Low insulin response: a marker of prediabetes.
Explore the source record for details and available documents.
Blood Glucose↗
Biomedical subjects
V Grill
Publications and source records attributed to V Grill.
The priming effect of glucose on insulin release does not involve redistribution of secretory granules within the pancreatic B-cell.
Short-term stimulation of the pancreatic B-cell with glucose produces a time-dependent potentiation of this cell, which markedly enhances the insulin response to a renewed stimulation with the hexose. To study if a redistribution of the B-cell secretory granules to a location close to the B-cell plasma membrane could underlie the priming effect of glucose, an investigation by ultrastructural morphometry was performed. After exposure of perfused rat pancreas to non-priming or priming concentrations of glucose, pale and dark B-cell secretory granules were distinguished and analysed both within a central and a peripheral zone of the B-cell. The pale secretory granules comprised 30-40% of the total granule population in the B-cell. Whereas no difference in diameter of the granules was observed, there was evidence for a greater numerical density of dark granules in the central than in the peripheral part of the B-cell. This finding may be in line with observations implying that newly synthesized insulin is released preferentially to older insulin. The present experiments did, however, not reveal any significant priming effect of glucose on the intracellular distribution of secretory granules in the pancreatic B-cell. The lack of morphological changes in the B-cell by glucose priming of insulin release should, rather, direct increased attention to the biochemical aspects of the priming phenomenon.
Animals↗
Effect of ketotifen on adriamycin toxicity: role of histamine.
The effect of ketotifen, an antianaphylactic drug which acts in part similarly to sodium cromoglycate, was tested on adriamycin-induced histamine release and toxicity. The intraperitoneal injection of various concentrations of ketotifen induced an important histamine release from rat mast cells. Thirty minutes after the injection, however, no more histamine was present in the peritoneum. When i.p. administered to mice 30 min before adriamycin (15 mg/kg), ketotifen significantly ameliorated the survival time and reduced the cardiotoxicity. On the contrary, when given simultaneously, the antiallergic drug increased the toxic effect of adriamycin.
Animals↗
Calcium ethylenediaminetetraacetate toxicity in the rat: ultrastructural effects on skin collagen.
The effect of calcium ethylenediaminetetraacetate (CaEDTA) i.v. infusion on skin ultrastructure was studied in the rat with the aid of transmission electron microscopy. High magnification electron micrographs of collagen fibrils were analysed with a computer aided image analyser, in terms of the Gaussian distribution of fibril diameter and the distance between cross striations of collagen fibrils (D-spacing). CaEDTA caused marked depletion of collagen fibrils in the skin. The collagen fibrils from CaEDTA treated rats exhibited significant increases in D-spacing (about 30%) and diameter (about 40%) compared to saline treated controls. These findings are consistent with earlier published biochemical data indicating that CaEDTA enhances collagen degradation in the rat.
Animals↗
Local radiotherapy for pedal manifestations of HLA-B27-related arthropathy.
Four males with characteristic foot manifestations of HLA-B27-related arthropathy are reported. The severity of this problem and its recalcitrance to standard therapies led to the use of local radiotherapy. The beneficial outcome and minimal short-term side effects of this treatment are discussed in relation to previous experience with radiotherapy in ankylosing spondylitis.
Adolescent↗
Urinary metabolites of thromboxane and prostacyclin in diabetes mellitus.
The in vivo synthesis of thromboxane A2 and prostacyclin was estimated in 23 diabetics through measurements of the major urinary metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-PGF 1 alpha utilizing gas chromatography-mass spectrometry. Mean excretion was similar to that in non-diabetic subjects. The possible influence of hyperglycemia on the excretion of 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-PGF 1 alpha was evaluated in three ways: by measuring excretion before and during an acute 9-h normalization of hyperglycemia through an artificial pancreas (Biostator) as well as by comparing excretion before and 7-12 days or 40-180 days after the initiation of insulin treatment. Despite significant reducing effects on hyperglycemia or on levels of hemoglobin A 1c, no effects on the excretion of the thromboxane and prostacyclin metabolites could be found. Abnormal formation of thromboxane or prostacyclin is not a generalized feature of the diabetic state.
6-Ketoprostaglandin F1 alpha↗
Histochemical study on melanocytes in the inner ear vestibulum of guinea pig.
Explore the source record for details and available documents.
Animals↗
Morphological analysis of metastatic potential and antimetastatic drug effects in mice bearing two lines of Lewis lung carcinoma.
Two lines of Lewis lung carcinoma with a different potential to metastasize spontaneously to the lungs have been examined for their cytological and histological characteristics. Metastatic potential appears to be related with parenchymal organization of the primary tumours, since large haemorrhagic areas containing detached tumour cells and the absence of endothelialized capillaries are observed only in the line with high metastatic potential. At the same time, the cytological characteristics of the cells of the two tumour lines are similar, and do not seem to be related with metastatic potential. After treatment with the selective antimetastatic drugs ICRF-159 and DM-COOK, and with DTIC, the histological appearance of the line with high metastatic potential becomes similar to that of the line with low metastatic potential. These data seem to indicate that the early phases of tumour spread occurring in the primary tumour are of relevance for metastatic potential and control by antimetastatic drugs, and suggest that for DTIC such antimetastatic action may participate to its clinical antitumour effects.
Animals↗
Studies of high and low insulin responders with the hyperglycemic clamp technique.
We have investigated insulin responsiveness in relation to insulin sensitivity during sequential hyperglycemic clamping in low insulin responders (LIR), high insulin responders (HIR) and in women with a history of gestational diabetes (GD). Designation of HIR and LIR was done on the basis of mathematical modeling of the insulin response to a glucose infusion test. Insulin sensitivity was determined by a somatostatin-insulin-glucose infusion test (SIGIT) according to which LIR were subdivided into groups with higher or lesser sensitivity. Hyperglycemic clamping (60 min, 11 mmol/L of glucose) induced diphasic insulin and C-peptide responses in all groups. Insulin and C-peptide responses were significantly higher in HIR than in other groups. The ratio of first phase to total insulin response was higher in HIR v GD but did not differ between other groups. A second identical clamp was performed after a 60-minute rest period. Except in HIR, insulin levels attained were then moderately but significantly higher than during the first clamp. Conversely, the glucose utilization (mg/kg/min) to insulin (mU/L) = M/L ratio was markedly increased in LIR with high insulin sensitivity but not in other groups. We conclude that (1) large and consistent differences exist in glucose-induced insulin secretion from the pancreas between nondiabetic subjects; (2) time dynamics of insulin secretion and priming effects of glucose are similar in LIR with lesser and higher sensitivity; and (3) in the latter group a glucose stress affects insulin sensitivity more markedly than insulin responsiveness.
Blood Glucose↗
B cell insensitivity in a rat model of non-insulin-dependent diabetes. Evidence for a rapidly reversible effect of previous hyperglycemia.
In perfused pancreas of rats rendered diabetic by streptozotocin injection (STZ) during neonatal age the insulin response to 27 mM glucose was significant but impaired. It was unaffected by the alpha adrenergic blocker phentolamine. When 27 mM mannoheptulose was added simultaneously with 27 mM glucose, insulin release was inhibited, but less promptly than in pancreases from non-diabetic rats. When mannoheptulose was introduced 15 min after starting perfusion with 27 mM glucose, inhibition was apparent in non-diabetic rats, but not in STZ. In non-diabetic rats perfusion without glucose for 40 min failed to affect the subsequent response to 27 mM glucose. Conversely, in STZ, glucose omission enhanced 3.7-fold the response to 27 mM glucose. Insulin release in response to 3-isobutyl-1-methylxanthine (IBMX) was more marked in STZ than in non-diabetic rats. After glucose omission the IBMX-induced response was, however, reduced (67%) in STZ, but not significantly (7%) in non-diabetic rats. Thus, glucopenia in vitro sensitizes B cells of STZ to glucose, but desensitizes them to IBMX. Abnormal responsiveness may be linked to metabolic consequences of B cell fuel abundance.
1-Methyl-3-isobutylxanthine↗
Evidence that hyperglycemia increases muscarinic binding in pancreatic islets of the rat.
We studied the effects of fasting and of diabetes on binding of [3H]methylscopolamine to pancreatic islets of the rat. In nondiabetic rats, fasting for 36 h decreased binding of the muscarinic antagonist by 33% (P less than 0.05). Fasting also abolished the insulin response to 10 microM acetylcholine. Diabetes was induced by injecting streptozotocin (STZ) neonatally in rats. At the time of the experiments (6-10 weeks of age) these rats exhibited hyperglycemia (12.6 +/- 1.0 vs. 7.1 +/- 0.3 mM blood glucose in nondiabetics) but had a normal weight. Relative to islets from age- and sex-matched nondiabetic rats, islets from STZ rats were smaller (0.7 +/- 0.1 vs. 1.9 +/- 0.2 nl islet volume) and contained less insulin (218 +/- 33 vs. 1390 +/- 71 microU/islet). When calculated per islet volume, binding of [3H]methylscopolamine to STZ islets was enhanced by 80% in comparison to binding to normal islets (P less than 0.001). Scatchard analysis indicated that enhanced binding was due to increased number of binding sites. Cholinergic-induced insulin release, as assessed by carbamylcholine, was 37% higher in STZ than in normal islets (P less than 0.05) when expressed per islet volume and 3- to 4-fold enhanced in STZ islets when expressed per islet insulin content. Insulin treatment of STZ rats for 3 days lowered blood glucose, diminished binding of [3H]methylscopolamine, and abolished carbamylcholine-induced insulin secretion. We conclude that the level of glycemia in vivo participates in the regulation of the number of muscarinic receptors in the pancreatic islet and that such regulation is associated with changes in cholinergic-induced insulin secretion.
Acetylcholine↗
Abnormal B-cell function in neonatally streptozotocin-diabetic rats: insensitivity to alloxan toxicity.
The apparent toxicity of alloxan was compared in nondiabetic rats and rats made diabetic by injection with streptozotocin during neonatal life (STZ). In the perfused pancreas of nondiabetic rats, 1 mM alloxan rapidly but evanescently stimulated insulin secretion; this effect was followed by pronounced inhibition of the insulin response to 27 mM glucose (94% inhibition) or 1 mM 3-isobutyl-1-methylxanthine (76% inhibition). Conversely, in STZ-diabetic rats the stimulatory effect of alloxan was reduced to 22% of that elicited in nondiabetic rats. In further contrast, the inhibitory effect of alloxan exposure was abolished with regard to subsequent glucose-induced insulin secretion and attenuated with regard to 3-isobutyl-1-methylxanthine-induced insulin secretion. A relative insensitivity to alloxan was also seen in collagenase-isolated islets, where alloxan completely abolished glucose-induced insulin secretion in islets from nondiabetic rats, but only nonsignificantly reduced secretion (by 37%) in islets from STZ-diabetic rats. Insensitivity to glucose in STZ diabetic rats is associated with insensitivity to alloxan. This implies a common defect in the initial recognition site of glucose and alloxan.
1-Methyl-3-isobutylxanthine↗
Basal and meal-induced somatostatin-like immunoreactivity in healthy subjects and in IDDM and totally pancreatectomized patients. Effects of acute blood glucose normalization.
We investigated the impact of blood glucose normalization on plasma levels of somatostatin-like immunoreactivity (SLI) in subjects with C-peptide-negative insulin-dependent diabetes mellitus (IDDM) and in totally pancreatectomized patients. Patients were studied during hyperglycemia and during normoglycemia, which was attained by Biostator-directed feedback insulin infusion. The experiments were performed in the fasted state and after a standardized breakfast. In IDDM (n = 6), basal levels of SLI were significantly higher than in nondiabetic subjects (n = 18). In IDDM, normalization of hyperglycemia was followed by a 40% decline in basal SLI (P less than .05). After the meal, SLI increased to the same absolute levels with or without feedback insulin treatment; however, the incremental response was 60% higher during feedback insulin treatment (P less than .05). Treatment also suppressed fasting and postprandial levels of glucagon, whereas gastric inhibitory polypeptide (GIP) levels were unaltered. In four pancreatectomized patients, normoglycemia tended to lower plasma levels of SLI by 50% (P less than .1). After breakfast, an SLI response was noted during normoglycemia, whereas no significant effect of the meal was seen during hyperglycemia. We conclude that in IDDM and in totally pancreatectomized patients, administration of insulin with subsequent normalization of blood glucose is accompanied by a decline in plasma levels of SLI in the fasted state, whereas the apparent response to a meal is enhanced. These effects on plasma levels of SLI probably reflect to a major extent release of somatostatin from the gastrointestinal tract.
Adolescent↗
Histochemical study on catecholamines in human coronary endothelium.
Specific catecholaminergic granules had been previously described in the endothelial cells of blood and lymphatic vessels. 2 histochemical techniques were used in this work for detecting catecholamines in human coronary vessels: both the postfixation with OsO4-KI mixture and the formaldehyde induced fluorescence (FIF) reaction. Ultrastructural examinations of bioptic specimens processed with the OsO4-KI staining showed a marked positivity in the coronary endothelial cells, as well as in the smooth muscle fiber cells of the coronary arteriolae and the adventitial nerve endings. These findings were confirmed by a high level of fluorescence in the same structures, obtained using the FIF reaction. Myocardial fiber cells never reacted. Therefore, an important role of the endothelium of human coronary vessels in the turn-over of catecholamines could have been supposed.
Biopsy↗
Localization of an aminoglycoside (streptomycin) in the inner ear after its systemic administration. A histochemical study using fluorescence microscopy.
We used the simple method of direct cytofluorescence to detect the presence of the aminoglycoside, streptomycin, in the inner ear after its systemic administration. In the cochlea, fluorescence was observed in the organ of Corti, the spiral ganglion, the nerve fibres, the vascular stria and Reissner's membrane; in the vestibulum, fluorescence was seen in the crista ampullaris and the planum semilunatum. The localization of the drug was related to the distribution of its specific receptor, triphosphoinositide (TPI); therefore, it is reasonable to assume that aminoglycosides exert their toxic effects by binding to TPI.
Animals↗
Sulfonylurea-induced inhibition of glucagon secretion from the perfused rat pancreas: evidence for a direct, non-paracrine effect.
The effects of sulfonylurea on glucagon secretion were characterized in the perfused rat pancreas using glibenclamide (1 microgram/ml) or tolazamide (10 micrograms/ml) in the presence of 3.3 mmol/l glucose. Glucagon release, which was unaffected by glibenclamide at 2.75 mmol/l calcium, was suppressed at 1.19 and 0.64 mmol/l but transiently stimulated at 0.25 mmol/l extracellular calcium. The insulinogenic effect of glibenclamide at 0.64 and 0.25 mmol/l calcium was enhanced by 35% and 89%, respectively, compared to the response at 2.75 mmol/l calcium. The stimulatory effect of the compound on somatostatin secretion, however, was lost at the lower calcium levels. The effects of tolazamide at 2.75 and 0.64 mmol/l calcium mimicked those of glibenclamide, thus indicating that our results with the latter compound may be representative for all sulfonylureas. In pancreata from insulin-deficient alloxan-diabetic rats, glibenclamide completely lost its inhibitory effect on glucagon release at 0.64 mmol/l calcium. Inhibition was not restored by adding insulin (25 U/l) to the perfusate. However, when diabetic rats had been treated with insulin for 6-7 days, glibenclamide suppressed glucagon release at low calcium levels in the absence of stimulated insulin and somatostatin release. It is concluded that, at low calcium concentrations, sulfonylureas suppress glucagon secretion by a direct action on the A cell and not through paracrine interactions by insulin and somatostatin. Prolonged insulin deficiency impairs the sulfonylurea action on glucagon secretion.
Animals↗
Effect of polyethylene glycol 400 on adriamycin induced histamine release.
The activity of polyethylene glycol 400, a widely used drug solvent, was tested on the release of histamine induced by adriamycin in vitro on peritoneal rat mast cells and in vivo in a mouse model. Preincubation of mast cells with high (10 and 5%) concentrations of polyethylene glycol 400 significantly inhibited the important histamine release induced by 100 micrograms/ml of adriamycin; furthermore, polyethylene glycol 400 (3.45 g/kg; 0.345 g/ml) pretreatment almost completely abolished the peritoneal and pericardial mast cell degranulation and the cardiac toxicity caused by an intraperitoneal injection of 15 mg/kg of adriamycin. This effect of polyethylene glycol 400 on adriamycin-induced histamine release could explain the protective action exhibited in vivo on adriamycin treated animals, therefore confirming that adriamycin cardiotoxicity could be related to the release of histamine and other vasoactive substances.
Animals↗
Differences in long-term effects of L-glutamine and D-glucose on insulin release from rat pancreatic islets.
We have compared the effects of long-term exposure to L-glutamine or D-glucose on nutrient-induced insulin release from pancreatic islets of the rat. After 3 days of culture islets were finally tested in 1 h incubations for insulin responses to 16.7 mM of glucose, glutamine, leucine or a combination of leucine and glutamine. After culture at 11 mM glucose + 2 mM glutamine (A), glucose, leucine and glutamine stimulated release to a similar extent from islets. After culture at 1.7 mM glucose + 10 mM glutamine (B), only leucine stimulated insulin release. After culture at 11 mM glucose + 10 mM glutamine (C), both leucine and glutamine increased the insulin response. After culture at 1.7 mM glucose and 2 mM glutamine (D), only glutamine slightly stimulated release. After culture in high glutamine (B or C), a combination of leucine and glutamine significantly inhibited release as compared to leucine alone. A switch in culture media from B to A for 1 h prior to final incubations revived insulin release in response to glucose but not to glutamine. The reverse switch (A to B) abolished both subsequent glucose-and glutamine-induced insulin release. A switch from D to B revived an insulin response to leucine. Exposure of B-cells to 11 mM glucose during 30 min in another experimental system (perfused pancreas) induced a significant insulin response to subsequent stimulation with glutamine; this response was, however, only 17% of that to glucose per se observed in the same experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗