bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renal Function and Effects of Partial Rehydration During Diabetic Ketoacidosis
Authors: Owen Oliver E , Hamilton Licht J , Sapir Daniel G 
Published: September 2013

Although diabetic ketoacidosis is characterized by increased renal excretion of glucose, ketone bodies, and nitrogenous compounds, there are few quantitative studies pertaining to renal function during this state. Therefore, renal function was studied in 10 adult patients in moderate to severe diabetic ketoacidosis before insulin administration. Admission plasma concentrations were: glucose 21.4 (9.2–39.4) mM or 386 (166–710) mg/dl, acetoacetate 3.0 (1.3–7.4) mM, beta-hydroxybutyrate 7.9 (2.9–15.2) mM, acetone 4.4 (1.3–8.9) mM, and HCO3 12.8 (9.5–17.8) mM. Arterial blood pH was 7.28 (7.21–7.38). Partial rehydration was achieved with 0.45% saline. Inulin was used to measure GFR. Renal clearance of acetoacetate, beta-hydroxybutyrate, acetone, glucose, and urinary excretion of nitrogenous compounds were determined.
Partial rehydration reduced plasma glucose concentration, primarily because of renal excretion, amounting to 384 ± 73 μmol/min or 69 ± 13 mg/min. Partial rehydration had no effect on plasma ketone bodies, on bicarbonate or urea concentrations, or on arterial pH. Partial rehydration had no effect on ketone body or nitrogenous compound excretory rates.
Reabsorptive rates of acetoacetate, beta-hydroxybutyrate, acetone, and glucose increased linearly with their filtered loads, and no maximal renal tubular transport rates were demonstrated for any ketone body or glucose. Because renal absorption of ketone bodies was less than 100%, ketonuria increased as filtered loads increase. Unlike ketone bodies, glucose reabsorptive rate was directly related to GFR.
Total renal excretion of nitrogen in the forms of urea, ammonium, creatinine, and uric acid amounted to 16 ± 2 mg/min. This huge loss of body nitrogen reflected ongoing protein catabolism and not heightened renal excretion of preformed compounds, as the plasma concentrations of urea, creatinine, and uric acid did not change during the study. Urea nitrogen accounted for 12 ± 2 mg/min (72%) of the total nitrogen excreted. Ammonium excretion was markedly augmented, ranging from 76 to 537 μmol/min, and was inversely related to arterial pH.
We conclude that the fall in plasma glucose concentration is primarily caused by renal glucose excretion, and that the absence of a maximal renal tubular reab-sorption rate for either acetoacetate (AcAc) or beta-hydroxybutyrate (β-OHB) serves to mitigate urinary losses of sodium and potassium during diabetic ketoacidosis.
Differential Response to Infusions of Highly Purified and Conventional Bovine and Porcine Insulins
Authors: Nosadini R , Noy G , Kurtz A B , Alberti K G M M 
Published: September 2013

The glucose clamp technique allows quantification of tissue sensitivity to insulin without modulation by the effects of hypoglycemia. The amount of glucose infused to maintain euglycemia during an insulin infusion gives a direct measure of tissue sensitivity. We have used this technique to compare the metabolic effects of highly purified porcine, highly purified bovine, and conventional insulins in diabetic subjects: (A) a group normally taking conventional bovine insulin, and (B) diabetics who had originally been treated with conventional bovine insulin and had changed to highly purified porcine insulin. Subjects were studied while attached to the Biostator with blood glucose values clamped at the basal level during a 2-h insulin infusion (0.01 U/kg/h). Both groups of diabetics received significantly more glucose in the first hour of the monocomponent porcine insulin infusion than during the same period either of conventional or of highly purified bovine insulin infusion. Highly purified porcine insulin infusion was also associated with a more rapid fall in blood ketone body concentrations.
Highly purified porcine insulin infusion was accompanied by a greater and earlier increase in free insulin concentrations. All diabetics had antibodies to insulin but no differential antibody binding of beef and pork insulin was found in the two groups of patients. Thus, use of highly purified porcine insulin is associated with a more rapid onset of action and a greater initial increment in free insulin values.
Effect of Ethanol, Acetaldehyde, and Acetate on Insulin and Glucagon Secretion in the Perfused Rat Pancreas
Authors: Tiengo A , Valerio A , Molinari M , Meneghel A , Lapolla A 
Published: September 2013

The effects of varying concentrations of ethanol (1,10, and 30 mM) and its metabolites (1 mM acetate and 1 and 10 mM acetaldehyde) on insulin and glucagon secretion induced by glucose (11.1 mM) and arginine (20 mM) were studied in isolated perfused pancreas of Sprague-Dawley rats
Ethanol and its metabolites did not significantly modify basal secretion of the two hormones. Ethanol reduced glucose-induced insulin secretion by means of a dose-related effect. Arginine-induced insulin output did not seem to be influenced to any significant degree. Acetate and acetaldehyde significantly inhibited glucose and arginine-induced insulin secretion. While ethanol (10 and 30 mM) did not modify glucagon output during arginine perfusion, acetate and acetaldehyde markedly enhanced it.
The block of insulin secretion and the increased secretion of glucagon could explain the diabetogenic effect of ethanol demonstrated in vivo. The mechanism by which ethanol acts on the pancreatic β- and α-cells is discussed.
Regional Localization of Cerebral Edema Following Fluid and Insulin Therapy in Streptozotocin-Diabetic Rats
Authors: Tornheim Patricia A 
Published: September 2013

To evaluate the location and early time course for development of cerebral edema following therapy for diabetes, streptozotocin-diabetic rats were subjected to constant i.v. infusion with saline and regular insulin. At the end of 1, 2, and 5 h of therapy, these rats were killed and tested for density of the cerebral cortex, subcortical white matter, caudate-putamen, thalamus, and medulla. Density data from treated animals were compared with those from control animals. From these data, change in brain tissue volume as water was calculated.
Diabetic animals killed after 1 h of fluid and insulin therapy demonstrated a modest increase in brain water content of all areas tested except white matter. Following 2 h of therapy, all regions tested were edematous, with a magnitude of edema that was similar to that seen at 1 h. After 5 h of therapy, there was further increase in water content of the cerebral cortex, but not the other regions examined. Treatment with saline alone did not result in central overhydration.
The findings of this study suggest that aggressive therapy with fluids and insulin, but not fluid alone, results in global overhydration of the brains of diabetic animals. Prolonged fluid and insulin treatment with a return of blood glucose to normal values causes further and preferential accumulation of edema fluid in the cerebral cortex.
Increase of Plasma Acetaldehyde: An Objective Indicator of the Chlorpropamide Alcohol Flush
Authors: Jerntorp Peter , Öhlin Hans , Bergström Bengt , Almér Lars-Olof 
Published: September 2013

Chlorpropamide alcohol flushing (CPAF) in non-insulin-dependent diabetics (NIDDs) has been reported to be associated with a lower tendency to develop late complications. The flush was thought to be mediated by enkephalins and prostaglandins. Early studies could not correlate CPAF to increased levels of acetaldehyde in blood and the flush was not regarded as an antabuse-like reaction.
In this study, the increase of plasma acetaldehyde during the flush in 13 CPAF positive diabetics was significantly (P &lt; 0.005) higher than in 13 CPAF negative diabetics during a CPAF challenge test. The increase of plasma acetaldehyde was reduced to the level of CPAF negative diabetics in three CPAF positive diabetics when they were exposed to alcohol without premedication with chlorpropamide and they did not flush. The normal breakdown of ethanol to acetic acid via acetaldehyde appears to be inhibited by chlorpropamide in the flushers. Acetaldehyde measurement is an objective method to study the chlorpropamide alcohol flush and it appears superior to the measurement of skin temperature.
Metabolic Control of Prevention of Nephropathy by 2-Tetradecylglycidate in the Diabetic Mouse (db/db)
Authors: Lee Stanly M , Tutwiler Gene , Bressler Rubin , Kircher Charles H 
Published: September 2013

The genetically diabetic mouse (db/db) exhibits hyperphagia, progressive weight gain, hyperglycemia, and hyperinsulinemia during the first few months of life during which time characteristic pathologic changes occur in several organ systems including the kidney. The extent to which long chain fatty acid oxidation (LCFAO) contributes to excessive gluconeogenesis and hyperglycemia in these animals in unknown. Therefore, the synthetic fatty acid analogue 2-tetradeclyglycidate (TDHA), a potent inhibitor of LCFAO, was given orally to db/db mice to evaluate its capacity to control the blood glucose and prevent their diabetic nephropathy. Five groups of diabetic mice (N = 6) were assigned to receive TDGA in a dose of 5, 10, and 25 mg/kg/day, vehicle (tragacanth), or nothing (control). TDGA had no observable effects on food intake or growth patterns. Drug-treated animals had significant lowering of fasting glucose at 0 and 4 h after dosing during the midportion of the study (2–6 wk). In the latter part of the study (wk 8–11), blood glucose 4 h after dosing was lowered in mice given 10 and 25 free fatty acids. Animals receiving TDGA 25 mg/kg/day exhibited significant inhibition of immunopathologic changes in the kidney. Heart weight was significantly increased in mice receiving TDGA 25 mg/kg/day, and the total amount of myocardial carnitine content was increased in all three drug-treated groups. Increased tissue deposition of lipid was not apparent on histologic examination of liver in drug-treated animals.
Inhibition of long chain fat oxidation in the db/db mouse results in significant lowering of blood glucose, and decreases the renal immunopathologic features of diabetic nephropathy in this animal model.
Genetic and Immunologic Factors in Microvascular Disease in Type I Insulin-Dependent Diabetes
Authors: Bodansky H J , Wolf Eva , Cudworth A G , Dean Betty M , Nineham Lynn J , Bottazzo G F , Matthews Judith A , Kurtz A B , Kohner Eva M 
Published: September 2013

A detailed study of 133 subjects with insulin-dependent (type I) diabetes with severe microvascular disease has failed to substantiate the hypothesis that HLA factors influence the predisposition to this type of complication. A significant association between proliferative retinopathy and raised levels of circulating immune complexes was found. The distribution of insulin-binding levels in serum was similar to that in patients without complications. There was no correlation between insulin binding and the presence of immune complexes and no evidence was found that these complexes contained anti-insulin, anti-nuclear, or organ-specific antibodies.
The distribution of insulin-binding levels in these subjects with diabetes of long duration was similar to that observed in 270 subjects with juvenile-onset short-duration type I diabetes. When the data were combined, significant associations between HLA-B8 and low/absent insulin binding levels and B7 with moderate/high insulin-binding levels were observed. HLA-BW62 was not associated with either high or low insulin-binding capacity.
It is concluded that HLA genetic factors, insulinbinding capacity, and autoimmunity are unrelated to the pathogenesis of microvascular disease. Raised levels of circulating immune complexes may well be secondary to widespread tissue damage in diabetes of long duration.
Metabolic and Underlying Causes of Diabetes Mellitus
Authors: Grodsky Gerold M , Anderson Carol E , Coleman Douglas L , Craighead John E , Gerritsen George C , Hansen Carl T , Herberg Lieselotte , Howard Charles F , Lernmark Ake , Matschinsky Franz M , Rayfield Elliot , Riley William J , Rossini Aldo A 
Published: September 2013

It is emphasized that animai models should be used to study specific genotypic or phenotypic expressions associated with diabetes rather than assuming a single animal model can reflect diverse forms of the human disease. Diabetic and normal animals are reviewed on the basis of their usefulness as models of genetic, viral, and chemically induced diabetes, including the often associated immune phenomena. Characteristics of spontaneously diabetic animals with and without obesity are also described with an emphasis on both genetics and metabolic derangements.
Recommendations for future animal experimentation include: more longitudinal studies evaluating the role of sex, prenatal environment, diet, and viral or chemical attack on B-cell function; characterization of the immune phenomena associated with B-cell lesions (and insulitis) in diabetic and immunologically incompetent lines; clarification of relationships between obesity and islet-ceil function with emphasis on the role of fuel metabolism, vitamins, and minerals; and, finally, the development of new models with specific genetic aberrations placed in normal or diabetic lines.
Evidence for an Intrahepatic Contribution to the Waning Effect of Glucagon on Glucose Production in the Conscious Dog
Authors: Cherrington Alan D , Diamond Michael P , Green Donald R , Williams Phillip E 
Published: September 2013

We previously showed that infusion of glucagon at four times the basal rate into conscious dogs given somatostatin and basal replacement amounts of insulin caused hyperglycemia (217 ± 15 mg/dl) for at least 3 h and an initial increment in hepatic glucose production of 5.5 ± 0.8 mg/kg · min. After 3 h, however, the effect of hyperglucagonemia on glucose production had declined by 85%. The aim of the present study was to determine the importance of hyperglycemia in the “downregulation” of the action of glucagon.
Six overnight-fasted conscious dogs were given somatostatin (0.8 μg/kg · min) plus basal intraportal replacement amounts of insulin (263 μU/kg · min) and glucagon (0.65 ng/kg · min). Hyperglycemia (276 ± 12 md/dl) was established after 2 h by the infusion of exogenous glucose. The glucagon infusion rate was then increased fourfold 1 h later, so that the plasma glucagon level rose from 95 ± 16 to 227 ± 35 pg/ml. The glucose concentration was maintained at a fixed value despite the increase in glucagon by decreasing the glucose infusion rate by an amount equal to the increase in endogenous glucose production induced by the hormone. Glucose production was measured using a primed infusion of 3H-glucose. With the insulin (11 ± 2 μU/ml) and glucose levels fixed, the elevation in glucagon caused an initial increment of 5.1 ± 0.7 mg/kg · min in glucose production which was followed by a fall of only 2.5 · 0.4 mg/kg · min (50%) over the next 3 h. Thus, when the plasma glucagon level is raised fourfold under conditions in which insulin mobilization cannot occur, the effect of hyperglucagonemia on glucose production will be partially offset by the resulting hyperglycemia and partly inhibited by an hepatic factor(s).
Nonenzymatic Glucosylation of Low-Density Lipoprotein Alters Its Biologic Activity
Authors: Witztum Joseph L , Mahoney Eileen M , Branks Michael J , Fisher Milton , Elam Richard , Steinberg Daniel 
Published: September 2013

Human low-density lipoprotein (LDL) was glucosylated by incubation in vitro with glucose (20–80 mM) with or without addition of cyanoborohydride. The incorporation of covalently bound glucose was linear over time, and amino acid analysis showed the presence of glucosyllysine residues. The glucosylated LDL (glc LDL) moved more rapidly than normal LDL on agarose electrophoresis.
The rate of degradation of 125I-labeled glucosylated LDL (glc LDL) by cultured human fibroblasts was reduced compared with that of native 125I-LDL, the difference increasing with extent of glucosylation. Effects were seen with blockage of as few as 6–15﹪ of the LDL lysine residues; high-affinity degradation was completely lost when one-third of the lysine residues were blocked. Conjugation of LDL with glucose-6-phosphate also blocked high-affinity uptake and degradation. Whereas native LDL uptake inhibited the activity of β-hydroxy-β-methylglutaryl coenzyme A reductase and stimulated acyl coenzyme A:cholesterol acyltransferase activity, glc LDL had no effects on these enzymes. The fractional catabolic rate of glc LDL in guinea pigs was reduced. Degradation of glc LDL by mouse peritoneal macrophages was not significantly faster than that of native LDL. Finally, the presence of glc LDL in human plasma was demonstrated. Preliminary data show that 1.3﹪ of lysine residues in normal LDL and 2–5.3﹪ of lysines in diabetic LDL were glucosylated. Since, like other plasma proteins, LDL undergoes glucosylation in diabetes, its turnover and sites of catabolism may differ from normal and this may be relevant to the accelerated atherosclerosis of diabetes.
Immunocytochemical Localization of HLA-DR in Human Islets of Langerhans
Authors: Alejandro Rodolfo , Shienvold Frances Litz , Hajek Shirley Vaerewyck , Ryan Una , Miller Joshua , Mintz Daniel H 
Published: September 2013

Previous reports of allogeneic transplantation studies in rodents have postulated that the primary carriers of la antigen in islets of Langerhans are passenger leukocytes. We sought to demonstrate directly the localization of the analogous human antigen, HLA-DR, in islet-enriched fractions (IEFs), utilizing a nonpolymorphic monoclonal anti-DR (αDR) antibody.
The presence of DR in the IEFs was first demonstrated by radioimmunobinding assay. Light microscopic immunocytochemistry, in frozen sections of intact (unfixed) human pancreas, revealed a staining pattern suggestive of a vascular distribution of DR in islets.
Ultrastructural localization of DR was then carried out by indirect immunoperoxidase labeling in the presence of NaN3 (to prevent internalization of bound αDR). The major site of DR expression in the islet was the endothelial cell surface. Endocrine cells were entirely devoid of αDR binding. Nonislet endothelium was also heavily labeled, but acinar and ductal cells were completely negative. Leukocytes bound αDR but were relatively rare in the IEFs. Human islets, therefore, clearly express HLA-DR, but predominantly on insular endothelial cells. Isolation of pure endocrine cell populations, specifically free of endothelium, would appear to be a rational approach to reducing immunogenicity in allogeneic transplantation.
Survival of Intrasplenically Implanted Islets in Mice with Experimental Insulitis and Hyperglycemia
Authors: Sandler Stellan , Andersson Arne 
Published: September 2013

Injections of repeated, subdiabetogenic doses of streptozotocin to C57BL/KsJ mice induced a slowly developing hyperglycemia and pancreatic insulitis similar to that observed in human type I diabetes. It was found that the hyperglycemia could be normalized in these animals by the intrasplenic implantation of syngeneic islets. This could be achieved both 9 and 14 days after the first streptozotocin injection. At the first time point there was a severe insulitis in the pancreas of the recipient. When animals that had been cured by an intrasplenic islet implant were given three subdiabetogenic booster-doses of streptozotocin, they reverted to hyperglycemia. This suggests that cell-mediated immune reactions are of etiologic significance in this diabetes model, since mice made diabetic by a single large dose of streptozotocin and subsequently cured by islet transplantation remained unaffected by the booster-dose administration of streptozotocin.
To test the hypothesis that the β-cell destruction induced by streptozotocin is the triggering mechanism for the insulitis process, syngeneic islets were implanted into the spleen after being exposed in vitro to a weak streptozotocin concentration. This treatment led to normoglycemia in only two of seven alloxan-di-abetic recipients. Streptozotocin-treated islets implanted into normoglycemic recipients were recovered intact in the spleens, and pancreatic islet morphology was not influenced by this treatment.
The present data do not speak against ongoing attempts to cure human diabetics with islet cell transplantation despite the fact that islet lesions that may reflect immunologic mechanisms are encountered in type I diabetes.
Insulin-induced Loss of Insulin-like Growth Factor-I Receptors on IM-9 Lymphocytes
Authors: Rosenfeld Ron G , Hintz Raymond L , Dollar Laura A 
Published: September 2013

Preexposure of IM-9 lymphocytes to the somatomedin peptide insulin-like growth factor-I (IGF-I) results in a time- and concentration-dependent reduction in specific receptors for IGF-I. Since insulin and proinsulin are structurally homologous to IGF-I, we investigated the ability of insulin analogues to compete for occupancy and to directly modulate IGF-I receptor concentrations.
IGF-I binds rapidly and reversibly to IM-9 cells at 15°C, with half-maximal displacement of 125I-I-IGF-I at IGF-I concentrations of 3.6 × 10−9 M and insulin concentrations of 5 × 10−7 M. Preexposure of cells at 37°C to either IGF-I or insulin produced a concentration-dependent reduction in binding of 125I-IGF-I. A 50% decrease in binding was observed following preincubation of cells with IGF-I at 2.5 × 10−9 M and insulin at 2 × 10−7 M. At higher insulin concentrations (10−6–10−5 M), up to 70% reduction in 125I-IGF-I binding occurred. Bovine proinsulin and guinea pig insulin competed less potently than porcine insulin for the IGF-I receptor, and produced receptor loss in proportion to their ability to occupy the IGF-I receptor. Scatchard analysis indicated that at all insulin concentrations, the decrease in binding was secondary to loss of available IGF-I receptors, with no change in affinity. Receptor loss was evident following 1–2 h preexposure to insulin, with a t½ of 4 h and maximal receptor loss within 10 h. Similarly, IGF-I and IGF-II competed for occupancy of the IM-9 insulin receptor, with 50% displacement of 125I-insulin occurring at peptide concentrations of 3.5 × 10−9 M (insulin), 3.5 × 10−8 M (IGF-II), and 3 × 10−7 M (IGF-I). Preexposure of cells to these peptides at 37°C for 20 h resulted in a concentration-dependent reduction in binding of 125I-insulin, with the order of analogue effectiveness being insulin &gt; IGF-II &gt; IGF-I.
These data emphasize the structural and functional homology of insulin and the somatomedin peptides, IGF-I and II, as well as their respective receptors. Additionally, the data support the conclusion that the insulin and somatomedin peptides not only bind to both receptors, but downregulate each receptor in proportion to their ability to occupy that receptor.