bluuebunny/crossref_metadata_2025 huggingface dataset:
Down regulation of SPAG9 reduces growth and invasive potential of triple-negative breast cancer cells: possible implications in targeted therapy
Authors: Sinha Abhilasha , Agarwal Sumit , Parashar Deepak , Verma Archana , Saini Shikha , Jagadish Nirmala , Ansari Abdul S , Lohiya Nirmal K , Suri Anil
Published: September 2013

Background

Recently, we reported an association of a novel cancer testis (CT) antigen, sperm-associated antigen 9 (SPAG9) expression in breast cancer clinical samples, indicating its potential role in carcinogenesis. Around 15% breast cancers are designated as triple-negative for which treatment modalities are limited. Therefore, in the present study, we assessed the role of SPAG9 in triple-negative breast cancer cells.

Methods

SPAG9 mRNA and protein expression was investigated in various breast cancer cells of different hormone receptor status and different subtypes by employing reverse transcriptase-polymerase chain reaction (RT-PCR), real time PCR, Western blotting, indirect immunofluorescence (IIF) and fluorescence activated cell sorting (FACS). Employing plasmid-based small interfering RNA (siRNA) approach, knockdown of SPAG9 was carried out in triple-negative breast cancer cells, MDA-MB-231, to assess its role on various malignant properties in vitro and in vivo.

Results

SPAG9 mRNA and protein expression was detected in all breast cancer cells. Further, IIF results showed that SPAG9 was predominantly localized in the cytoplasm of breast cancer cells. FACS analysis revealed distinct SPAG9 surface localization in breast cancer cells. Gene silencing of SPAG9 resulted in significant reduction in cellular proliferation, colony forming ability, migration, invasion and cellular motility of MDA-MB-231 cells. Further, ablation of SPAG9 expression resulted in reduction in the tumor growth of human breast cancer xenograft in nude mice in vivo.

Conclusions

In summary, our data indicated that down regulation of SPAG9 reduces growth and invasive potential of triple-negative breast cancer cells, suggesting that SPAG9 may be a potential target for therapeutic use.
Analysis of Flame Characteristics in a Laboratory-Scale Turbulent Lifted Jet Flame via DNS
Authors: Wang Haiou , Luo Kun , Yi Fuxing , Fan Jianren
Published: September 2013

A fully compressible 3D solver for reacting flows has been developed and applied to investigate a turbulent lifted jet flame in a vitiated coflow by means of direct numerical simulation (DNS) to validate the solver and analyze the flame characteristics. An eighth-order central differencing scheme is used for spatial discretization and a fourth-order Runge-Kutta method is employed for time integration. The DNS results agree well with the experimental measurements for the conditional means of reactive scalars. However, the lift-off height is under predicted. The mean axial velocity develops into a self-similar profile after x/D = 6. The normalized flame index is employed to characterize the combustion regime. It is found that at the flame base the gradients of the reactants are opposed and diffusion combustion is dominant. Further downstream, the contribution of premixed combustion increases and peaks at x/D = 8. Finally, the stabilization process is examined. The turbulent lifted flame is proved to stabilize in the lean mixtures and low scalar dissipation rate regions.
Immanuel Kant Revisited - A Note on the U.S. Innovation Policy
Authors: Andersson E. , Jansson Bjarne , Lundblad Jan
Published: September 2013

A fundamental discussion is lacking in the current document on U.S innovation policy from the National Research Council [1] of how invalid innovation styles and business cultures in different combinations discriminates innovation in science and industry. With credit to the philosophy of Immanuel Kant, we redefine innovation as similar to a research process and argue for improvements in the innovation literature to avoid poor results and failed innovation in the future; i.e. the innovation paradox. A critical review of the U.S. innovation policy document originates from our own university-based research and innovation in the occupational safety and health area, which is an area where both research and industry have failed thus far. Our article includes both proposals for a revised national mission based on Kant, as well as examples of how investment in research and innovation can translate and transform innovation ideas into commercial products in networks and eco-systems; and also how collaborative channels might be opened between independent inventors and universities. Our findings are important for both scientists and politicians, as well as for individuals - in industry and in society - who want to commercialize inventions.
Development of a Multidirectional Simple Shear Testing Device
Authors: Rutherford C. J. , Biscontin G.
Published: September 2013

A new simple shear testing device capable of applying multidirectional loading to soil specimens has been developed. The Texas A&M University multidirectional simple shear (TAMU-MDSS) device provides the ability to apply a large range of shear stresses and complex loading paths, such as figure-eight and circular patterns, to a cylindrical soil specimen confined by a wire-reinforced membrane. The load and torque experienced by the sample are directly measured by a multi-axis load cell installed above the specimen. Backpressure saturation of the specimen is made possible by the device’s ability to apply pressure in the chamber and backpressure to the water lines. Excess pore pressure is measured by a pressure transducer during the shearing phase of the testing. This paper describes the development of the TAMU-MDSS system and the capabilities of the device and presents test results on saturated clay soil specimens subjected to monotonic, unidirectional cyclic, and multidirectional loading.
Comparative Analyses Identify the Contributions of Exotic Donors to Disease Resistance in a Barley Experimental Population
Authors: Fang Zhou , Eule-Nashoba Amber , Powers Carol , Kono Thomas Y , Takuno Shohei , Morrell Peter L , Smith Kevin P
Published: September 2013

Introgression of novel genetic variation into breeding populations is frequently required to facilitate response to new abiotic or biotic pressure. This is particularly true for the introduction of host pathogen resistance in plant breeding. However, the number and genomic location of loci contributed by donor parents are often unknown, complicating efforts to recover desired agronomic phenotypes. We examined allele frequency differentiation in an experimental barley breeding population subject to introgression and subsequent selection for Fusarium head blight resistance. Allele frequency differentiation between the experimental population and the base population identified three primary genomic regions putatively subject to selection for resistance. All three genomic regions have been previously identified by quantitative trait locus (QTL) and association mapping. Based on the degree of identity-by-state relative to donor parents, putative donors of resistance alleles were also identified. The successful application of comparative population genetic approaches in this barley breeding experiment suggests that the approach could be applied to other breeding populations that have undergone defined breeding and selection histories, with the potential to provide valuable information for genetic improvement.
Allelic Variation in a Cellulose Synthase Gene (PtoCesA4) Associated with Growth and Wood Properties in Populus tomentosa
Authors: Du Qingzhang , Xu Baohua , Pan Wei , Gong Chenrui , Wang Qingshi , Tian Jiaxing , Li Bailian , Zhang Deqiang
Published: September 2013

Lignocellulosic biomass from trees provides a renewable feedstock for biofuels, lumber, pulp, paper, and other uses. Dissecting the mechanism underlying natural variation of the complex traits controlling growth and lignocellulose biosynthesis in trees can enable marker-assisted breeding to improve wood quality and yield. Here, we combined linkage disequilibrium (LD)-based association analysis with traditional linkage analysis to detect the genetic effect of a Populus tomentosa cellulose synthase gene, PtoCesA4. PtoCesA4 is strongly expressed in developing xylem and leaves. Nucleotide diversity and LD in PtoCesA4, sampled from the P. tomentosa natural distribution, revealed that PtoCesA4 harbors high single nucleotide polymorphism (SNP) diversity (πT = 0.0080 and θw = 0.0098) and low LD (r2 ≥ 0.1, within 1400 bp), demonstrating that the potential of a candidate-gene-based LD approach in understanding the molecular basis underlying quantitative variation in this species. By combining single SNP, multi-SNP, and haplotype-based associations in an association population of 460 individuals with single SNP linkage analysis in a family-based linkage populations (1200 individuals), we identified three strong associations (false discovery rate Q < 0.05) in both populations. These include two nonsynonymous markers (SNP49 associated with α-cellulose content and SNP59 associated with fiber width) and a noncoding marker (SNP18 associated with α-cellulose content). Variation in RNA transcript abundance among genotypic classes of SNP49 was confirmed in these two populations. Therefore, combining different methods allowed us to examine functional PtoCesA4 allelic variation underlying natural variation in complex quantitative traits related to growth and lignocellulosic biosynthesis.
Influence of Body Mass Index on Survival in Veterans With Multiple Myeloma
Authors: Beason Tracey S. , Chang Su-Hsin , Sanfilippo Kristen M. , Luo Suhong , Colditz Graham A. , Vij Ravi , Tomasson Michael H. , Dipersio John F. , Stockerl-Goldstein Keith , Ganti Arun , Wildes Tanya , Carson Kenneth R.
Published: September 2013

Learning Objectives

Describe the association between baseline BMI, weight loss, and survival in MM. Explain the importance of BMI and baseline weight loss as part of the standard history obtained in patients with MM.
Effects of nano-TiO2 on properties of cement-based materials
Authors: Lee Bo Yeon , Jayapalan Amal R. , Kurtis Kimberly E.
Published: September 2013

The effect of titanium dioxide (TiO2) nanoparticles on early age and long-term properties of cement-based materials is examined experimentally through isothermal calorimetry, chemical shrinkage, setting time, compressive strength and surface microhardness, where part of the cement is replaced with TiO2. Early age hydration is accelerated by TiO2 nanoparticles which also increase degrees of hydration of Portland cement, as evidenced by isothermal calorimetry and chemical shrinkage results. With increasing amounts of TiO2, setting time is reduced, despite decreasing cement content, due to TiO2 replacement, again showing accelerated hydration. Comparing TiO2–cement composites from two different TiO2 manufacturers, results suggest that size of nanoparticles and dispersability are critical in the rate of hydration, with smaller size agglomerates, but not necessarily smaller size particles, producing a greater effect. Compressive strength increases with higher TiO2 nanoparticle replacement at lower water-to-solids ratio (w/s = 0·40) and strength is not compromised by up to 10% TiO2 replacement at higher w/s = 0·60. However, microhardness of the composite decreases with higher TiO2 amount. Broadly, these results indicate that mineral addition as cement replacement can be optimised in terms of dosage and dispersability to achieve lower cement fractions without compromising strength, but that the potential for reductions in hardness should be considered.
Relations between the scaling exponents, entropies, and energies of fracture networks
Authors: Guđmundsson Agust , Mohajeri Nahid
Published: September 2013

Fracture networks commonly show power-law length distributions. Thermodynamic principles form the basis for understanding fracture initiation and growth, but have not been easily related to the power-law size distributions. Here we present the power-law scaling exponents and the calculated entropies of fracture networks from the Holocene part of the plate boundary in Iceland. The total number of tension fractures and normal faults used in these calculations is 565 and they range in length by five orders of magnitude. Each network can be divided into populations based on ‘breaks’ (abrupt changes) in the scaling exponents. The breaks, we suggest, are related to the comparatively long and deep fractures changing from tension fractures into normal faults and penetrating the contacts between the Holocene lava flows and the underlying and mechanically different Quaternary rocks. The results show a strong linear correlation (r = 0.84) between the population scaling exponents and entropies. The correlation is partly explained by the entropy (and the scaling exponent) varying positively with the arithmetic average and the length range (the difference between the longest and the shortest fracture) of the populations in each network. We show that similar scaling laws apply to other lineaments, such as streets. We propose that the power-law size distributions of fractures are a consequence of energy requirements for fracture growth.
Metabolic Studies in the Pyelonephritic Rat
Authors: Davidson Mayer B
Published: September 2013

Insulin antagonism characterizes infection, but the mechanism is unknown. Previous studies have been performed during the acute catabolic stage of infection, and the resultant metabolic changes reflect this decreased food intake and weight loss. To delineate metabolic alterations due to infection itself, rats with pyelonephritis induced by tail-vein injection of 1 ml. of Streptococcus faecalis (109 bacteria per milliliter) were studied two weeks later during a period of near-normal weight gain and food intake.

Fasting growth hormone concentrations (nanograms per milliliter) in the pyelonephritic rats were nearly five times normal (45.8 vs. 9.9). Intra-arterial glucose and insulin tolerance tests were impaired. Early glucose-induced insulin release was depressed. Fat pads from infected rats manifested higher basal lipolysis per cell. Glycerol-mediated gluconeogenesis by liver slices was decreased. This pathway was unaffected by insulin in infected rats but readily inhibited in control rats.

The following metabolic parameters were similar in control and infected animals: (in vivo) fasting concentrations of plasma glucose, free fatty acids, triglycerides, total corticoids, creatinine, insulin, glucagon, molar ratios of insulin and glucagon, glucose and insulin responses to tolbutamide, and glucagon and free fatty acid suppression after glucose; (in vitro) glucose metabolism by muscle and fat, epinephrine- and theophylline-stimulated lipolysis and re-esterification by epididymal fat pads, fasting hepatic glycogen content, glucose production by liver slices with and without alanine. No plasma insulin antagonist was found in the infected rats.

Metabolic alterations in infected rats can be demonstrated independently of the associated catabolism. Increased growth hormone secretion cannot explain all of these changes.
Insulin Metabolism in Hypothyroidism
Authors: Shah Jayendra H , Motto George S , Papagiannes Elaine , Williams Gerald A
Published: September 2013

Insulin resistance has been invoked to explain the glucose intolerance observed in hypothyroid patients. This possibility was studied by determining fractional and metabolic clearances of intravenously administered porcine crystalline insulin (0.1 U./kg.) and its effect on plasma glucose concentration in ten hypothyroid patients, ten normal subjects, and six treated euthyroid patients.

Following administration of porcine insulin, serum immunoreactive insulin concentrations during the period of observation were similar in hypothyroid patients, in normal control subjects, and in treated euthyroid patients. Similarly, no significant differences in the mean half-life, distribution space, or fractional and metabolic clearances of insulin were observed among any of the three groups.

In response to insulin administration, plasma glucose concentrations declined to the nadir of 36 ± 4, 43 ± 3, and 38 ± 4 mg. per 100 ml. in hypothyroid patients, normal control subjects, and treated euthyroid patients, respectively. Thereafter, plasma glucose steadily increased and approached the baseline value at ninety minutes in normal subjects and treated euthyroid patients. In contrast, the plasma glucose values remained significantly lower than the baseline for the rest of the procedure in hypothyroid patients.

The present study demonstrates that there is no evidence of resistance to the action of insulin in hypothyroid patients. The observation of prolonged hypoglycemic action of exogenously administered insulin in hypothyroid patients might in fact suggest increased sensitivity to insulin action. These findings indicate that glucose intolerance of the hypothyroid state is not characterized by insulin resistance.
Modulation of Fatty Acid Metabolism by Glucagon in Man. III. Role of Pharmacologic Limitation of FFA Availability
Authors: Schade David S , Eaton R Philip
Published: September 2013

This study was undertaken to examine the contribution of plasma free fatty acid availability upon the regulation of ketone body and endogenous triglyceride concentration in man. This substrate-product relationship was examined both in the basal state and during hormonally induced ketogenic stimulation.

Five insulin-deficient diabetics receiving a fixed dose of exogenous insulin were studied after a twelve-hour fast and twenty-four hours after their last therapeutic insulin injection. Reduction in basal free fatty acid concentration was induced with two weeks of clofibrate administration, and hormonal ketogenic stimulation was induced with glucagon administration.

A highly significant correlation was observed between the basal free fatty acid level and the basal ketone body concentration. This substrate-product relationship persisted throughout hormonally induced ketogenic stimulation, suggesting that the basal free fatty acid concentration is a major determinant of the plasma ketone body concentration in man. In contrast, alterations in basal free fatty acid concentration were not accompanied by consistent changes in plasma triglyceride concentration, suggesting that plasma free fatty acid concentration may not be the principal determinant of the endogenous triglyceride concentration in clofibrate-treated diabetic man.
Antidiabetic Action of Somatostatin–Assessed by the Artificial Pancreas
Authors: Meissner C , Thum Ch , Beischer W , Winkler G , Schröder K E , Pfeiffer E F
Published: September 2013

By means of a glucose-controlled insulin- and glucose-infusion system (GCIGIS) we examined the effect of somatostatin on insulin and glucose requirements following meals or oral glucose loads in juvenile diabetics.

In six of seven patients the insulin requirement with somatostatin was remarkably reduced to between 38 per cent and 79 per cent of that of otherwise identical control experiments. No reduction could be found in the seventh case, fed only 575 kcal. In all cases we observed an increase in dextrose demanded from the GCIGIS ranging between 28 per cent and 192 per cent of the control amounts. In addition, a lowering and smoothing of postprandial blood glucose curves caused by somatostatin application was a general finding.

It seems to us most likely that the well-known suppression of the secretion of growth hormone and glucagon, both insulin antagonists, is responsible for the antidiabetic action of somatostatin.
Quantification of Collagen in Renal Glomeruli Isolated from Human Nondiabetic and Diabetic Kidneys
Authors: Klein L , Butcher D L , Sudilovsky O , Kikkawa R , Miller Max
Published: September 2013

Previous studies of diabetic renovascular complications have measured morphologic changes in relatively few glomerular vessels by electron microscopy. The present study samples 20,000 to 80,000 glomeruli from each of ten nondiabetic and ten diabetic age and sex-matched subjects. Glomeruli were isolated and fractionated by size with a sieving method. Three samples of glomeruli from each subject were analyzed for size, mass, and hydroxyproline content as an index of basement membrane collagen. Approximately 40 per cent of the glomeruli in each sample were isolated. Glomeruli comprised 94 per cent of the tissue elements present, and 92 per cent of the isolated glomeruli were intact. Diabetic glomeruli are larger than nondiabetic glomeruli (mean diameter ± S.E.M. = 258 ± 10 μ versus 196 ± 6 μ) and heavier (499 ± 63 ng. versus 232 ± 16 ng.). Diabetic glomeruli have greater hydroxyproline content than nondiabetic glomeruli when content is expressed per glomerulus (21.9 ± 3.3 ng. versus 7.1 ± 0.5 ng.) and when expressed per milligram dry weight of glomeruli (44.0 ± 2.4 μg. versus 31.6 ± 1.9 μg.). Glomeruli from diabetics of longest duration show the greatest increases in mass and hydroxyproline values. A pathologist's semiquantitative estimation of diffuse glomerulosclerosis revealed a high correlation between hydroxyproline values and histologic determination of the extent of the renal lesion. These measurements allow quantification of basement membrane collagen and may be used to follow development of diabetic vascular complications.
Influence of Antecedent Carbohydrate Intake on the Biphasic Insulin Response to Intravenous Glucose
Authors: Fujita Yoshikuni , Chacra Antnio R , Herron Arthur L , Seltzer Holbrooke S
Published: September 2013

The insulin secretory response to a sudden and sustained intravenous glycemic stimulus was measured in three groups of dogs whose antecedent carbohydrate intake ranged from zero to 300 or more grams daily. Insulin outflow rate from the pancreaticoduodenal vein was measured every minute for ten minutes, then at increasing intervals through sixty minutes. It was found that starvation erased the first phase of the biphasic insulin response shown by dogs on ordinary carbohydrate intake and that high-carbohydrate intake abolished the trough between the two phases. The data suggest that, during truly physiologic stimulation of insulin secretion, the latter represents the final stage of a continuum of hormonal synthesis, storage, and release, rather than emanating from one of two separate pools of fast-versus-slow insulin secretion.
Fast and Slow Axoplasmic Flow in Sciatic Nerve of Diabetic Rats
Authors: Schmidt R E , Matschinsky F M , Godfrey D A , Williams A D , McDougal D B
Published: September 2013

Accumulation of acetylcholinesterase (AChE) and choline acetylase (ChAc) activities proximal to a tie placed on the sciatic nerve was measured in control, untreated diabetic, and insulin-treated diabetic rats. In the diabetic animals AChE accumulation was reduced by about 20 percent and ChAc accumulation by about 40 percent. Insulin treatment eliminated the impairment. It remains an open question whether these reversible functional changes in rat have any counterpart in the diabetic neuropathy of man.
Hormonal Regulation of Glycogen Metabolism in Human Fetal Liver: II. Regulation of Glycogen Synthase Activity
Authors: Schwartz Alan L , Rall Theodore W
Published: September 2013

During the first two thirds of gestation, the concentrations of UDPG, ATP, ADP, and Mg++ in human fetal liver remain constant, whereas the concentration of Pi decreases twofold and the G-6-P and AMP concentrations increase. Incubation of human fetal liver explants with glucagon or insulin did not alter the concentrations of any of these intermediates.

ATP, ADP, and Pi are inhibitors of human fetal liver glycogen synthase D-form activity, while G-6-P and AMP and Mg++ are stimulators. Ca++ at concentrations of < 0.1 mM was found to stimulate glycogen synthase D activity. This effect of Ca++ was also observed in “physiologic” mixtures containing UDPG, G-6-P, ATP, ADP, AMP, Pi, and Mg++ at concentrations found either in liver in utero or in explants. 45Ca++ efflux from perifused (rat) fetal liver explants was stimulated by glucagon. These data provide a picture of the metabolite regulation of human fetal liver glycogen synthase activity in which the D-form may largely control glycogen synthesis in utero and hormonal effects on glycogen synthase may be induced by effects of Ca++ on the D-form.
Plasma Renin Activity and Blood Volume in Uncontrolled Diabetes: Ketoacidosis, a State of Secondary Aldosteronism
Authors: Christlieb A Richard , Assal Jean-Philippe , Katsilambros Nicholas , Williams Gordon H , Kozak George P , Suzuki Tadao
Published: September 2013

The renin-angiotensin-aldosterone system was evaluated in two types of uncontrolled diabetes: a) diabetic ketoacidosis, and b) nonketotic hyperglycemia. In thirteen patients with ketoacidosis, mean plasma renin activity (PRA) was 58 ± 12 (S.E.M.) ng. per milliliter per hour and in four patients, plasma aldosterone was 82 ± 17 ng. per 100 ml. Corresponding values for upright saltdepleted subjects were 13 ± 2 and 62 ± 8. In eleven diabetics with nonketotic hyperglycemia (mean glucose 318 ± 19 mg. per cent), mean blood volume was 4,660 ml. and PRA 2.1 ± .7. After control of the diabetes (mean glucose 129 ± 13) blood volume was 4,553 ml. and PRA 3.3 ± 1 (N.S.).

The results suggest that: 1) diabetic ketoacidosis is a state of severe secondary aldosteronism, 2) no significant change in blood volume or PRA occurs during short periods of hyperglycemia, and 3) insulin is not necessary for renin release.
Hyperinsulinemia and Enlarged Adipocytes in Patients with Endogenous Hyperlipoproteinemia without Obesity or Diabetes Mellitus
Authors: Bernstein Robert S , Grant Neville , Kipnis David M
Published: September 2013

Studies of adipocyte metabolism were performed in twelve male subjects with normal plasma lipids and eleven male patients with Type IV or Type V hyperlipoproteinemia. Patients with obesity or diabetes mellitus were excluded from the study. Although all patients had normal glucose tolerance tests, the blood glucose levels during these tests were higher in the hyperlipoproteinemic patients than in the normal control subjects and the plasma insulin responses were even more strikingly elevated in the hyperlipemic group.

Adipocytes isolated from hypertriglyceridemic subjects were larger than those obtained from normal individuals and exhibited increased activities of both Type I and Type II hexokinase and increased rates of glucose oxidation and lipogenesis from glucose. Cell size, hexokinase isoenzyme activities and rates of lipogenesis from glucose were all strongly correlated with each other, but none of these measurements were correlated with glucose oxidation. It is not known how the adipocyte abnormalities are related to the lipid transport disorder.
Insulin Sensitivity of Isolated Perfused Rat Liver
Authors: Mondon Carl E , Dolkas Constantine B , Olefsky Jerrold M , Reaven Gerald M
Published: September 2013

The responsiveness of the isolated perfused rat liver to different metabolic effects of insulin was investigated during recycling perfusion. Infusion of porcine insulin at rates of 6,9,16 and 33 mU/hr. resulted in stable perfusate insulin levels averaging 41, 72, 120 and 229 μU/ml., respectively. Since the portal vein insulin concentration in the intact rat averaged 48 μU/ml. after a twenty-six-hour fast and 125 μU/ml. two hours after removal of food, the studies were conducted at insulin levels within the physiological range. The effect of each insulin concentration on the net accumulation of K+, amino acid nitrogen, urea nitrogen and glucose in the perfusing medium was assessed against the net accumulation of perfusate constituents during perfusion of control livers and livers perfused with perfusate insulin levels greater than 500 μU/ml. The results indicate that essentially maximal suppression of amino acid nitrogen outflow and retention of K+ occurred at insulin concentrations of 72 μU/ml., with lesser effects being noted at 41 μU/ml. Inhibition of ureogenesis was demonstrated at insulin levels above 120 μU/ml. However, significant effects of insulin on suppressing net glucose outflow was not observed until insulin levels had reached 500 μU/ml. due presumably to the absence of a sustained rate of glycogenolysis by control livers. The observation that perfused livers from normal rats are extremely sensitive to several metabolic effects of insulin at physiological concentrations suggests that this experimental approach can provide useful information as to the role of the liver in the pathogenesis of various insulin resistant states.
Responses to Arginine of the Perfused Pancreas of the Genetically Diabetic Chinese Hamster
Authors: Frankel Barbara J , Gerich John E , Fanska Rudolph E , Gerritsen George C , Grodsky Gerold M
Published: September 2013

Nonketotic, genetically diabetic Chinese hamsters show subnormal pancreatic insulin release and impaired suppression of glucagon in response to glucose.

To study the pancreatic effects of other agents, dynamic insulin and glucagon release was measured from the in vitro perfused pancreases of normal and diabetic Chinese hamsters in response to various combinations of arginine (20 mM), glucose (100 or 150 mg. per 100 ml.), and theophylline (10 mM).

Theophylline alone caused identical insulin and glucagon release in diabetics and normals. Glucose, alone and in the presence of theophylline, caused subnormal insulin release and less suppression of glucagon release in the diabetics than in the normals. Arginine, in the presence of glucose and theophylline, caused excessive glucagon release but nearly normal insulin release in the diabetics Arginine, in the absence of glucose or theophylline, caused excessive glucagon release in the diabetics and undetectable insulin release in either diabetics or normals. Pancreatic content after perfusion did not correlate with release during perfusion. Infusion of arginine alone markedly decreased the amount of extractable pancreatic insulin and glucagon.

These results indicate that the pancreatic alpha cell of the diabetic Chinese hamster responds excessively to arginine, as is seen in the human diabetic. This defect is not related to acute insulin release or the presence of glucose. Further, these results confirm that the diabetic Chinese hamster's alpha and beta cells respond normally to theophylline, but are relatively insensitive to glucose.
Effect of Glucose Priming on Insulin Response in the Premature Infant
Authors: Grasso S , Distefano G , Messina A , Vigo R , Reitano G
Published: September 2013

Our paper deals with premature infants in the first twenty-four hours of life and reports the effect of a preinfusion of glucose on glucose administration. Glucose infusion (2.5 gm.) resulted in a slight elevation of serum insulin. When this administration of glucose was preceded by a two-hour infusion of glucose, there was a striking increase in serum insulin.
Stimulation of Glucagon Secretion by Ethanol-induced Hypoglycemia in Man
Authors: Palmer Jerry P , Ensinck John W
Published: September 2013

In fasted man, ethanol lowers plasma glucose by inhibiting gluconeogenesis with concomitant suppression of insulin release. Since glucose regulation of glucagon (IRG) secretion may be insulin dependent, we have evaluated IRG secretion in this setting of hypoglycemia and insulin deficiency. Mean IRG levels in six men fasted for fifty-six hours rose gradually from a basal level of 57 pg/ml. to 101 pg/ml. During the subsequent four-hour ethanol infusion, mean glucose concentration fell only 18 mg. per 100 ml. (26 per cent of pre-infusion values) yet IRG tripled to 265 pg/ml. Insulin (IRI) fell to unmeasurably low values. Alcohol given after only eight hours of fasting has no effect on plasma levels of glucose, IRG and IRI. These results suggest that the small decrease in extracellular glucose combined with relative insulin deficiency may cause inordinate intra-alpha cell glucopenia and result in exaggerated glucagon release.
Plasma Glucagon Levels During Rapid Exsanguination with and without Adrenergic Blockade
Authors: Alfred Lindsey C , Faloona Gerald R , Unger Roger H
Published: September 2013

In eleven dogs made hypotensive by means of rapid exsanguination over a period of forty to seventy minutes, mean glucagon rose to a peak of 516 ± (S.E.) 150 pg/ml. and mean glucose to a peak of 341 ± 27 mg. per 100 ml. The hyperglucagonemia induced by exsanguination was substantially reduced, although not abolished, by propranolol infusion, but was not diminished by phentolamine, suggesting that it was largely a β-adrenergic effect. Its possible contribution to survival during shock is considered.
Dynamics of Tolbutamide, Glucose, and Insulin Interrelationships Following Varying Doses of Intravenous Tolbutamide in Normal Subjects
Authors: Ganda O P , Kahn C B , Soeldner J S , Gleason R E
Published: September 2013

Four healthy adult subjects received intravenous tolbutamide (TOL) at six different doses (twenty-four tests): 0.0625 gin., 0.125 gin., 0.25 gm., 0.5 gin., 1.0 gm. and 1.5 gm. Blood glucose (BG), serum immunoreactive insulin (IRI) and serum TOL levels were determined before and for 180 minutes after TOL. There was a highly significant correlation of the dose of TOL with the peak IRI (p<.01), zero to ten minute IRI area (p<.001), and zero to sixty minute IRI area (p<.001) and with the decline in BG expressed as zero to sixty minute BG area (p<.001). Similar significant correlations were observed between levels of TOL and both IRI and BG. At each dose level the IRI response correlated significantly with the BG fall.

An additional eighteen subjects received the 1.0 gm. dose. In these, serum TOL levels did not correlate with either BG or IRI. These subjects also received intravenous glucose (0.5 gm. per kilogram body weight). BG levels did not correlate with IRI. However, there were striking correlations between TOL and glucosestimulated peak IRI (p<.001), zero to ten minute IRI area (p<.001) and zero to sixty minute IRI area (p<.05). Also, the zero to ten minute BG areas in the two tests were negatively correlated (p<.05).

The mean (± SEM) space of distribution for glucose (G.S.) and tolbutamide (T.S.) was found to be 13.45 ± 0.71 and 6.34 ± 0.31 L., respectively. There was a significant correlation between G.S. and T.S. (r = 0.70; p<.01).

Within individuals a significant dose-response relationship exists between TOL and IRI. TOL- and glucose-induced IRI secretion dynamics suggest strong similarities between mechanisms of rapid IRI release and/or size of available IRI storage pools.
Degradation of Insulin by Isolated Rat Liver Cells
Authors: Le Cam Alphonse , Freychet Pierre , Lenoir Pierre
Published: September 2013

The degradation of insulin by isolated rat liver cells has been studied. The phenomenon is time- and temperature-dependent. After sixty minutes' exposure to 1.5 × 106 cells/ml, about 50 per cent, 15 per cent, and less than 5 per cent of insulin at 1.5 μM. are degraded at 37° C., 20° C., and 0° C., respectively. The methods used to measure the hormone degradation affect the apparent Vmax. Higher values of Vmax are found when radioimmunoassay rather than precipitation by trichloracetic acid and adsorption to talc is used. However, the apparent Km. (0.27 μM.) is virtually the same with any of the methods used. N-ethyl-maleimide and Trasylol are potent inhibitors, whereas GSH increases the hormone degradation. Proinsulin acts as competitive inhibitor (apparent Ki = 0.35 μM.).

Gel filtration patterns of incubation supernates suggest that several enzymatic systems may be operative in the degradation of insulin by the liver cells. Glutathione-insulin-transhydrogenase is suggested by the appearance of a component that has the same elution volume as the A chain, but the inhibitory effects of trasylol on insulin degradation, as well as qualitative and quantitative similarities with insulin proteases, suggest that a proteolytic mechanism is involved. The insulin-degrading system in isolated liver cells closely resembles that observed in purified liver plasma membranes and in the isolated perfused liver. Such similarities stress the possible significance of the degradation process in the regulation of insulin action. These studies are also important for the quantitative analysis of insulin interaction with its specific receptors in isolated liver cells.
Amelioration of Hypoglycemia in a Patient with Malignant Insulinoma During the Development of the Ectopic ACTH Syndrome
Authors: Sadoff Leonard , Gordon Jack , Goldman Stuart
Published: September 2013

A patient with functioning islet cell carcinoma is described who had amelioration of her hypoglycemia during the development of the ectopic ACTH syndrome. Moon facies and hyperkalemic metabolic acidosis were also present in this patient, features uncommonly seen in the ectopic ACTH syndrome. At autopsy, she was found to have active tuberculosis. Prophylactic antituberculous therapy should be given to high-risk patients with the ectopic ACTH syndrome. High doses of ACTH may be palliative in refractory hypoglycemic states.
Effect of Phenformin on Gluconeogenesis from Lactate and Intracellular pH in the Isolated Perfused Guinea Pig Liver
Authors: Lloyd M H , Iles R A , Walton B , Hamilton C A , Cohen R D
Published: September 2013

Gluconeogenesis from lactate and hepatic cell pH (pHi) were measured in the isolated perfused livers of starved guinea pigs in the presence and absence of phenformin (phenethylbiguanide). The observed decrease in lactate consumption and glucose output in the presence of phenformin was associated with a fall in pHi. The fall in glucose output observed was considerably greater than accountable for by the decrease in lactate consumption. A possible mechanism for the pathogenesis of clinical lactic acidosis due to phenformin therapy is suggested.
Hormonal Regulation of Incorporation of Alanine-U-14C into Glucose in Human Fetal Liver Explants: Effect of Dibutyryl Cyclic AMP, Glucagon, Insulin, and Triamcinolone
Authors: Schwartz Alan L , Rall Theodore W
Published: September 2013

Incorporation of alanine-U-14C into glucose and liver glycogen increased linearly over sixty-five hours in culture of human fetal liver explants. This rate of incorporation was stimulated two- to tenfold by incubation with N6,2′O-dibutyry I adenosine 3′-5′:cyclic monophosphate (dibutyryl cyclic AMP) (0.1 mM) plus theophylline (0.5 mM) or glucagon (7.5 μg./ml.) plus theophylline. No apparent lag period was detected, and the hormonal effect continued throughout the observation period. Insulin (1 U./ml.) significantly decreased both the basal rate of incorporation and the stimulated rate resulting from dibutyryl cyclic AMP or glucagon incubation. These effects were observed at both high (10 mM) and low (2.8 mM) media glucose and from both 2.3 μM and 5 mM alanine-U-14C. Triamcinolone (20 μg./ml.) alone stimulated the rate of alanine-U-14C incorporation into glucose, whereas triamcinolone in the presence of dibutyryl cyclic AMP produced an increase in incorporation greater than the sum of the individual effects.

The basal incorporation of alanine-U-14C into glucose by these human fetal liver explants provide a rate of approximately 4 nmoles glucose/gm. min, which is discussed in relation to the physiologic needs of the fetus and newborn.
Glucose Intolerance in the Carcinoid Syndrome
Authors: Feldman Jerome M , Plonk James W , Bivens Carl H , Lebovitz Harold E
Published: September 2013

We assayed glucose tolerance and insulin secretion in ten patients with metastatic carcinoid tumors and the carcinoid syndrome (“active tumors”) and in seven patients with metastatic carcinoid tumors without the carcinoid syndrome (“inactive tumors”). The patients with “active tumors” had elevated serum serotonin levels while the patients with “inactive tumors” had normal serum serotonin levels. Of the ten patients with “active tumors”, five had diabetic and three had borderline intravenous glucose disposal rate constants (KG = 0.88 ± 0.07, M. ± S.E.M.). Their KG was significantly lower (p<0.01) than a group of agematched normals. AH of the patients with “inactive tumors” had normal KG values (KG = 1.67 ± 0.24). Their KG did not differ from that of age-matched normal subjects. Both groups of carcinoid patients had a comparable decrease in their insulinogenic index. Two days' administration of the serotonin antagonist cyproheptadine (Cypro) to eight of the patients with “active tumors” resulted in a significant increase in the “insulinogenic index” (50 per cent) but a nonsignificant increase in the KG (12 per cent). Administration of p-chlorophenylalanine, a compound that blocks serotonin synthesis, resulted in an increase in both the KG (60 per cent) and the “insulinogenic index” (55 per cent). The insulin half-life (½) of patients with “active tumors” (6.1 ± 0.4 min.) did not differ from the t½ of normal subjects (6.6 ± 0.4 min.), suggesting that the decreased plasma insulin levels following intravenous glucose were due to impaired insulin secretion rather than accelerated insulin destruction. Seven of the patients received treatment with the antitumor agent streptozotocin (Strepto). The patients received cumulative doses of from 70 to 300 mg. of Strepto per kilogram body weight with no impairment in glucose tolerance or insulin secretion. We conclude that there is high incidence of glucose intolerance (80 per cent) and impaired insulin secretion in patients with the carcinoid syndrome and that serotonin plays a role in producing these alterations.
Plasma Lipid Levels in Diabetic Children: Effect of Diet Restricted in Cholesterol and Saturated Fats
Authors: Kaufmann R L , Assal J Ph , Soeldner J S , Wilmshurst E G , Lemaire J R , Gleason R E , White P
Published: September 2013

Plasma lipids, blood glucose, and urinary glucose excretion were measured in 270 juvenile diabetic children upon admission to and throughout periods of summer camping during which the effect of a usual and a modified diabetic diet was assessed. The usual diabetic diet contained 700-1,500 mg. cholesterol daily with a polyunsaturated/saturated (P/S) ratio of 0.1, while the modified diet limited cholesterol to 300 mg. daily with a P/S ratio of 1.0. Both diets maintained calories with 40 per cent as fat, 40 per cent as carbohydrate, and 20 per cent as protein. Analysis of fasting blood glucose, qualitative and quantitative glucose excretion, and body weight indicated that groups were comparable except for the diet used.

Elevated mean levels of cholesterol and triglycerides were approximately equally distributed in diabetic children of both sexes upon admission to camp, with 24 per cent demonstrating hyperlipoproteinemia. Eleven per cent had type II, 10 per cent type IV, and 3 per cent type V hyperlipoproteinemia upon admission. After following the usual diet, 21 per cent were type II, 1 per cent type IV, and none type V, with no reduction in the over-all incidence of hyperlipoproteinemia despite lower triglyceride and glucose levels. After consumption of the modified diet, hyperlipoproteinemia was reduced to 5 per cent, with 4 per cent type II and 1 per cent type IV.

Results of this study indicated that plasma lipids in juvenile diabetics were elevated when first observed and that the control of blood sugar levels along with a diabetic diet with lower cholesterol and increased polyunsaturated fat significantly reduced the incidence of hyperlipoproteinemia more effectively than control of blood sugar levels alone.
Decrease in Myelin Content of Rabbit Sciatic Nerve with Aging and Diabetes
Authors: Spritz Norton , Singh Harbhajan , Marinan Barbara
Published: September 2013

Previous studies of the amount of peripheral nerve myelin have been based on histologic examination. In this study, myelin content was measured directly after quantitative isolation from sciatic nerve. There was a decrease in the amount of myelin beginning at nine months, the time of maximal myelin content in normal rabbits, and beginning at six months, the amount was decreased in diabetic as compared with control animals. Composition of myelin isolated from young (age three to four months) and old (age nine to thirteen months) rabbit sciatic nerves was also determined and is similar to that of other species. Although the composition was not affected by diabetes, with aging there was a significant decrease in the amount of cholesterol and an increase in glycolipid.
Inhibition of Labile Aggregation-stimulating Substance (LASS) and Platelet Aggregation in Diabetes Mellitus
Authors: Colwell John A
Published: September 2013

Irreversible second-phase aggregation of platelets in diabetic patients is prevented in vitro by 5, 8, 11, 14-eicosatetraynoic acid (TYA), a competitive inhibitor of the labile aggregationstimulating substance (LASS) which is formed from arachidonic acid. Thus, inhibition of prostaglandin synthesis inhibits platelet aggregation in diabetic subjects. These findings indicate that platelets from diabetics are subject to control by intracellular mechanisms operative in the regulation of platelet function in normal individuals.
Red Cell 2, 3-Diphosphoglycerate Levels Among Diabetic Patients with and Without Vascular Complications
Authors: Kanter Yoram , Bessman Samuel P , Bessman Alice N
Published: September 2013

There have been differences of opinion among authors concerning the levels of red cell 2,3-diphosphoglycerate (2,3-DPG) and nucleotides in nonacidotic diabetic patients. Our data suggest that abnormal levels of 2,3-DPG in diabetic patients are related to the presence of vascular complications and not to the duration of the disease per se. 2,3-DPG levels are normal in diabetic patients with no evidence of vascular complications (group A). In ambulatory patients with vascular complications (group B), significantly higher levels of 2,3-DPG are found than in normal subjects and patients in group A. In hospitalized diabetic patients with active peripheral vascular complications (group C), levels of 2,3-DPG are likewise significantly increased over those of normal subjects and patients of group A. 2,3-DPG was found to be significantly elevated in patients of group C as compared with group B. 2,3-DPG levels in venous blood from infected legs as compared with those of the peripheral venous blood were not significantly different, thereby ruling out local factors. There were no differences in the blood lactate levels in any of the groups studied. The elevation of the 2,3-DPG levels may be a reflection of attempted red blood cell compensation for tissue hypoxia in the diabetic with vascular disease.
Lactic Acidosis Associated with Phenformin Therapy: Evidence that Inhibited Lactate Oxidation is the Causative Factor
Authors: Searle G L , Siperstein M D
Published: September 2013

Using uniformly labeled 14C L-lactate, we have studied the turnover and oxidation of lactic acid in a patient who presented with a mild lactic acidosis while on phenformin medication. As with other cases of lactic acidosis associated with phenformin therapy, this subject had impaired renal function as evidenced by serum creatinine levels of 2 mg./100 ml. and BUNs of 40 mg./l00 ml. Comparison of the rate of lactate oxidation relative to the rate of lactate turnover in this subject while on and off phenformin therapy suggests that a prime factor leading to the elevated lactate levels in this situation is impaired peripheral aerobic metabolism. Although lactate oxidation was increased in the presence of phenformin, the control studies clearly demonstrate that aerobic metabolism was not keeping pace with the increased level of anaerobic carbohydrate metabolism brought on by the drug. It is concluded that it is this imbalance in lactate metabolism that is responsible for the lactic acidosis that accompanies phenformin therapy.