bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reactions of Biologic Aldehydes with Proteins
Authors: Fantl Wendy J , Stevens Victor J , Peterson Charles M 
Published: September 2013

The amino functions of proteins are susceptible to modification by the carbonyl moieties of aldehydes that are found in vivo, such as formaldehyde, glyceraldehyde, acetaldehyde, and glucose.
Formaldehyde reacts fairly nonspecifically with proteins. However, under controlled conditions, it may be used as a structural probe to supply the carbonyl component for the reductive alkylation of proteins. Glyceraldehyde reacts less extensively with proteins, as exemplified by its reaction with hemoglobin, and has therapeutic potential as an antisickling agent.
Recent work has focused on the modification of hemoglobin by acetaldehyde. This primary metabolite of ethanol metabolism is elevated in alcoholics. Clinical studies on fast-chromatographing hemoglobins (hemoglobin A1a–c) have suggested that a novel adduct may be formed in persons abusing alcohol. Alcoholic patients have an elevated concentration of minor hemoglobins but normal or subnormal amounts of glycosylated hemoglobin (hemoglobin A1c) as determined by radioimmunoassay. Acetaldehyde was found to form adducts with hemoglobin (HbAAA), both in vitro and in vivo, leading to a change in Chromatographic properties. Browning occurred with higher concentrations of acetaldehyde. HbAA formation thus provides a potential marker for alcoholism in addition to providing a biochemical hypothesis regarding the secondary sequelae of alcohol intake.
The Reversal of Diabetes by Pancreatic Islet Transplantation
Authors: Prowse S J , Lafferty K J , Simeonovic C J , Agostino M , Bowen K M , Steele E J 
Published: September 2013

In this paper the theoretical basis of aiioreactivity and its relevance to transplantation biology is discussed prior to a review of work showing that culture of adult mouse pancreatic islets for 7 days in 95% O2 and 5% CO2 facilitates successful grafting to nonimmunosuppressed allogeneic recipients. These allografts function by reversing both chemically induced and spontaneous diabetes. The fetal mouse pancreas is more immunogenic than adult islets, and even after a culture period of 10 days in 95% O2 and 5% CO2, BALB/c allografts are consistently rejected by nonimmunosuppressed recipient mice. The immunogenicity of fetal pancreas is thought to be due to the presence of contaminating lymphoreticular celis in the mesentery surrounding the fetal pancreas. Digestion of the fetal pancreas with coilagenase allows the isolation of proislets that develop into functional islet tissue on transplantation. Fetal proislets are less immunogeneic than the whole fetal pancreas and may provide a source of tissue for clinical transplantation.
Established islet allografts are relatively stable and are not rejected following nonspecific stimulation of the recipient's immune system or following passive transfer of either antibody or antibody and complement. After prolonged residence in the recipient a state of a I log raft tolerance develops and such grafts resist rejection by specific stimulation of the recipient. The administration of donor antigen in the form of uvirradiated cells enforces this state of eliografi tolerance.
Role of the Kidney in the Metabolism of Fructose in 60-hour Fasted Humans
Authors: Björkman Ola , Felig Philip 
Published: September 2013

SUMMARY
Arterial (A) and renal venous (RV) concentrations and net splanchnic exchange of glucose, fructose, lactate, pyruvate, glycerol, and alanine were studied in the basal state and during a 135-min intravenous infusion of fructose at 2 mmol/min in healthy subjects after a 60-h fast. After 45 min of the fructose infusion, somatostatin (9 μg/min) was infused for 60 min to induce hypoglucagonemia.
Fructose infusion resulted in a net uptake of this hexose by the kidney as well as the splanchnic bed. Estimated renal uptake of fructose could account for the disposal of 20% of the administered fructose load while splanchnic uptake accounted for 38%. The fructose infusion resulted in a rise in blood glucose of 0.9 mmol/L, a 35% increase in net glucose output from the splanchnic bed, and a consistent net output of glucose from the kidney (A-RV = −0.17 ± 0.05 mmol/L as compared with 0 ± 0.03 in the basal state, P &lt; 0.02). Net glucose release from the kidney could account for 55% of the net renal uptake of fructose. The fructose infusion also resulted in a marked change in renal lactate balance from a net uptake in the basal state (A − RV = 0.05 ± 0.01 mmol/L) to a net output during fructose administration (A − RV = −0.10 ± 0.04). Administration of somatostatih resulted in a fall in arterial glucagon levels and a 35% decrease in splanchnic glucose output but failed to alter the arterial-renal venous difference for glucose observed during the fructose infusion.
We conclude that in 60-h fasted man: (a) intravenous infusion of fructose results in a net uptake of this hexose by the kidney as well as the liver, (b) this uptake is accompanied by stimulation of renal as well as hepatic glucose production and renal production of lactate, and (c) hypoglucagonemia inhibits splanchnic but not renal glucose output during fructose infusion. These data indicate that the kidney is an important site of fructose disposal and that glucose and lactate are end products of renal fructose metabolism.
Influence of Plasma Glucose and Insulin Concentration on Plasma Glucose Clearance in Man
Authors: DeFronzo Ralph A , Ferrannini Eleuterio 
Published: September 2013

We examined the influence of plasma glucose concentration on whole-body glucose uptake and glucose clearance at two physiologic levels of hyperinsulinemia. Twelve healthy, young volunteers were divided into two groups (A and B); each subject participated in three studies. In group A, plasma insulin was raised and maintained by ∼100 μU/ml for 3 h, while plasma glucose concentration was clamped at hypoglycemic (60 ± 1 mg/dl), euglycemic (89 ± 1 mg/dl), or hyperglycemic (165 ± 3 mg/dl) levels. In group B, plasma insulin was raised by ∼50 μU/ml, while plasma glucose was clamped at 62 ± 1,86 ±2, or 143 ± 3 mg/dl for 3 h.
At the higher insulin level (group A), glucose uptake rose from 5.2 ± 0.5 to 7.3 ± 0.6 to 12.2 ±1.0 mg/min· kg as plasma glucose was varied from low to high levels; glucose clearance fell slightly from 8.8 ± 1.0 to 7.8 ± 0.7 to 7.3 ± 0.6 ml/min·kg during the hypo-, eu-, and hyperglycemic clamps (P = NS). At the lower insulin level (group B), glucose uptake rose from 6.0 ± 1.2 to 8.1 ±1.7 mg/min·kg (P &lt; 0.05) with increasing glucose levels, whereas glucose clearance fell significantly (P &lt; 0.01) from 9.7 ± 1.8 to 5.6 ±1.1 ml/min·kg. When the data from both groups were analyzed together, insulin had a stimulatory effect on both glucose uptake and clearance. Elevation of the plasma glucose level had a similar stimulatory effect on glucose uptake (P &lt; 0.001) but inhibited glucose clearance (P &lt; 0.01). This inhibition, however, was modest (14% for the change from hypo- to euglycemia, and 16% for the change from eu- to hyperglycemia).
We conclude that physiologic hyperglycemia exerts a modest inhibitory effect on glucose clearance, which is largely overcome at higher, yet still physiologic, plasma insulin levels (∼100 μU/ml).
The Measurement of Glycosylated Hemoglobin in Man and Animals by Aminophenylboronic Acid Affinity Chromatography
Authors: Yue D K , McLennan S , Church D B , Turtle J R 
Published: September 2013

Glycosylated hemoglobin (GHb) was estimated in normal and diabetic human, rat, and dog hemolysate by m-aminophenylboronic acid (PBA) affinity chromatography and the results compared with the values determined using two ion-exchange (ION-E) methods and a colorimetric thiobarbituric acid (TBA) method. There was a good correlation between the values estimated by PBA and both ION-E chromatography methods for the human samples (r = 0.83, P &lt; 0.0002, r = 0.86, P &lt; 0.002). In diabetic rat and dog hemolysates, PBA chromatography demonstrated higher glycosylated hemoglobin than in normal hemolysate. In both species, there was an excellent correlation between the PBA-estimated GHb and plasma glucose levels (rat r = 0.79, P &lt; 0.001; dog r = 0.67, P &lt; 0.003). The IONE and TBA methods were not as effective in separating diabetic from normal samples and correlated less well with plasma glucose levels.
PBA chromatography relies on the interaction of mamino phenylboronate with the hydroxyl groups of the glucose residues attached to hemoglobin. It is not affected by intra- or interspecies variations in the hemoglobin moiety and should be adaptable for measurement of GHb in a number of laboratory animals and in patients with hemoglobinopathy. It is not affected significantly by temperature and may offer advantages over the ION-E method in the routine determination of human glycosylated hemoglobin.
Diabetes Susceptibility of BALB/cBOM Mice Treated with Streptozotocin: Inhibition by Lethal Irradiation and Restoration by Splenic Lymphocytes
Authors: Paik Sang-Gi , Blue Marie L , Fleischer Norman , Shin Seung-Il 
Published: September 2013

In genetically susceptible strains of mice, repeated injections of a subdiabetogenic dose of streptozotocin induces the development of progressive insulin-dependent hyperglycemia. We showed previously that host T-cell functions play an obligatory etiologic role in this experimental disease by demonstrating that the athymic nude mouse is resistant to diabetes induction unless its T-cell functions are reconstituted by thymus graft (Paik et al., Proc. Natl. Acad. Sci. USA 77:6129–33, 1980).
Here we show that lethal irradiation of euthymic (+/nu) mice of BALB/cBOM background causes selective resistance of the mice to the diabetogenic effects of the multiple low doses of streptozotocin without affecting their sensitivity to a high pharmacologic dose of the toxin. We also show that reconstitution of the irradiated mice with splenic lymphocytes causes the restoration of diabetes susceptibility. Lethally irradiated mice thus represent a useful experimental model for analyzing the host functions involved in the development of this disease. These results provide an additional support for the hypothesis that the induction of diabetes in this model system is mediated by an autoimmune amplification mechanism.
The Effect of Continuous Subcutaneous Insulin Infusion on Very-Low-Density Lipoprotein Triglyceride Metabolism in Type I Diabetes Mellitus
Authors: Pietri Angel O , Dunn Fredrick L , Grundy Scott M , Raskin Philip 
Published: September 2013

The effect of continuous subcutaneous insulin infusion (CSII) on very-low-density lipoprotein triglyceride (VLDL-TG) metabolism was studied in seven normolipidemic type I diabetic patients. VLDL-TG transport was determined using 3H-glycerol as an endogenous precursor of VLDL-TG, and the resultant turnover curves were evaluated by multicompartmental analysis. Kinetic studies were performed in the diabetic patients during conventional insulin therapy and again after 3 wk of euglycemia achieved with CSII, and the results were compared with those obtained in 5 age-, weight-, and sex-matched normolipidemic nondiabetic subjects.
After 3 wk of CSII, the mean (± SEM) 24-h plasma glucose levels in the diabetic patients decreased from 238 ±15 mg/dl on conventional therapy to 99 ± 11 mg/dl (P &lt; 0.05) on CSII therapy. The total glycosylated hemoglobin levels decreased from 10.2 ± 0.5 to 6.5 ± 0.4%. There was a significant decrease in fasting plasma cholesterol (172 ± 13 mg/dl to 136 ± 4 mg/dl), LDL cholesterol (104 ± 9 mg/dl to 82 ± 4 mg/dl), plasma triglyceride (114 ± 24 mg/dl to 71 ± 9 mg/dl), and VLDL-TG (68 ± 18 mg/dl to 37 ± 5 mg/dl) levels. There was no change in the HDL cholesterol concentration.
Results of the kinetic studies in the conventionally treated diabetic patients revealed normal VLDL-TG transport rates and fractional catabolic rates (FCR). CSII caused a marked and significant fall in mean VLDL-TG transport rates (12.2 ± 3.5 to 4.1 ± 0.8 mg/h/kg IW, P &lt; 0.05) to levels below those observed in the nondiabetic subjects (10.2 ± 2.1 mg/h/kg IW, P &lt; 0.05). There was no change in the mean FCR with CSII. These data thus suggest that the mechanism responsible for the observed change in plasma triglyceride levels in normolipidemic type I diabetic patients that occurs with 3 wk of CSII treatment is due to suppression of hepatic VLDL-TG synthesis rather than the result of increased lipoprotein clearance.
Low Plasma Somatomedin-C in Streptozotocin-induced Diabetes Mellitus: Correlation with Changes in Somatogenic and Lactogenic Liver Binding Sites
Authors: Maes Marc , Ketelslegers Jean-Marie , Underwood Louis E 
Published: September 2013

To determine the mechanism for the decrease of somatomedin levels in insulin-dependent diabetes, the relationships among plasma immunoreactive somatomedin-C (Sm-C), plasma growth hormone (GH) and prolactin (PRL), and the somatogenic and lactogenic binding sites in liver were assessed in rats with nonketotic diabetes mellitus of different duration (1 wk or 1 mo) and severity (50 or 60 mg streptozotocin/kg BW). One week after administration of 60 mg streptozotocin (STZ)/kg, plasma Sm-C concentrations were significantly decreased (0.23 ± 0.03 versus 0.43 ± 0.03 U/ml in controls; mean ± SEM, P &lt; 0.01). In contrast, plasma GH concentrations, bovine GH (bGH) binding, and human GH (hGH) binding were not significantly changed. After 1 mo of diabetes, no further decrease in plasma Sm-C content was observed despite a reduction in plasma GH and PRL concentrations and reduced hepatic bGH binding capacity (5 ± 2 versus 38 ± 4 fmol/mg protein; P &lt; 0.01). In the group of rats injected with 50 mg STZ/kg, the Sm-C was reduced at 1 mo but hepatic GH binding was not.
In a second study, diabetic rats (75 mg STZ/kg) were treated after 3 wk with insulin (10 U lente per day for 7 days). This treatment normalized Sm-C levels and partially restored the GH binding capacity (treated: 49 ± 4 fmol/mg protein versus untreated diabetics: 28 ± 6 fmol/mg protein; P &lt; 0.01 and versus controls: 68 ± 4 fmol/mg protein; P &lt; 0.05). In contrast, prolactin binding capacity remained low (treated: 23 ± 3 fmol/mg protein versus untreated diabetics: 13 ± 2 fmol/mg protein; P &gt; 0.05) and mean plasma GH and PRL were unchanged.
The findings suggest that in an early phase of nonketotic diabetes, the low plasma Sm-C is not due primarily to reduced GH receptor number. Rather, it may reflect diminished Sm-C synthesis at a site distal to the binding of growth hormone to its tissue receptor.
Preparation of High-Potency, Non-aggregating Insulins Using a Novel Sulfation Procedure
Authors: Pongor Sándor , Brownlee Michael , Cerami Anthony 
Published: September 2013

The marked propensity of insulin to self-associate into large aggregates causes significant mechanical problems in insulin delivery devices and may also stimulate production of a tissue-amyloid A precursor in some patients. Although conventionally prepared sulfated insulin (SI) resists aggregation, clinical application has been limited by major insulin bioactivity losses that occur during synthesis.
To eliminate this problem, insulin sulfation was carried out in the organic solvent dimethylformamide in the presence of condensing agents such as N,N'-dicyclohexyl carbodiimide (DCC) and a sulfate donor. With this new procedure, the degree of sulfation could be controlled over an eightfold range by varying the amount of condensing agent. The bioactivity of these new SI derivatives varied between 78% and 87% of unmodified insulin. Insulin aggregation, induced by passage through a syringe and needle, did not occur with derivatives having two or more sulfate moieties per insulin molecule. Diffusion velocity studies using “non-aggregated” insulin solutions demonstrated that aggregates were present in crystalline zinc and sodium porcine insulin. In contrast, SI having more than 0.5 mole sulfate per mole of insulin dialyzed as if it were predominantly in the monomeric form.
Results from the studies described in this report now provide the means for selectively designing and preparing specific high-potency, non-aggregating insulins, which may be necessary for optimal use of current and future insulin delivery devices.
Nutrition and Somatomedin. XI. Studies of Somatomedin Inhibitors in Rats with Streptozotocin-induced Diabetes
Authors: Phillips L S , Bajaj V R , Fusco A C , Matheson C K 
Published: September 2013

Diabetics may have normal somatomedins by radioimmunoassay yet decreased somatomedin activity by bioassay. The discrepancy appears due to circulating inhibitory factors; inhibitors in whole diabetic serum antagonize the action of both somatomedins and insulin via noncompetitive interactions. Since little is known about the nature of the inhibitory activity, serum from streptozotocin-diabetic rats was fractionated, and inhibitory activity measured as the ability of fractions to blunt stimulation of SO4 uptake by hypophysectomized rat costal cartilage exposed in vitro to somatomedins in normal rat serum.
After establishing that inhibitory activity was stable to pH and lyophilization, diabetic rat serum was gel filtered at pH 7 (somatomedins bound to carrier proteins) and 2.4 (somatomedins dissociated, mol wt ∼8000). Using Sephadex and Sephacryl columns at neutral pH, inhibitors were detected at mol wt ∼250,000, ∼24,000, and ∼940. Predominant activity was at ∼24,000 and ∼940. In contrast, Sephadex columns at acid pH revealed inhibitors only at mol wt ∼21,000. Diabetic rat serum was also subjected to ion-exchange chromatog-raphy on CM-Sepharose. A single band of activity at pH 5–7 was found on elution with increasing pH, suggesting an isoelectric point(s) lower than that of the somatomedins. However, three areas of activity were seen on elution with increasing ionic strength at pH 5— at 0.02 M and 0.14–1.4 M and at 2.0 M pH 5.0–5.5.
These studies indicate that reduced anabolism in diabetes may be due in part to three species of circulating somatomedin inhibitors, largely of mol wt ∼ 21–24,000 and∼940, and also of mol wt ∼250,000. The inhibitors have generally acidic properties, and molecular weights both larger and smaller than the somatomedins.
Red Cell Deformability, Platelet Aggregation, and Insulin Action
Authors: Vague Philippe , Juhan Irène 
Published: September 2013

Abnormalities of rheologic and hemostatic properties of blood are present in uncontrolled diabetics and play a role in the development of structural micro- and macroangiopathies.
Red blood cell deformability is decreased in diabetics and shows negative correlation with fast hemoglobin and actual blood glucose levels. In uncontrolled insulin-dependent diabetics, normalization of plasma glucose by an insulin infusion improves red cell deformability in 2 h. Insulin infusion (0.2 U/kg/h) [the initial hyperglycemia being maintained (hyperglycemic clamp)] also improves red cell deformability. Deformability of normal erythrocytes is reduced by incubation in plasma from uncontrolled diabetics but is normal in plasma from diabetics controlled by a 24-h insulin infusion or in diabetic plasma with insulin added in vitro. Therefore, insulin appears to have a direct effect on erythrocyte deformability.
Platelet aggregation measured in whole blood is raised in uncontrolled diabetics. Aggregation of normal platelets rises in the presence of “diabetic” red cells but not in the presence of red cells from the same patients controlled by 24-h treatment with insulin. The effect of insulin on platelet aggregation, therefore, seems to be at least partly mediated by erythrocytes.
Determinants of the Penetration of Proteins Through the Glomerular Barrier in Insulin-dependent Diabetes Mellitus
Authors: Viberti Giancarlo , Mackintosh David , Keen Harry 
Published: September 2013

To investigate the determinants of the glomerular filtration of proteins in insulin-dependent diabetic patients we studied the fractional clearance of albumin (θAlb) and IgG (θIgG) and the selectivity index (SI = IgG clearance/Alb clearance) in 32 subjects with macroproteinuria (albustix positive), in 29 subjects with microproteinuria (albustix negative), and in 24 healthy control subjects. Fractional clearances of both albumin and IgG were higher in macroproteinuric than in microproteinuric patients, with both groups having higher values than controls (all P &lt; 0.001). In microproteinuric patients with albumin excretion rate (AER) not exceeding 60 μg/min, there was a highly significant correlation between the clearance of albumin and that of IgG. The SI was normal for AERs up to 30 μg/min, but above that albumin filtration increased disproportionately and SI progressively fell.
In insulin-dependent diabetics with macroproteinuria, there was a negative correlation between SI and glomerular filtration rate (GFR) (r = −0.68; P &lt; 0.001); the lower SI (0.133 ± 0.06) at higher GFRs also was due to a preferential increase in albumin clearance. Selectivity was progressively lost as GFR declined, and the SI returned to normal values when GFR fell below 10 ml/min/1.73 m2; this was due to a progressively higher rise in the fractional clearance of IgG relative to albumin. We suggest that glomerular filtration of proteins is governed by different determinants at different stages of the disease. In microproteinurics with AER below 60 μg/min, increased intraglomerular pressure seems primarily responsible for the higher proportional filtration of both albumin and IgG. A charge selectivity defect accounts for the proteinuria of microproteinuric diabetics with AERs above 60 μg/min and for that of macroproteinuric diabetics with unreduced GFR since albumin, a polyanion, is preferentially filtered. Pore size selectivity loss is added to the depletion of membrane polyanions in the proteinuria of late nephropathy because the filtration of IgG, a larger but neutral protein, increases relatively more than that of albumin.
Glucose Insensitivity and Amino-acid Hypersensitivity of Insulin Release in Rats with Non-insulin-dependent Diabetes: A Study with the Perfused Pancreas
Authors: Giroix Marie-Hélène , Portha Bernard , Kergoat Micheline , Bailbe Danielle , Picon Luc 
Published: September 2013

Non-insulin-dependent diabetes (NIDDM) was obtained in adult rats following a neonatal streptozotocin injection. Rats with NIDDM exhibited slightly lowered plasma insulin, slightly elevated basal plasma glucose values (&lt;200 mg/dl), anancreatic insulin stores (50% of the controls). Insulin secretion was studied in this model using the isolated perfused pancreas technique.
Insulin response to glucose stimulation over the range 5.5–22 mM was lacking, thus indicating complete loss of B-cell sensitivity to glucose. Even in presence of theophylline, the B-cells remained insensitive to glucose. In contrast, glyceraldehyde elicited an insulin release as important as that obtained in the control pancreata. This could possibly suggest that the Bcell dysfunction in rats with NIDDM involves a block in glucose metabolism in the early steps of glycolysis prior to the triose-phosphate. Mannose stimulated insulin secretion less in the diabetics than in the controls. The insulin secretion obtained in response to isoproterenol indicated that the ability of the adenylcyclase to generate cAMP in the B-cells of the diabetics was not decreased. The insulinotropic actions of acetylcholine and tolbutamide were normal and increased, respectively, as compared with the controls.
In the absence of glucose, the B-cells of the diabetics were unexpectedly hypersensitive to arginine and leucine. The α-ketoisocaproate effect in the diabetics was not significantly different from that obtained in the controls. The possibility that enhancement of insulin response to leucine in the diabetics might be related to a more active conversion of leucine to ketoisocaproate along the first steps of intraislet leucine metabolism is proposed.