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  • Electronic Resource  (35)
  • 2000-2004
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  • Insulin
  • 1
    ISSN: 1432-1440
    Keywords: Growth hormone-Releasing hormone ; Somatostatin ; Insulin ; Type 1 diabetic patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Following a mixed meal, plasma hormone responses were measured in four type 1 diabetic children and in eight short normal children. Between 60 and 150 min after ingestion of the mixed meal there was a significant increase in circulating growth hormone-releasing hormone values both in diabetic and in normal children. Mean plasma GHRH peak values were not different between diabetic patients (27.0±3.9 ng/l) and controls (24.6±4.9 ng/l). No time relationship to spontaneous growth hormone peaks was observed. Whereas normal children showed a characteristic biphasic plasma somatostatin response, somatostatin plasma levels in diabetic children did not change. In normal children plasma insulin values increased between 30 and 150 min, but remained unchanged in type 1 diabetic patients. Blood glucose response was more pronounced in diabetic children than in short normal children. These results indicate that circulating growth hormone-releasing hormone does not play a dominant role in the regulation of insulin and somatostatin.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 66 (1988), S. 924-927 
    ISSN: 1432-1440
    Keywords: Hypertension ; Insulin ; Glucagon ; Skeletal muscle ; Glycogen ; Glucose ; Glycogen synthetase ; Glycogen phosphorylase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The present study was performed to investigate as to whether peripheral insulin resistance exists in spontaneously hypertensive rats (SHR). After a 12 h fasting period, SHR had significantly higher serum glucose and higher plasma glucagon values in comparison to normotensive control rats (WKY). There was a tendency for higher serum insulin concentrations as well, but this difference did not reach significance. After oral glucose loading or glucose/insulin administration, serum glucose and insulin levels were also higher in SHR compared to WKY rats. Muscle glycogen and glucose concentrations were identical in fasted SHR and WKY rats. With an oral glucose load or glucose/insulin treatment there was a significant increase in muscle glycogen, whereas glucose values declined in skeletal muscle. Both total (a+b-form) phosphorylase activity as well as the active a-form of the enzyme were similar in skeletal muscle of SHR and WKY rats. Glucose/insulin administration or oral glucose loading induced a considerable reduction of both a+b-form and a-form activities. The decrease in muscle phosphorylase activities was almost identical in both groups of animals. There was also a comparable activity of muscle glycogen synthetase activity in all groups of rats. Despite subtile changes of glucose, glucagon and to a lesser degree insulin levels which would be suggestive of insulin resistance, the data obtained from skeletal muscle argue against peripheral insulin resistance in spontaneously hypertensive rats.
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  • 3
    ISSN: 1432-2307
    Keywords: AVP/SV40 transgenic mice ; Immunocytochemistry ; Insulin ; Pancreatic polypeptide ; Large T-antigen ; Heterochromatin ; Dysplasia ; Neoplasia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insertion into the mouse genome of the hybrid oncogene made up of bovine vasopressin gene derived 5′ upstream sequences and the coding sequences of SV40 large T-antigen promoted tumours in anterior pituitary and endocrine pancreas of mice bearing this transgene. In order to investigate the morphology of the steps in the neoplastic process, we used light and electron microscopy to study these organs in 42 animals belonging to the 3rd, 4th and 5th generations, subdivided into 4 age groups from 20 days to 100 days of life. Antibodies to large T-antigen were used to identify sites of expression of the hybrid oncogene, thus monitoring the steps in neoplastic transformation. Large T-antigen immunoreactivity was identified in dysplastic lesions of younger animals and in both dysplastic lesions and tumours of older mice. Insulin (100% of cases) and pancreatic polypeptide (25% of cases) immunoreactivities were revealed in pancreatic lesions but no hormonal immunoreactivity was detected in the pituitary lesions. The ultrastructural study confirmed that the majority cell population of the pancreatic neoplasms was B-type and that the anterior pituitary tumours were poorly granulated. The subcellular localization of large T-antigen immunoreactivity was investigated by the immunogold method and was confined to the heterochromatin of tumour cell nuclei. These findings provide evidence for the dysplasia-neoplasia sequence in the genesis of endocrine tumours of pituitary and pancreas of transgenic mice. The vasopressin-SV40 large T-antigen transgenic mice may therefore be an useful model for the study of endocrine cell oncogenesis,
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Research in experimental medicine 188 (1988), S. 27-33 
    ISSN: 1433-8580
    Keywords: Carbon tetrachloride ; Insulin ; Glucagon ; Cytochrome P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rats given a dose of carbon tetrachloride (CCl4) immediately received injections of glucagon and insulin every 4h. They frequently died after 4h and showed a significantly higher mortality between 8h and 28h as compared to the control rats where such deaths occurred 16h later. At 8h, the derangements of SGPT values and prothrombin time were significantly greater in the hormone-treated rats than in the control rats. In these CCl4-intoxicated rats, hepatic reduced glutathione content at 4h was significantly reduced after hormone treatment. The treatment significantly enhanced CCl4 metabolism, conversion of14CCl4 into14CO2 in vitro, by microsomes isolated from the liver, whereas it did not affect the microsomal cytochrome P450 content. These results suggest that glucagon and insulin treatment increased CCl4 hepatotoxicity in rats through activating the cytochrome P450-dependent mono-oxygenase system. This would merit consideration for the clinical application of this treatment.
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  • 5
    ISSN: 1432-0568
    Keywords: Pancreatic islet ; Insulin ; Glucagon ; Ontogeny ; Immunohistochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ontogenetic appearances of glucagon, insulin and tyrosine hydroxylase (TH) were immunohistochemically investigated on developing pancreatic islets of rats. Glucagon immunoreactivity appeared first in some epithelial cells (g-cells) of the dorsal anlage of the pancreas on day 11.5 of gestation. On day 12.5, g-cells increased in number manufacturing the primitive islets, in which some cells appeared to be immunoreactive for insulin (i-cells) and about 40% of g-cells indicated also a slight immunoreactivity for insulin (g/i-cells). Afterwards, all the islet cells, especially g-cells, increased in number, and almost half of g-cells were g/i-cells. After day 16.5 of gestation, numerical increase of the cells with insulin immunoreactivity exceeded that of the cells with glucagon immunoreactivity, and about one fifth of g-cells were g/i-cells. After 20.5 days, however, no g/i cells were found. On day 16.5 of gestation, the immunoreactivity for TH appeared in occasional cells of the islets, but the cells did not show immunoreactivity for glucagon or insulin. It is concluded that the progenitor cells of the pancreatic islets appear to synthesize both glucagon and insulin by day 20.5 of gestation, but differentiate giving rise to mature A and B cells of adult isoets afterward.
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  • 6
    ISSN: 1432-0428
    Keywords: Insulin ; glucose ; age ; children ; puberty
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pattern of insulin secretion was studied in 107 normal individuals aged 5 to 50 years. Intravenous glucose tolerance tests were performed on 64 islet-cell antibody negative siblings of diabetic children and on 43 normal adults. Puberty was staged using Tanner's criteria and subjects were grouped as follows: I — stage 1 (n=22), II — stages 2 and 3 (n=18), III — stages 4 and 5 (n=20), IV — adults 〉17 years (n=47). Basal and stimulated (incremental 0–10 and 10–60 min areas) insulin responses rose throughout puberty (Groups I–III), declined following puberty until the third decade (Groups III and IV) and then appeared constant thereafter. Insulin levels in the 17.6–22.5 year group were lower than in the 12.6–15 year group (p〈0.01). Fasting insulin to glucose ratios and incremental 0–60 min insulin to glucose area ratios produced a similar age-related pattern indicating that changes in insulin levels were independent of glucose concentrations. Gender did not affect these changes and multiple regression analysis showed that HLA haplotype sharing did not influence insulin responses in siblings of diabetic patients. Age and pubertal status must be carefully considered when interpreting intravenous glucose tolerance tests from patients suspected of having early abnormalities of carbohydrate metabolism.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 31 (1988), S. 51-53 
    ISSN: 1432-0428
    Keywords: Insulin ; erythrocyte ; diabetes ; glucose metabolism ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Alloxan-induced diabetes in rats significantly impaired the capacity of the erythrocytes to metabolise glucose in vitro to either lactic acid or CO2. Both these metabolic activities were initially insensitive to insulin in normal as well as in diabetic animals; but became responsive when these cells were subjected to insulin and glucose ‘starvation’ for 1 h through incubation in their absence. This action of insulin in starved cells showed concentration dependence and required preincubation with the hormone prior to addition of glucose.
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  • 8
    ISSN: 1432-0428
    Keywords: Insulin ; glucagon ; thyroid hormones ; glucose turnover ; glucose production ; glucose utilisation ; glucoregulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The glucoregulatory function of glucagon was investigated in hypo-, eu- and hyperthyroid miniature pigs. Infusion glucagon, (3 ng x kg body weight−1 · min−1) transiently increased blood glucose (p〈0.01) and hepatic glucose production (p〈0.01) in euthyroidism, but was without effect in hyperthyroidism. Infusing glucagon plus somatostatin (2 ng x kg body weight−1 · min−1 and 0.2 μg x kg body weight−1 · min−1) transiently increased blood glucose (Δ 3.0 to 4.3 mmol/l) and hepatic glucose production (Δ 3.3 to 7.7 umol x kg body weight−1 · min−1) in all thyroid states, the effect was less pronounced in hyperthyroid pigs. By contrast, hypoglucagonaemia (74 to 107 pg/ml) at basal insulin (28 to 35 μU/ml) provoked hypoglycaemia (1.4 to 2.2 mmol/l) and a fall in glucose production (Δ 4.7 to 8.3 umol x kg body weight−1 · min−1), which was independent of the thyroid state; the effect was most pronounced in hyperthyroidism (p〈0.01). Hepatic glycogen content, arterial gluconeogenic precursor concentrations as well as the glycaemic response (Δ 0.60 mmol/l) to alanine infusion (23 umol x kg body weight−1 · min−1) were all unaffected by hyperthyroidism. We conclude that moderate experimental hyperthyroidism reduces glucagon action due to reduced glycogen mobilisation. This may in part result from increased insulin sensitivity.
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 44 (1988), S. 1-9 
    ISSN: 1420-9071
    Keywords: Insulin ; glucagon ; pancreatic polypeptide ; somatostatin ; fetal pancreas ; ontogeny ; immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The ontogeny of insulin, glucagon, PP and somatostatin in the mammalian fetal pancreas has been examined in recent years largely by immunocytochemistry and in some instances by radioimmunoassay. Complete ontogenic data are available only for the rat, human pig and sheep. Figure 3 compares the time of appearance of the endocrine cell-types within the fetal pancreas when the periods of gestation of the four species are converted to a uniform scale. The striking ontogenic difference in the rat probably reflects the immaturity of the rodent fetus at birth compared with the human, pig and sheep. In the fetal pancreas, differences in cell number of glucagon and PP cells in the dorsal and ventral lobes become apparent from an early gestational period. Factors responsible for the functional and structural maturation of the fetal pancreatic endocrine cells and the processes involved in pancreatic organogenesis are poorly understood. Studies in these areas would have clinical implications since it may be possible in the future to employ agents for selective replication of fetal β-cells for transplantation in patients with Type I diabetes, bearing in mind that such cells must have the capacity to respond to normal stimuli and repressors when transplanted. The presence of the other islet cell-types may be obligatory for these appropriate responses. This would require a more complete knowledge of those factors which produce the normal selectivity of the four hormonal cell-types.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Pflügers Archiv 412 (1988), S. 258-263 
    ISSN: 1432-2013
    Keywords: Acetylcholine ; Quanta ; Na+−K+ exchange pump ; Ouabain ; Adrenaline ; Insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Pretreatment with hypertonic solutions, insulin, or adrenaline increases the size of quanta at the frog neuromuscular junction, as determined by measurements of miniature end plate potentials or currents (Van der Kloot and Van der Kloot 1985, 1986). The increase in quantal size apparently is due to an increase in acetylcholine (ACh) content of individual quanta. These treatments, therefore, can be used to study the packaging of ACh. Previously, I reported that increases are blocked by an inhibitor of active ACh uptake into vesicles (Van der Kloot 1986b, 1987b). The present study shows that the increases in quantal size were antagonized by inhibiting the Na+−K+ exchange pump with 100 μM ouabain, 10 μM dihydroouabain, or K+-free solutions. The increases in quantal size were also antagonized by 10 μM monensin, a Na+ ionophore, or by 5 μM aconitine, which opens Na+ channels at normal resting potentials. Apparently a rise in intracellular [Na+] inhibits the addition of ACh to quanta. The mechanism by which a rise in intracellular Na+ inhibits ACh packing is unknown, but apparently it is not due to inhibition of choline reuptake into the terminals. Also consistent with the above hypothesis is that the increase in quantal size following depolarization for 2 h in elevated [K+]out was substantially enhanced when tetrodotoxin (TTX) was present, suggesting that in the absence of TTX there is a rise in [Na+]in that antagonizes the incorporation of additional ACh into the quanta.
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  • 11
    ISSN: 1432-2013
    Keywords: Nephron microdissection ; Glomeruli ; Tubules ; [125I] Insulin binding ; Insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Binding of [125I] Tyr A14 human insulin ([125I] insulin) was measured at 4°C in glomeruli and pieces of tubule microdissected from collagenase-treated rat kidneys. For glomeruli and all segments tested, total and non specific binding increased linearly with glomeruli number or tubular length. When determined with 4.0 nM labelled hormone, the distribution of specific binding sites (expressed as 10−18 mol [125I] insulin bound per glomerulus or mm tubule length) was as follows: glomerulus, 2.5±0.3; proximal convoluted tubule (PCT), 12.6±0.6; pars recta (PR), 4.0±2.3; thin descending limb (TDL), 0.6±0.2; thin ascending limb (TAL), 0.6±0.2; medullary thick ascending limb (MAL), 0.8±0.1; cortical ascending limb (CAL), 2.1±0.1; distal convoluted tubule (DCT), 5.6±1.1; cortical collecting tubule (CCT), 3.2±0.3 and outer medullary collecting tubule (MCT), 2.3±0.1. Specific [125I] insulin binding to glomeruli and tubule segments was time- and dose-dependent, saturable, reversible after elimination of free labelled ligand, and inhibited by unlabelled human insulin. When analysed in Scatchard and Hill coordinates, the binding data revealed a negative cooperation in the interaction processes between [125I] insulin and glomerular and tubular binding sites, with apparent dissociation constants and Hill coefficients of the following values: glomerulus, 0.6 nM and 0.60; PCT, 10.0 nM and 0.55; MAL, 4.3 nM and 0.80; CAL, 2.0 nM and 0.74; CCT, 7.6 nM and 0.80 and MCT, 1.0 nM and 0.57 respectively. The stereospecificity of nephron binding sites was assessed in competitive experiments showing that unlabelled bovine and procine insulins were as efficient as human insulin for displacing [125I] insulin, whereas A and B chains of insulin and unrelated peptide hormones were almost inactive. These results indicate that the detected [125I] insulin binding sites may correspond to physiological insulin receptors.
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  • 12
    ISSN: 1432-2307
    Keywords: Insulin ; Insulinomas ; Ultrastructure ; Immunogold technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Localisation of insulin-like immunoreactivity has been studied using the immunogold staining procedure on thin sections of 6 human insulinomas, conventionally processed for electron microscopy. The labelling was restricted to the secretory granules. Depending on their morphology, these either resembled B-cell granules of human adult pancreas or belonged to the atypical (non-diagnostic) group. Within the former group, those with a crystalloid core or an amorphous dense or moderately dense core were strongly immunoreactive, whereas others, filled with a pale material, were poorly labelled. Most granules of this type were stored together within the heavily granulated cells of 3 insulinomas, presenting the classical features of clinical and biological behaviour and a typical light microscopic staining pattern. In contrast, the non-diagnostic granules, characterized by their smaller size, a very dense core and a thin halo, were mainly found within the poorly granulated cells making up the other tumours, and showed a very uneven labelling. Strongly labelled granules were found in one insulinoma that also belonged to the classical type; these were stored together with a few diagnostic granules within the same cells. Only poorly labelled atypical granules were present in two cases revealing a number of unusual features; these included moderate elevation of insulinaemia, uncertain tumour histology, as well as weak immunostaining for insulin/proinsulin and variable argyrophilia of the tumour in paraffin sections. These findings suggest that human insulinomas differ not only in storage capacity but also in their degree of granule maturation. This may involve some deficiency of either the prohormone conversion or the subsequent processing of the cleavage products.
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  • 13
    Electronic Resource
    Electronic Resource
    Springer
    Cell & tissue research 252 (1988), S. 9-15 
    ISSN: 1432-0878
    Keywords: Pancreas, endocrine ; Insulin ; Immunocytochemistry ; Lysosomes ; Crinophagy ; Mouse (NMRI)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Ultrastructural studies of pancreatic islets have suggested that crinophagy provides a possible mechanism for intracellular degradation of insulin in the insulin-producing B-cells. In the present study, a quantitative estimation of crinophagy in mouse pancreatic islets was attempted by morphometric analysis of lysosomes containing immunoreactive insulin. Isolated islets were incubated in tissue culture for one week in 3.3, 5.5 or 28 mmol/l glucose. The lysosomes of the pancreatic B-cells were identified by morphological and enzyme-cytochemical criteria and divided into three subpopulations comprising primary lysosomes and insulin-positive or insulin-negative secondary lysosomes. Both the volume and numerical density of the primary lysosomes increased with increasing glucose concentration. The proportion of insulin-containing secondary lysosomes was highest at 5.5 and lowest at 3.3 mmol/l glucose. Insulin-negative secondary lysosomes predominated at 3.3 mmol/l glucose. Studies of the dose-response relationships of glucose-stimulated insulin biosynthesis and insulin secretion of the pancreatic islets showed that biosynthesis had an apparent Km-value for glucose of 7.0 mmol/l, whereas it was 14.5 mmol/l for secretion. The pronounced crinophagic activity at 5.5 mmol/l glucose may thus be explained by the difference in glucose sensitivity between insulin biosynthesis and secretion resulting in an intracellular accumulation of insulin-containing secretory granules. The predominance of insulin-negative secondary lysosomes at 3.3 mmol/l glucose may reflect an increased autophagy, whereas the predominance of primary lysosomes at 28 mmol/l glucose may reflect a generally low activity of intracellular degradative processes.
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  • 14
    ISSN: 1432-0878
    Keywords: Pancreas, endocrine ; Stomach ; Intestine ; Immunohistochemistry ; Thyrotropin-releasing hormone (TRH) ; Somatostatin ; Avian pancreatic polypeptide ; Insulin ; Gastrin ; Rat ; Guinea pig
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary By use of the indirect immunofluorescence technique, the cellular localization of thyrotropin-releasing hormone (TRH) was studied in the gastrointestinal tract of rats and guinea pigs of different ages. TRH-like immunoreactivity (LI) was observed in many pancreatic islet cells of young rats and guinea pigs but only in single cells of 6-month-old rats. In aged guinea pigs, a reduction in the number of TRH-positive cells was evident; however, numerous strongly fluorescent cells were still present. In the guinea pig, TRH-LI was in addition observed in gastrin cells in the stomach. TRH-positive nerve fibers occurred in the myenteric plexus of the oesophagus, stomach and intestine of the rat, and in the muscle layers of the guinea pig. These results suggest a functional role of TRH both as hormone and neuroactive compound in various portions and sites of the gastro-intestinal tract of the rat and guinea pig
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  • 15
    ISSN: 1439-6327
    Keywords: Energy metabolism ; Carbohydrate-rich diet ; Lipoprotein lipase ; Free fatty acids ; Insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A comparison of the influence of simple and complex carbohydrate (CHO) consumption on adipose tissue- and skeletal muscle-lipoprotein lipase activity (AT-LPLA, SM-LPLA) was examined. Twenty male marathon runners were divided into two equal dietary groups: simple-CHO and complex-CHO. Half of the subjects in each group consumed either a low-CHO (15% energy [E] intake), or a mixed diet (50% CHO) for 3 days. Immediately following this dietary period, the subjects consumed a CHO-rich diet (70% E intake) predominant in simple-CHO or in complex-CHO for an additional 3 days. Thereafter, all subjects returned to a normal mixed diet. Skeletal muscle biopsies, adipose tissue aspirations, and venous blood samples were obtained prior to dietary manipulation (PRE), upon completion of the 6 day diet (POST I), and 2 weeks after returning to a normal diet (POST II). The samples were analysed for AT-LPLA, SM-LPLA, serum insulin, and free fatty acids (FFA), and blood glucose, and lactate. SM-LPLA fell 71% from PRE values of 0.39±0.30 μ mol · g−1 · h−1 to POST I values of 0.11 ±0.09 μ mol · g−1 · h−1 (means±SD) (p〈0.05), after a complex-CHO diet. However, the simple-CHO diet did not alter SM-LPLA. AT-LPLA similarly decreased (p〈0.05) after the complex-CHO diet, and no significant decrease was noted after the simple-CHO diet. Serum FFA decreased significantly (p〈0.05) after a simple-CHO diet (0.82±0.13 to 0.65±0.10 mmol l−1) but were unchanged after a complex-CHO diet. Blood glucose and lactate, and serum insulin were not altered following a CHO-rich diet.
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  • 16
    ISSN: 1439-6327
    Keywords: Glucose and fat feeding ; Glycogen sparing ; Ketone bodies ; Insulin ; Lipolysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of this study was to test the hypothesis that oral ingestion of lipids could increase endurance by slowing the rate of glycogen depletion. Trained rats were killed after a 2 h run on a rodent treadmill, following an intragastric infusion of water, glucose, medium chain triglycerides (MCT) or long chain triglycerides (LCT). Glucose and triglycerides were administered in equicaloric concentrations (50 kJ). The results show that oral ingestion of lipids (MCT or LCT) did not reduce glycogen depletion in liver, heart or skeletal muscle after exercise whereas the fat diet increased muscle and heart glycogen stores in resting conditions. In contrast, glucose feeding induced a significant sparing effect on endogenous carbohydrate utilization and reduced physical exercise lipolysis. These data indicated, firstly, that enhanced lipid availability induced by a single lipid meal before exercise was not able to modify the glycogen depletion occuring after exercise and, secondly, that the glucose/fatty acid cycle was not effective in these conditions. The comparison between lipids indicated that the effect on glycogen use of MCT did not differ from that of LCT, and did not seem to be of any particular importance during physical exercise.
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  • 17
    ISSN: 1573-739X
    Keywords: Absorption, transdermal ; Brilliant Blue ; Dodecyl-l-pyroglutamate ; Insulin ; Laurocapram ; N-Methyl-2-pyrrolidone ; Permeability, enhancement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The study reports on penetration enhancers used to improve drug absorption through the skin. All experiments were carried out in permeation cellsin vitro. Insulin (2.5 mg/ml) and Brilliant Blue (50.0 mg/ml) served as model drugs. They were formulated into a 40% solution of propylene glycol with increasing concentrations ofN-methyl-2-pyrrolidone (NMP) (0.0 to 20.0%), dodecylazacycloheptan-2-one (laurocapram) and a new compound dodecyl-l-pyroglutamate (DLP; 0.0 to 0.5%). The maximum amount of insulin permeated within 24 h was almost 200 μU/ml in the case of 0.1% laurocapram, while in the case of 0.1% DLP it was approximately half of that. The optimum concentration of NMP was 12.0%. Experiments performed with Brilliant Blue showed no significant difference among formulations containing either 6.0, 12.0 or 20.0% of NMP. When NMP was omitted, flux, permeability as well as the maximum concentration estimated after 26 h reached 50% of the values obtained with NMP. The lag time was twice as long in this case in comparison with the formulations containing NMP.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Pharmacy world & science 10 (1988), S. 213-216 
    ISSN: 1573-739X
    Keywords: Adsorption ; Equipment and supplies ; Infusions, parenteral ; Insulin ; Polyethylenes ; Polyvinylchloride
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A comparison between human and porcine insulins with regard to their adsorption to administration sets was performed. A125I-mono(A14)-iodinated insulin was used to follow the adsorption phenomenon over time and the adsorption was quantified with radioimmunoassays of unlabelled insulin. The obtained data were similar for both methods. No relevant difference in adsorption was found between human and porcine insulin. Both insulins showed a significantly more pronounced initial drop in delivered insulin when polyethylene tubing was used. After 3 h a steady state was reached, resulting in the administration of a more predictable dose. Particularly in the initial phase an important reduction in the amount of both insulins actually delivered to the patient was observed when compared to the expected amount as calculated from the concentration present in the container and the infusion rate. Therefore, the mainstay in treatment of a patient with ketoacidosis remains frequent serum glucose measurement and making appropriate infusion rate adjustments on that basis.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    Neurochemical research 13 (1988), S. 1119-1124 
    ISSN: 1573-6903
    Keywords: Insulin ; astroglia ; cultures ; GABA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Astroglial cultures from newborn mouse cerebral cortex contain [125I]insulin binding sites. Binding was specific reversible, time dependent and reached equilibrium after 45 min. Insulin analogues compete for this [125I]Insulin binding. Incubation of cerebral cortex astroglial cultures with insulin induced a time-and dose-dependent inhibition of the [3H]GABA high affinity uptake. A decrease in theV max rather than, an effect on theK m was observed. This effect was dose-dependent and effective at 10−10 M. Autoradiographic observations on the cell monolayer showed the presence of two groups of cells: one which strongly takes up [3H]GABA and consist in smaller GFAP positive process-bearing cells and another group of much flatter and larger GFAP positive cells which uptake was lower. The smaller stellate cells were apparently the most sensitive to insulin effect. These results: 1) confirm the presence of insulin binding sites on astroglial primary cultures, 2) show an effect of insulin of [3H]GABA high affinity uptake of these cells; this effect being optimal on a stellate-like population of astrocytes, and 3) indicate, that insulin may interfere in neuromodulation through astroglial signals.
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  • 20
    ISSN: 1573-6903
    Keywords: Insulin ; receptors ; brain ; cultures
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The presence and specificity of insulin receptors was investigated in cultured cells obtained from 15–16 days old embryonic mouse cerebra. Developmental studies suggested that the maximum insulin binding occurred at about 11 days in vitro (DIV). Scatchard analysis of binding data revealed two types of binding sites. One type of receptor was the high affinity type (K d=7.77×10−9 M; number of receptor sites,B max=350 fmol/mg protein) while the other type was of low affinity type (K d=5.75×10−8 M;B max=1150 fmol/mg protein). The specificity of receptors for insulin was also confirmed by showing that [125I]insulin was displaced by non-radioactive insulin but not by glucagon or growth hormone. Insulin displayed a clear dose-dependent stimulation of thymidine incorporation. It also stimulated the activity of the enzyme 2′,3′-cyclic nucleotide phosphohydrolase (CNPase), which is specifically associated with myelin produced from oligodendroglia. Thus insulin has a positive influence on the proliferation and differentiation of brain cells.
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  • 21
    Electronic Resource
    Electronic Resource
    Springer
    Neurochemical research 13 (1988), S. 887-892 
    ISSN: 1573-6903
    Keywords: Insulin ; streptozotocin ; diabetes ; noradrenaline ; dopamine ; p-tyrosine ; hypothalamus ; olfactory tubercles
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A single intracardial injection of streptozotocin produced a significant increase in rat hypothalamic noradrenaline while no changes were observed in the olfactory tubercles. The parenteral administration of a single dose of insulin decreased rat hypothalamic noradrenaline; the effect had a rapid onset and lasted for at least six hours. Similar noradrenaline reductions were observed in the olfactory tubercles but in this tissue the depletion started later and recovered earlier. In addition, in olfactory tubercles after insulin injection, tyrosine level and dopamine metabolism were increased. The results show that the increases in hypothalamic NA observed in streptozotocin diabetic rats are counteracted by insulin administration and possibly the consequence of changes in noradrenaline turnover.
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  • 22
    ISSN: 1432-0428
    Keywords: Insulin ; 3′,5′-AMP phosphodiesterase ; glycogen metabolism ; lipolysis ; insulin secretion ; antilipolytic action of insulin ; glycogen synthesis and insulin ; cyclic adenosine 3′,5′-monophosphate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé L'influence de l'insuline sur le métabolisme du glycogène hépatique et sur la lipolyse semble s'exercer par l'intermédiaire d'une diminution de la concentration de 3,′5′-AMP intracellulaire. Onamontré une diminution de la formation de 3′5′-AMP dans le tissu adipeux incubé avec de l'insuline. L'influence de l'insuline sur la dégradation du 3,′5′-AMP est étudiée. — L'activité de la 3,′5′-AMP-phos-phodiestérase (PDE) est diminuée dans le foie, le tissu adipeux et, de façon non-significative, dans le muscle strié des rats qui manquent d'insuline, c-à-d les rats rendus diabétiques par l'alloxane ou les rats privés de nourriture. L'injection intraveineuse d'une faible dose d'insuline (0.5 U/kg) ou la stimulation de la sécrétion d'insuline endogène par une injection de glucose provoquent une augmentation rapide de l'activité de la phosphodiestérase dans ces tissus. 15 min après l'injection d'insuline, l'activité de la phosphodiesterase du foie est augmentée. L'effet maximum est atteint après 30–45 min. L'activité de la phosphodiestérase rénale n'est pas diminuée dans le diabète alloxanique, l'injection d'insuline s'est avérée inefficace.In vitro, l'insuline cristalline a un effet activant sur la phosphodiestérase purifiée du coeur de boeuf. La concentration d'insuline requise pour doubler l'activité de l'enzyme est de l'ordre de 2 · 10−5 M. Le traitement avec actinomycin D empêche la stimulation par l'insuline de la PDE dans le foie. Ceci peut indiquer que l'action de l'insuline sur l'activité de la phosphodiestérase est essentiellement basée sur une synthèse accrue de l'enzyme. A cause de l'influence de la sécrétion d'insuline sur la concentration en 3,′5′-AMP du foie et du tissu adipeux, le métabolisme du glycogène et la lipolyse peuvent s'adapter rapidement à la prise de nourriture.
    Abstract: Zusammenfassung An der Steigerung der Glykogensynthese der Leber und der Verminderung der Lipolyse durch Insulin ist eine Abnahme der 3′,5′-AMP-Konzentration wesentlich beteiligt. Die 3′,5′-AMP-Bildung ist in Fettgewebe, das mit Insulin inkubiert wird, vermindert. Insulin beeinflußt jedoch auch den 3′,5′-AMP-Abbau. -Die 3′,5′-AMP-Phosphodiesterase (PDE)-Aktivität des Fettgewebes, der Leber und, in geringerem Grade, der Skeletmuskulatur ist im Insulinmangel vermindert, d.h. bei alloxandiabetischen oder hungernden Ratten. I.v. Injektion von 0,5 E/kg Insulin oder eine erhöhte Abgabe von Insulin aus dem Pankreas nach Glucoseinjektion führen in diesen Geweben zu einem raschen Anstieg der PDE-Aktivität. Dieser ist in der Leber schon 15 min nach Insulingabe nachweisbar und erreicht nach 30–45 min sein Maximum. In der Niere ist kein Einfluß von Insulin auf die PDE-Aktivität nachweisbar. — Aus Rinderherz isolierte PDE wirdin vitro durch Insulin aktiviert, jedoch werden2 · 10−5 M zur Verdopplung der Aktivität benötigt. Actinomycin D verhindert die Steigerung der Leber-PDE-Aktivität nach Insulininjektion. So kann die Wirkung des Hormons im wesentlichen auf eine gesteigerte PDE-Synthese zurückgeführt werden. — Durch diesen Einfluß der Insulininkretion auf die 3′,5′-AMP-Konzentration in Leber und Fettgewebe können Glykogenstoffwechsel und Lipolyse rasch an die Nahrungsaufnahme angepaßt werden.
    Notes: Summary Influence of insulin on liver glycogen metabolism and on lipolysis appears to be mediated by a decreased intracellular 3′,5′-AMP concentration. Reduced formation of 3′,5′-AMP had been shown in adipose tissue incubated with insulin. The influence of insulin on 3′,5′-AMP degradation has been investigated. — 3′,5′-AMP phosphodiesterase (PDE) activity was reduced in liver, adipose tissue and, insignificantly, in skeletal muscle of insulin deficient, i.e. alloxan diabetic or starved rats. I.V. injection of a low dose of insulin (0.5 U/kg) or stimulation of endogenous insulin secretion by injection of glucose led to a rapid increase of PDE activity in these tissues. 15 min after insulin injection liver PDE activity was increased. The maximal effect occurred after 30–45 min. Renal PDE activity was not decreased in alloxan diabetes, insulin injection has been found ineffective. —In vitro, there was an activating effect of crystalline insulin on PDE purified from beef heart. Insulin concentration required for duplication of enzyme activity was of the order of 2 · 10−5 M. Treatment with actinomycin D nearly prevented stimulation of liver PDE by insulin. This may indicate that the action of insulin on PDE activity is essentially based on an increased enzyme synthesis. — Owing to the influence of insulin secretion on liver and adipose tissue 3′,5′-AMP concentration, glycogen metabolism and lipolysis can be quickly adapted to food intake.
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  • 23
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    Diabetologia 4 (1968), S. 1-9 
    ISSN: 1432-0428
    Keywords: Human growth hormone ; Growth hormone ; Insulin ; Diabetes mellitus ; Experimental diabetes ; Acromegaly ; Pathogenesis of diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Il a été démontré récemment que l'hormone de croissance humaine (HGH) joue un rôle prééminent dans la régulation normale de la glycémie. De plus, il est bien connu que l'hormone de croissance peut créer un état semblable au diabète chez l'animal. Chez l'homme, l'injection de HGH ou l'hypersécrétion de l'hormone endogène dans l'acromégalie est suivie d'intolérance au glucose seulement dans 25% des cas. — Dans ce travail nous présentons des données qui mettent l'action dite diabétogène de HGH dans un contexte plus nuancé. Nous suggérons que HGH, bien que diminuant l'utilisation du glucose par les tissus périphériques, n'est pas une substance primairement diabétogène, car l'effet insulinotrope de l'hormone cause une hyperinsulinémie compensatrice, qui à son tour normalise la tolérance au glucose. HGH est diabétogène exclusivement chez les sujets prédiabétiques dont le pancréas est incapable de répondre à l'effet insulinotrope de l'hormone. Chez ces sujets, la diabétogénicité de HGH n'étant pas surmontée par une hyperinsulinémie compensatrice, la tolérance au glucose sera anormale. Ainsi, HGH peut être considérée comme unfacteur additif pour la pathogénèse du diabète sucré, la condition essentielle et primaire étant un état préexistant de prédiabète.
    Abstract: Zusammenfassung Wie kürzlich gezeigt wurde, spielt das menschliche Wachstumshormon (HGH) eine wichtige Rolle bei der Kontrolle der Blutzucker-Homöostase. Ferner ist schon lange bekannt, daß die Verabreichung von Wachstumshormon an Tiere zu einem diabetesähnlichen Zustand führen kann. Beim Menschen löst die Gabe der Substanz oder die Überproduktion des endogenen Hormons bei der Akromegalie nur in etwa 25 % der Fälle eine Glucosetoleranzstörung aus. — In dieser Arbeit werden Resultate beschrieben, die ein detaillierteres Bild der sogenannten diabetogenen Wirkung des HGH vermitteln. Wir möchten annehmen, daß das HGH, obwohl es den peripheren Glucoseverbraueh herabsetzt, kein primär diabetogener Faktor ist, da es über eine Insulin-mehrausschüttung zu einem Hyperinsulinismus führt, der eine normale Glucosetoleranz bewirkt. HGH zeigt Scine diabetogene Wirkung nur bei Prädiabetikern, deren Pankreas den stimulierenden Effekt des Hormons auf die Insulinausschüttung nicht beantworten kann. Bei diesen Personen kann eine Störung der Glucosetoleranz dadurch entstehen, daß die diabetogene Wirkung des HGH nicht durch einen kompensatorischen Hyperinsulinismus ausgeglichen wird. HGH kann daher als ein Zusatzfaktor bei der Diabetesentstehung angesehen werden, deren Hauptvorbedingung jedoch eine schon vorher bestehende prädiabetische Stoffwechselsituation darstellt.
    Notes: Summary Human growth hormone (HGH) has recently been shown to play a prominent role in the control of blood glucose homeostasis. Furthermore, it has long been known that administration of growth hormone in animals can induce a diabetes-like state. In human subjects, exogenous administration of HGH or hypersecretion of the endogenous hormone in acromegaly is accompanied by glucose intolerance in only about 25 per cent of the cases. — In this paper, data are presented which give a more diversified picture of the so-called diabetogenic action of HGH. It is suggested that HGH, although decreasing the peripheral utilization of glucose, is not a primary diabetogenic factor, since its insulinogenic action causes a compensatory hyperinsulinism, with normal glucose tolerance as the result. HGH is diabetogenic only in prediabetic subjects whose pancreas is unable to respond to the insulinogenic effect of the hormone. In such subjects, the diabetogenic action of HGH not being counterbalanced by a compensatory hyperinsulinism, glucose intolerance may result. Thus, HGH may be regarded as anadditional factor for the development of diabetes, the major prerequisite being a preëxisting prediabetic state.
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  • 24
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    Diabetologia 4 (1968), S. 111-117 
    ISSN: 1432-0428
    Keywords: Insulin ; diabetes ; insulinase ; rat diaphragm ; glycogen synthesis ; RNA turnover ; cell culture ; anti-insulin serum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Peu de progrès conduisant à la compréhension du diabète en termes moléculaires ont été réalisés. La possibilité qu'il existe une modification dans la structure de l'insuline des diabétiques, aussi bien circulante que pancréatique, s'appuie sur trois arguments expérimentaux obtenus au laboratoire des auteurs. — La purification immunochimique de l'insuline circulante de diabétiques jeunes non traités par l'insuline a d'abord conduit à la constatation que cette insuline est relativement résistante à l'action réductrice et protéolytique d'une préparation d'insulinase musculaire. De plus, l'insuline pancréatique, isolée à partir de cinq pancréas diabétiques, s'est avérée d'activité biologique diminuée quant à son pouvoir d'augmenter la synthèse du glycogènein vivo et à sa capacité d'accélérer le “turnover” du R.N.A. en culture tissulaire. — La nature de cette „insuline anormale” et son rôle possible dans la physiopathologie du diabète sont examinés à la lumière de la nécessité de donner une définition spécifique de la modification moléculaire précise.
    Abstract: Zusammenfassung Unsere Kenntnisse über den Diabetes in molekularbiologischer Sicht haben kaum Fortschritte gemacht. Die Möglichkeit, daß das zirkulierende und das Pankreas-Insulin des Diabetikers strukturelle Unterschiede aufweisen, wird durch die Ergebnisse von drei verschiedenen Untersuchungsreihen gestützt, die im Laboratorium der Verfasser durchgeführt wurden. — Immunologisch gereinigtes zirkulierendes Insulin von Diabetikern, die noch kein Insulin erhalten hatten, erwies sich als recht widerstandsfähig gegenüber dem Abbau durch ein Insulinase-Rohextrakt aus Muskelgewebe. Aus den Bauchspeicheldrüsen von 5 Diabetikern gewonnenes Insulin zeigte sowohl in seiner Fähigkeit, die Glycogen-Synthesein vivo, als auch den Ribonucleinsäuren-Umsatz in der Gewebskultur zu stimulieren, eine herabgesetzte biologische Aktivität. — Bei der Diskussion der Natur dieses „abnormen” Insulins und seiner hypothetischen Rolle in der Physiopathologie des Diabetes ergibt sich besonders deutlich, wie dringend erforderlich eine genauere Klärung des in diesem Falle vorliegenden molekularen Umbaus ist.
    Notes: Summary Understanding of diabetes in molecular terms has advanced very little. The possibility that a structural difference exists in the circulating and pancreatic insulin moiety of diabetics is supported by three lines of evidence obtained in the authors' laboratory. — Immunologically purified circulating insulin from diabetic subjects untreated with insulin was noted to be relatively resistant to degradation by a crude muscle insulinase preparation. The pancreatic insulin of five diabetic pancreases was found to have a decreased biological activity in its ability to enhance glycogen synthesisin vivo and in its capacity to stimulate RNA turnover in tissue culture. — The nature of this “abnormal insulin” and its hypothetical role in the physiopathology of diabetes are discussed in the light of the need for a specific definition of the precise molecular change.
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  • 25
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    Diabetologia 4 (1968), S. 68-70 
    ISSN: 1432-0428
    Keywords: Insulin ; proinsulin ; biosynthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Après incubation de tranches de pancréas d'embryon de veau, la leucine-H3 est incorporée dans une fraction protéique qui semble avoir les propriétés d'une “proinsuline”. Cette fraction protéique est de taille supérieure à l'insuline, possède l'immunoréactivité propre à l'insuline, et après traitement limité par la trypsine elle est transformée en un peptide semblable à l'insuline.
    Abstract: Zusammenfassung Die Inkubierung von Dünnschnitten des fötalen Rinder-Pankreas in Gegenwart vom H3- Leucin ergab einen Einbau dieser Amminosäure in eine Eiweißfraktion, die die Eigenschaften eines, Pro-Insulins' aufwies. Das Molekulargewicht dieser Eiweißfraktion war größer als dasjenige des Insulins; sie besaß die Immunreaktivität des Insulins und konnte durch teilweisen Abbau mit Trypsin in ein insulinähnliches Peptid umgewandelt werden.
    Notes: Summary Incubation of fœtal bovine pancreas slices resulted in the incorporation of3H-leucine into a protein fraction which appeared to have the properties of a ‘proinsulin’. This protein fraction was larger in size than insulin, possessed the immunoreactivity of insulin and was converted by limited trypsin treatment to a peptide similar to insulin.
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  • 26
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    Diabetologia 4 (1968), S. 281-285 
    ISSN: 1432-0428
    Keywords: Insulin ; radioimmunoassay ; bile ; bile acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé L'effet des acides biliaires sur le dosage radioimmunologique de l'insuline a été examiné et les résultats ont montré que les acides biliaires en concentrations physiologiques nuisent à la liaison de l'insuline avec le sérum anti-insulinique. La courbe de dilution de l'insuline immunoréaetive dans la bile de la vésicule biliaire porcine n'était pas parallèle à celle de l'insuline porcine standard. Après extraction de la bile porcine par du sérum antiinsulinique et après dosage de l'extrait, des taux d'insuline plus bas ont été trouvés. Les résultats suggèrent qu'une partie seulement de «l'insuline immunoreactive» de la bile de la vésicule biliaire représente de l'insuline véritable.
    Abstract: Zusammenfassung Die Wirkung von Gallensäuren auf die radio-immunologische Insulinbestimmung wurde untersucht. Aus den Resultaten geht hervor, daß Gallensäuren in physiologischen Konzentrationen zu einer Störung der Insulinbindung an Anti-Insulinserum führen. Die Verdünnungskurve von immunoreaktivem Insulin im Gallensaft aus Schweinegallenblasen verlief nicht parallel zur Standard-Eichkurve von Schweineinsulin. Nach Extraktion der Schweinegalle mit Anti-Insulinserum fanden sich im Extrakt niedrigere Insulinkonzentrationen. Die Ergebnisse deuten darauf hin, daß nur ein Teil des „immunoreaktiven Insulins” in der Blasengalle echtes Insulin ist.
    Notes: Summary The effect of bile acids on the radioimmunoassay of insulin has been investigated, and the results show that bile acids in physiological concentrations interfere with the binding of insulin by anti-insulin serum. The dilution curve of immunoreactive insulin in pig gall-bladder bile was not parallel to that of standard pig insulin. After extraction of pig bile with anti-insulin serum and assay of the extract, lower insulin levels were found. The results suggest that only a part of the “immunoreactive insulin” in gall-bladder bile is genuine insulin.
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  • 27
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    Pflügers Archiv 301 (1968), S. 254-258 
    ISSN: 1432-2013
    Keywords: Insulin ; Potassium Deficiency ; Membrane Potential ; Rat Diaphragm ; Insulin ; Kaliummangel ; Membranpotential ; Rattenzwerchfell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung An 102 Zellen des Zwerchfells von insgesamt 7 Ratten mit alimentärem Kaliummangel fanden wir unter dem Einfluß von Insulin (0,1 I.E./ml) eine Depolarisation um 11,2 mV, nämlich von −94,6 (s=±6,4) mV bei insgesamt 100 Zellen auf −83,4 (s=±6,8)mV (p 〈 0,001). Die Kaliumkonzentration in der Inkubationslösung betrug 4,7 (s=±0,29) mval/l. — Ferner steigt die bei kaliumverarmten Tieren erniedrigte intracelluläre Kaliumkonzentration unter Insulineinfluß von 107 (s=±12) mval/lH2O IZR auf 130 (s=±19,8) mval/lH2O IZR an (p〈0,05). Die Befunde sprechen dafür, daß Insulin bei kaliumverarmten Tieren einen Netto-Kaliumeinstrom bewirkt, der eine Abnahme des Membranpotentials zur Folge hat.
    Notes: Summary In 102 single muscle cells of 7 rats with alimentary potassium depletion we found under influence of insulin (0.1 I.U./ml) a depolarisation of 11.2 mV, i.e. from −94.6 (s=±6.4)mV (100 cells) to −83.4 (s=±6.8)mV (p〈0.001). The potassium concentration in the incubation medium was 4.7 (s=±0.29) mequ/l. — In addition we measured under influence of insulin (0.1 I.U./ml) an intracellular potassium concentration of 130 mval/lH2O IZR, which is probably higher than in potassium deficient animals without insulin (p〈0.05). These findings suggest that insulin produces a netto potassium influx in potassium deficient animals, which could explain the depolarisation.
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  • 28
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    Naunyn-Schmiedeberg's archives of pharmacology 260 (1968), S. 254-268 
    ISSN: 1432-1912
    Keywords: Bilirubin ; Glucuronates ; Insulin ; Liver ; Tolbutamide ; Bilirubin ; Glucuronidsynthese ; Insulin ; Leber ; Tolbutamid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Lebergewebe von Ratten, die mit Tolbutamid, mit anderen blutzuckerwirksamen Sulfonylharnstoffderivaten oder mit Insulin behandelt worden waren, bildet bei Inkubation in vitro mehr Bilirubinglucuronid als das Gewebe unbehandelter Kontrolltiere. Dieser Effekt wurde 2 Std nach der intraperitonealen Injektion der blutzuckersenkenden Stoffe nachgewiesen, er tritt dosisabhängig auf und ist mit der blutzuckersenkenden Wirkung gut korreliert. Ein dem Tolbutamid chemisch verwandtes, jedoch blutzuckerunwirksames Methylsulfonylharnstoffderivat hatte diese Wirkung nicht. Die Steigerung der Glucuronidsynthese ist dadurch bedingt, daß in der Leberzelle während einer Insulin- oder Sulfonylharnstoffhypoglykämie vermehrt aktivierte Glucuronsäure (UDPGA) für die Konjugation bereitgestellt wird. Die Aktivität des für die Konjugationsreaktion verantwortlichen Enzyms, der UDP-Glucuronyltransferase, war unter unseren Versuchsbedingungen nicht verändert. Es fanden sich keine Anhaltspunkte dafür, daß in der Insulin- oder Sulfonylharnstoffhypoglykämie die Bildung von UDPGA aus UDPG beschleunigt erfolgt. Die Aktivität der UDPG-Dehydrogenase war nicht verändert, auch Faktoren, die eine Bildung von UDPGA begünstigen könnten, wie ein erhöhter NAD+/NADH-Quotient und eine gesteigerte ATP-Konzentration im Gewebe, waren nach Tolbutamid nicht nachzuweisen.
    Notes: Summary Liver tissue of rats pretreated with tolbutamide, with other hypoglycaemic sulfonylurea compounds, or with insulin formed more bilirubinglucuronide when incubated in vitro than the tissue of untreated controls. The effect was present two hours after the blood sugar lowering agents had been injected intraperitoneally. It was dose-dependent and well correlated to the hypoglycaemic response. A methylated sulfonylurea compound, which is chemically closely related to tolbutamide but devoid of blood sugar lowering activity failed to show this effect. Glucuronide formation in hypoglycaemia induced by insulin or tolbutamide is increased as more activated glucuronic acid (UDPGA) is made available to the conjugation reaction. There was no change in the activity of the enzyme responsible for glucuronide synthesis, the UDP-glucuronyl-transferase, in our experiments. There was no indication that the formation of UDPGA from UDPG was accelerated by insulin or sulfonylureas. There was no change in the activity of the hepatic UDPG-dehydrogenase. Factors which could favour the formation of UDPGA such as an increased NAD+/NADH ratio or an elevated ATP concentration in the tissue were not present following tolbutamide.
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  • 29
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    Acta diabetologica 5 (1968), S. 279-298 
    ISSN: 1432-5233
    Keywords: Choline ; Clinical situation (diabetes) ; Glucagon ; Growth hormone ; Heparin ; Histamine ; Insulin ; Insulinemia ; Night vision ; Pro-insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resume Alors que mon intérêt pour l'insuline a été pratiquement continu depuis déjà sa découverte, il y a eu des périodes pendant lesquelles mon attention s'est concentrée sur la coline, l'histamine et l'héparine. Pendant les années de guerre, les sujets de recherche ont été naturellement très différents. Les points importants dans le développement de l'insuline, du point de vue chimique, ont été sa purification, cristallisation, détermination de la structure et synthèse. Les physiologistes ont été fascinés par les études regardant le point et le mécanisme d'action de l'insuline. On a appris beaucoup quant à l'action sur grand nombre de tissus différents et l'insuline se montra être la principale hormone anabolique. Les développements cliniques ne sont mentionnés que brièvement car mes intérêts personnels de recherche ont été exclusivement expérimentaux.
    Abstract: Resumen Mientras mi interés para insulina fue prácticamente continuo desde su descubrimiento, hubo períodos en que mi atención se concentró sobre colina, histamina y heparina. Durante los años de la guerra, los temas de investigación fueron naturalmente muy diferentes. Los puntos fundamentales en el desarrollo de la insulina desde el punto de vista químico, fueron su purificación, cristalización, determinación de la estructura y síntesis. Los fisiólogos fueron cautivados por los estudios sobre el punto y el mecanismo de acción de la insulina. Mucho se aprendió acerca de la acción sobre muchos tejidos diferentes y la insulina demostró ser la hormona anabólica principal. Los desarrollos clínicos se mencionan sólo brevemente pues mis intereses personales de investigación han sido exclusivamente experimentales.
    Notes: Riassunto Mentre il mio interesse per l'insulina è stato praticamente continuo sin dalla sua scoperta, ci sono stati periodi nei quali la mia attenzione si concentrò sulla colina, istamina ed eparina. Durante gli anni della guerra, i temi di ricerca furono naturalmente molto diversi. I momenti culminanti nello sviluppo dell'insulina, dal punto di vista chimico, furono la sua purificazione, cristallizzazione, determinazione della struttura e sintesi. I fisiologi sono stati affascinati dagli studi circa il punto ed il meccanismo di azione dell'insulina. Molto è stato appreso intorno all'azione su molti tessuti differenti e l'insulina dimostrò di essere l'ormone anabolico principale. Gli sviluppi clinici sono menzionati solo brevemente poichè i miei personali interessi di ricerca sono stati esclusivamente sperimentali.
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    Acta diabetologica 5 (1968), S. 347-363 
    ISSN: 1432-5233
    Keywords: Diabetes mellitus ; Gel-filtration ; Insulin ; 125J-insulin-plasma complex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resume Les AA. ont étudié la capacité des protéines plasmatiques de lier l'insuline125J avec la méthode de filtration surgel. Le fractionnement parSephadex G-100 a démontré que seulement le 10 % de l'insuline marquée était lié par le protéines plasmatiques des sujets sains, des femmes gravides et des diabétiques non traités. Un pourcentage d'insuline beaucoup plus élevé était liée par les protéines plasmatiques dans des sujets que étaient traités precédemment avec de l'insuline bovine, tandis que le degrée de la liason était tres élevé dans les diabétiques insulino-résistants. De recherches avecSephadex G-200 ont demontré que, après une courte période d'insulinothérapie, le complexe insuline-protéine migrait avec les globulines 19 S. Après une insulinothérapie prolongée et dans les cas insulino-résistants la plus grande partie de l'insuline marquée liée aux protéines était élui avec les globulines 7 S. Le phénomène est attribué à l'action des anticorps anti-insuline bovine.
    Abstract: Resumen La capacidad que poseen las proteínas para ligar la insulina marcada con125J se estudió mediante el método de filtración engel. El fraccionamiento medianteSephadex G-100 demostró que solamente el 10 % de la insulina marcada estaba ligada por las proteínas plasmáticas de sujetos sanos, de mujeres embarazadas y de pacientes diabéticos no tratados. Un porcentaje de insulina notablemente superior estaba ligado por las proteínas plasmáticas en pacientes que anteriormente habían sido tratados con insulina bovina, mientras el grado de enlace se volvía muy elevado en los diabéticos resistentes a la insulina. Experimentos realizados conSephadex G-200 demostraron que después de un breve tratamiento insulínico, el complejo insulina-proteína migraba con las globulinas 19 S. Después de un prolongado tratamiento insulínico y en los casos resistentes a la insulina, la mayor parte de la insulina marcada con las proteínas resultaba eluida con las globulinas 7 S. El fenómeno, discutido detalladamente, se atribuye a la acción de los anticuerpos anti-insulina bovina.
    Notes: Riassunto La capacità delle proteine plasmatiche di legare l'insulina marcata con125J è stata studiata mediante il metodo di filtrazione sugel. Il frazionamento medianteSephadex G-100 ha dimostrato che soltanto il 10% dell'insulina marcata era legato dalle proteine plasmatiche di soggetti sani, di donne gravide e di pazienti diabetici non trattati. Una percentuale di insulina notevolmente superiore era legata dalle proteine plasmatiche in pazienti che erano stati precedentemente trattati con insulina bovina, mentre il grado di legame diveniva molto elevato nei diabetici insulino-resistenti. Esperimenti eseguiti conSephadex G-200 hanno dimostrato che, dopo una breve terapia insulinica, il complesso insulina-proteina migrava con le globuline 19 S. Dopo prolungata terapia insulinica e nei casi insulino-resistenti la maggior parte dell'insulina marcata legata alle proteine era eluita con le globuline 7 S. Il fenomeno, discusso nei particolari, è attribuito all'azione degli anticorpi anti-insulina bovina.
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  • 31
    ISSN: 1432-5233
    Keywords: Bovine insulin ; Insulin ; Insulin antibodies ; Insulin resistance ; Pork insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resume Les AA. présentent les résultats obtenus avec une méthode très simple pour la recherche des anticorps anti-insuline, basée sur l'emploi d'insuline I125 ou I131 et sur la précipitation avec alcool absolu du complexe antigène-anticorp. Les anticorps anti-insuline ont été fréquemment observés seulement dans des sujets diabétiques déjà soumis à traitement avec insuline. Un taux élevé d'anticorps anti-insuline s'accompagne à une diminution de la sensibilité à l'insuline (0,1 U/kg i.v.).
    Abstract: Resumen Se expresan los resultados obtenidos con el empleo de un método que puede ser ejecutado en forma my simple, para la investigación de anticuerpos anti-insulina; el método se basa sobre el empleo de insulina I125 o I131; y sobre la precipitación sucesiva con alcohol absoluto del complejo antígeno-anticuerpo. Los anticuerpos anti-insulina han sido hallados con mucha frecuencia solamente en pacientes diabéticos, que recibían tratamiento insulínico. Un título elevado de anticuerpos antiinsulina se asocia a una disminución sensible de la sensibilidad a la insulina (0,1 U/kg i.v.).
    Notes: Riassunto Vengono presentati i risultati ottenuti con l'impiego di una metodica di semplice esecuzione per la ricerca di anticorpi anti-insulina, basata sull'impiego di insulina I125 o I131 e sulla successiva precipitazione con alcool assoluto del complesso antigene-anticorpo. Gli anticorpi anti-insulina sono stati riscontrati con grande frequenza solo in pazienti diabetici già sottoposti a trattamento insulinico. Un elevato titolo di anticorpi anti-insulina si associa ad una diminuzione marcata della sensibilità all'insulina (0,1 U/kg i.v.).
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  • 32
    ISSN: 1432-5233
    Keywords: Insulin ; Insulin antibodies ; Insulin binding properties of serum ; Insulin therapy ; Serum proteins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resume Les AA. ont observé que le sérum d'un sujet normal et celui d'un diabétique, jamais traité avec insuline, ont la possibilité de lier l'insuline dans la même mesure. Dans certains sérums, soit du sujet normal soit du diabétique, est présente une activité de liaison de l'insuline supérieure aux taux normaux plus élevés; cette activité diminue après administration de µU 500 d'insuline bovine. Les AA. présentent leurs considérations à propos de ce phénomène.
    Abstract: Resumen Los AA. observan que los sueros del individuo normal y del diabético nunca tratado con insulina poseen propiedades insulino-ligantes de entidad análoga. En algunos sueros — ya del sujeto normal, ya del diabético — está presente una actividad insulino-ligante superior a los valores máximos normales, que disminuye luego de haber agregado µU 500 de insulina bovina. Los AA. hacen algunas consideraciones interpretativas de tal fenómeno.
    Notes: Riassunto Gli AA. rilevano che i sieri dell'individuo normale e del diabetico mai trattato con insulina sono provvisti di proprietà insulino-legante di entità analoga. In alcuni sieri, sia del soggetto normale che del diabetico, è presente un'attività insulino-legante superiore ai valori massimi normali, che diminuisce dopo aggiunta di µU 500 di insulina bovina. Gli AA. fanno alcune considerazioni interpretative su tale fenomeno.
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  • 33
    Electronic Resource
    Electronic Resource
    Springer
    Acta diabetologica 5 (1968), S. 499-512 
    ISSN: 1432-5233
    Keywords: Entero-insular axis ; Gastrin ; Glucagon ; Gut hormones ; Insulin ; Pancreozymin ; Secretin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resume Des préparations hautement purifiées de gastrine, sécrétine et pancréozymine ont été injectées par voie endoportale chez des chiens anesthésiés, en vue d'examiner les influences possibles des hormones gastro-intestinales sur la sécrétion des îlots de Langerhans. On a vu que les trois hormones provoquent une augmentation immédiate de la concentration d'insuline dans la veine pancréatico-duodénale. L'effet de la gastrine sur la libération d'insuline était insignificant quantitativement, tandis que celui de la sécrétine était plus important et de plus grande durée; cependant la pancréozymine semblait être le stimulant le plus puissant et déterminer en outre une augmentation parallèle de la sécrétion pancréatique de glucagon. On a démontré de plus que la pancréozymine augmentait la réponse tant de l'insuline que du glucagon à l'hyperaminoacidémie. On a observé que l'administration intraduodénale d'acides aminés, qui représente notoirement la stimulation la plus puissante de la pancréozymine endogène, est en mesure de déterminer une libération plus grande et plus rapide d'insuline et de glucagon par rapport à l'administration intraveineuse d'acides aminés, ce qui fait supposer que la pancréozymine endogène joue un rôle physiologique lorsque la réponse de l'hormone des cellules insulaires aux acides aminés ingérés est augmentée. Le facteur physiologique qui augmente la réponse insulaire au glucose ingéré reste toutefois inconnu.
    Abstract: Resumen Medicamentos altamente purificados de gastrina, secretina y pancreozimina han sido inyectados por via intraportal a perros anestesiados, con el fin de examinar las posibles influencias de las hormonas gastro-intestinales sobre la secreción de las hormonas de las islas de Langerhans. Se ha notado que las tres hormonas producen aumento inmediato de la concentración de insulina en la vena pancreática-duodenal. El efecto de la gastrina sobre la liberación de insulina era insignificante cuantitativamente, mientras el de la secretina era apreciable y de mayor duración; sin embargo, parecía que la pancreozimina fuese el estimulante más potente y que además determinava aumento paralelo de la secreción pancreática de glucagón. Además se ha demostrado que la pancreozimina aumentava la respuesta, ya de la insulina, ya del glucagón, a la hiperaminoacidemia. La administración intraduodenal de aminoácidos, que representa notoriamente el más potente estímulo de la pancreozimina endógena, está en grado de provocar una liberación mayor y más rápida de insulina y glucagón, que la administración intravenosa de aminoácidos; cosa que hace pensar que la pancreozimina endógena ejerce un papel fisiológico cuando aumenta la respuesta de la hormona de las células de las islas a los aminoácidos ingeridos. Sin embargo, el factor fisiológico que aumenta la respuesta insular a la glucosa ingerida, queda desconocido.
    Notes: Riassunto Preparati altamente purificati di gastrina, secretina e pancreozimina sono stati iniettati per via endoportale in cani anestetizzati, allo scopo di esaminare le possibili influenze degli ormoni gastro-intestinali sulla secrezione degli ormoni delle isole di Langerhans. Si è riscontrato che tutti e tre gli ormoni provocano un immediato aumento della concentrazione di insulina nella vena pancreatico-duodenale. L'effetto della gastrina sulla liberazione di insulina era quantitativamente insignificante, mentre quello della secretina era più rilevante e di maggiore durata; tuttavia sembrava che la pancreozimina fosse il più potente stimolatore e che inoltre determinasse un aumento parallelo della secrezione pancreatica di glucagone. Per di più si è dimostrato che la pancreozimina aumentava la risposta sia dell'insulina che del glucagone alla iperaminoacidemia. La somministrazione intraduodenale di aminoacidi, che rappresenta notoriamente la più potente stimolazione della pancreozimina endogena, è stata riscontrata in grado di determinare una liberazione maggiore e più rapida di insulina e di glucagone rispetto alla somministrazione endovenosa di aminoacidi, il che fa pensare che la pancreozimina endogena svolga un ruolo fisiologico nell'aumentare la risposta dell'ormone delle cellule insulari agli aminoacidi ingeriti. Tuttavia il fattore fisiologico che aumenta la risposta insulare al glucosio ingerito rimane sconosciuto.
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  • 34
    Electronic Resource
    Electronic Resource
    Springer
    Clinical and experimental medicine 148 (1968), S. 22-27 
    ISSN: 1591-9528
    Keywords: Insulin ; Hypoglycemia ; Xylitol ; Insulin ; Hypoglykämie ; Xylit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Bei Kaninchen, Meerschweinchen, Mäusen und Ratten wurde der Einfluß von Xylit auf die Insulinhypoglykämie untersucht. Es zeigte sich, daß Xylit die durch große intravenöse Insulindosen hervorgerufenen neurogenen Störungen (Lähmungserscheinungen, Krämpfe) zu beseitigen bzw. zu verhüten vermag. Gleichzeitig kommt es zu einem Wiederanstieg der Glucosekonzentration im Blut. Die möglichen Mechanismen dieser Wirkung werden diskutiert.
    Notes: Summary The influence of xylitol on insulin-induced hypoglycemia was studied in rabbits, guinea pigs, mice, and rats. Relief of hypoglycemia and the concomitant disturbances of the nervous system was observed following the injection of xylitol. The possible mechanisms of this action are discussed.
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  • 35
    ISSN: 1591-9528
    Keywords: Insulin ; Monosaccharide ; Hormones ; Mammals ; Amphibians ; Insulinsekretion ; Monosaccharide ; Hormone ; Säugetiere ; Amphibien
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die Stimulierung der Insulinsekretion durch Monosaccharide und Hormone wurde mit der Technik der Inkubation von isolierten Pankreasstückchen untersucht. Der Insulingehalt der Inkubationsmedien und der Pankreasgewebe wurde mit der biologischen (Oxydation von14C-Glucose durch das epidydemale Fettgewebe der Ratte) und der radioimmunologischen Bestimmungsmethode mit Trennung des freien und gebundenen Insulins durch Amberlite ermittelt. Das Kaninchenpankreas reagierte auf Glucose, Fructose, Ribose, Xylose, STH und Sekretin mit gleichbleibender Insulinausschüttung, nicht dagegen auf Galaktose, D- und L-Arabinose und ACTH. Die Gewebe anderer Säugetiere (Hund und Kalb, nicht aber Ratten) und einer Amphibienart (Grasfrosch) zeigten eine übereinstimmende Insulinfreisetzung nach Gabe von Glucose, wobei die Säugetiere etwa 1%, das Amphibium etwa 10% des Insulingehalts abgaben. Das Froschpankreas wies in seiner Reaktion eine jahreszeitliche Abhängigkeit auf, indem es im Winter nicht, im Sommer am stärksten auf die Stimulationsreize ansprach.
    Notes: Summary The stimulation of insulin-secretion by monosaccharides and hormones was studied with the technique of incubation of isolated pieces of pancreas. The insulin content of the incubation medium and of the pancreatic tissue was measured using both biological (oxidation of 14-C-glucose by epidydimal fat tissue of rats) and radio-immunological methods (separation of free and bound insulin with amberlite). The rabbit pancreas was stimulated by glucose, fructose, ribose, xylose (with constant insulin release), STH, and secretin, but not by galactose,d- andl-arabinose, and ACTH. The pancreatic tissue of other mammals (dog and calf, not rats) and one amphibian species (gras frog) showed the same insulin release after glucose which was 1% by mammals and 10% by amphibian of the insulin content of the tissue. The reaction of the frog pancreas depended upon the time of the year. In summer it reacted strongly to stimulants but in the winter it did not.
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