin-dependent children. All children were without signs of vascular disease based on negative funduscopy, negative fluorescein angiography, normal serum creatinine levels, and absence of proteinuria. Children with poor actual control of diabetes had significantly higher VIII C values than did children with good actual control of diabetes based on HbA1 values, but VIM C:Ag values did not differ in children with good or poor actual control of diabetes. A significant elevation of VIM C over VIII C:Ag values was observed in children with poor actual control of diabetes, but no elevation of VIII C over VIM C:Ag was found in children with good actual control. VIM R:Ag values were higher in children with poor actual control. VIM C, VIM C:Ag, and VIII R:Ag did not differ significantly in children with short or long duration of clinical diabetes.
Our observation of significantly higher VIM C values, than VIM C:Ag levels strongly suggests intravascular activation of the factor VIM coagulant moiety during poor diabetes control. The process leading to activation of the coagulant moiety seems to be different from the process leading to the elevation of the other moiety of the factor VIM complex, the factor VIII-related antigen, in diabetic subjects.
Stimulatory Effect of Insulin on Aortic Smooth Muscle Cell Migration Induced by 12-L-Hydroxy-5,8,10,14-Eicosatetraenoic Acid and Its Modulation by Elevated Extracellular Glucose Levels
Authors: Nakao Junko , Ito Hideki , Kanayasu Toshie , Murota Sei-Itsu 
Published: September 2013

In investigations on the role of insulin on migration of rat aortic smooth muscle cells, migration of the cells was measured by a modified Boyden chamber technique with 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) as a chemoattractant. Insulin itself was not a chemoattractant for these cells, and insulin added just before the migration assay did not affect cell migration in the presence or absence of 12-HETE.
Cells pretreated with insulin in culture dishes for a long period, however, showed a significant increase in migration induced by 12-HETE, and the increase depended on the insulin concentration: concentrations of insulin of &gt;50 μlU/ml caused about twofold increase in cell migration. On the other hand, long-term incubation with various concentrations of insulin (0.15–1000 μIU/ml) did not affect nonspecific cell migration in the absence of 12-HETE. The stimulatory effect of insulin on cell migration gradually increased with the duration of insulin treatment, reaching a plateau after 4 days. Thus, insulin stimulated 12-HETE-induced smooth muscle cell migration in a time- and dose-dependent manner.
When the extracellular D-glucose concentration in the Boyden chamber was increased from 100 to 300 mg/dl, the stimulatory effect of insulin on 12-HETE-induced cell migration was augmented. This modulation by D-glucose was not due to an increase in the osmotic pressure of the medium, since addition of mannitol to increase the osmotic pressure did not enhance the effect of insulin on cell migration. The present results indicate that insulin in a physiologic or pathophysiologic range stimulates 12-HETE-induced smooth muscle cell migration in a manner dependent on the extracellular D-glucose concentration. These findings are relevant to the increased development of atherosclerosis in subjects with hyperinsulinemia and hyperglycemia, as is seen in obesity and diabetes mellitus.
The Pump Life: Patient Responses and Clinical and Technological Problems
Authors: Pickup John C , Sherwin Robert S , Tamborlane William V , Rizza Robert A , Service F John ,   The Kroc Collaborative Study Group
Published: September 2013

As part of a randomized, prospective trial in subjects with insulin-dependent diabetes assigned to either continuous subcutaneous insulin infusion (CSII) or to their unchanged conventional insulin treatment (CIT) for 8 mo, patients completed questionnaires dealing with general responses and clinical and technological problems.
Although there was no significant difference between treatment groups with respect to the number of patients experiencing severe hypoglycemia (i.e., requiring intravenous glucose or intramuscular glucagon injection), there were nine episodes in six patients during CSII compared with one episode during CIT. Diabetic ketoacidosis occurred significantly more often in the CSII group (nine episodes in eight patients) than in the CIT group (no episodes).
A number of CSII-related failures occurred, including omission of premeal bolus, needle dislodgement, pump accidentally turned off, and leakage at the infusion site. At 8 mo, 85% of CSII-treated patients wished to continue indefinitely on the pump, and almost all would continue with self-monitoring of blood glucose even if they Stopped CSII.
Demonstration that the Vitamin D Metabolite 1,25(OH)2-Vitamin D3 and Not 24R,25(OH)2-Vitamin D3 Is Essential for Normal Insulin Secretion in the Perfused Rat Pancreas
Authors: Kadowaki Seizo , Norman Anthony W 
Published: September 2013

It has previously been shown that vitamin D deficiency impairs arginine-induced insulin secretion from the isolated, perfused rat pancreas (Science 1980; 209:823–25). Since vitamin D is known to be metabolized to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) and 24R,25-dihydroxyvitamin D3 (24,25[OH]2D3), it is essential to clarify which vitamin D metabolite has the important role of enhancing insulin secretion. In this report, a comparison is made of the relative efficacy of 3-wk repletion with vitamin D3 (980 pmol/day), 1,25(OH)2D3 (39 pmol/day or 195 pmol/day), and 24,25(OH)2D3 (650 pmol/day) on arginine-induced insulin secretion from the isolated, perfused rat pancreas; in this experiment, the daily caloric intake of the animals receiving vitamin D or its metabolites was controlled by pair feeding to the caloric intake of the vitamin D-deficient rats. 1,25(OH)2D3 repletion was found to completely restore insulin secretion to the levels seen in vitamin D3-replete, pair-fed controls in both the first and second phases, while 24R,25(OH)2D3 only partially improved insulin secretion, and then only in the first phase.
Changes of both serum calcium levels and dietary caloric intake after vitamin D metabolite administration are concluded to play a lesser role on the enhancement of insulin secretion, since, in a separate experiment, vitamin D-deficient rats with normal serum calcium levels did not show recovery of insulin secretion equivalent to the vitamin D-replete animals under conditions of dietary pair feeding. These results suggest that 1,25(OH)2D3but not 24,25(OH)2D3 plays an essential role in the normal insulin secretion irrespective of the dietary caloric intake and prevailing serum calcium levels.
Anti-islet Cellular and Humoral Immunity, T-Cell Subsets, and Thymic Function in Type I Diabetes
Authors: Quiniou-Debrie M C , Debray-Sachs M , Dardenne M , Czernichow P , Assan R , Bach J F 
Published: September 2013

Peripheral lymphocyte subsets were enumerated, using OKT monoclonal sera, in 56 diabetic (43 adults and 13 children) and 20 control subjects. Concomitantly, anti-islet humoral and cellular immunity was tested in vitro and serum thymulin level was measured.
In the newly diagnosed patients (&lt;30 days; 18 cases), the percent of OKT4+ and OKT8+ cells was reduced, the OKT8+ depletion being particularly pronounced in children. Tests for cellular immunity were positive in 83% of the newly diagnosed diabetic subjects and anti-islet cytotoxic antibodies were detected in 50%. The serum thymulin level was decreased in 2 children. Later on in the course of the disease, a marked reduction in OKT3+, OKT4+ and OKT8+ cell percentage was observed, the mean OKT4/OKT8 ratio being normal or lower than normal. The percent of antibody-positive sera rose to 64%, while anti-islet cellular immunity was detectable in 54%. When extrapancreatic manifestations of probable autoimmune nature were present, anti-islet cellular immunity was detected in 100% of cases, accompanied by cytotoxic antibodies in 54%.
(1) the magnitude of T-cell depletion and/or imbalance in diabetic subjects depended mainly on the duration of the disease, (2) anti-islet cellular immunity was the anomaly most frequently detectable, and (3) a decrease in serum thymulin level was infrequently detected.