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Biomedical subjects

A Andersson

Publications and source records attributed to A Andersson.

At least 307 records · Page 17Linked to original sources
PubMed1984

Survival of human fetal pancreatic explants in organ culture as reflected in insulin secretion and oxygen consumption.

Human fetal pancreatic explants were maintained in organ culture for up to 12 days in medium TC 199 or RPMI 1640 supplemented with 20% fetal calf serum. The explants were cultured at their air-liquid interface on a Millipore filter supported by surgical gel foam (ALI technique). The insulin accumulation in the culture medium decreased considerably when explants were maintained for 6 days in RPMI 1640. No corresponding decline was observed with medium TC 199. Four out of 9 RPMI 1640-cultured and 8 out of 11 TC 199-cultured explants responded with an increased insulin release when challenged with high glucose-plus-theophylline after one week of culture. With these explants there was a statistically significant correlation between their rates of respiration and insulin secretion. Furthermore, significant correlations were found between the fetal crown-heel length on the one hand--and the insulin content, insulin response, and oxygen uptake on the other--of the TC 199 cultured explants. There was no apparent change in the rate of insulin accumulation by addition of high glucose or amino acids to the TC 199 medium. It is concluded that oxygen uptake measurements, requiring only minute amounts of tissue, are useful for assessing the viability of human fetal pancreatic explants, and that the ALI technique for maintaining human fetal pancreas in culture offers no obvious advantage over that of the submersion technique. There is also evidence that suggests a better functional preservation in culture medium TC 199 than in RPMI 1640.

Fetus↗
PubMed1984

Nicotinamide does not protect islet B-cell metabolism against alloxan toxicity.

Nicotinamide, a poly(ADP-ribose)synthetase inhibitor, protected NMRI mice against alloxan-induced hyperglycemia when given 10 min before, but not 10 min after, the injection of the drug. Pretreatment in vivo with nicotinamide induced hyperglycemia at the time of alloxan injection, and this could account for the protective action of nicotinamide against alloxan diabetes. Exposure of islets to alloxan (2 mM) in vitro caused a marked inhibition of both glucose-stimulated proinsulin biosynthesis and insulin release, and this was not affected by the action of nicotinamide. Alloxan-impaired islet glucose oxidation was partly restored by nicotinamide. The decreased islet content of NADH plus NAD, which was observed after alloxan treatment, could be prevented by nicotinamide. Glucose-stimulated islet oxygen uptake was abolished after treatment with alloxan, and nicotinamide had no protective effect in this process. Leucine (10 mM) plus glutamine (10 mM), however, were still able to evoke an islet respiratory response after alloxan exposure. Alloxan caused an immediate increase in the islet efflux of radiolabeled nucleotides, which was followed after about 5 min by a further increase. This latter increase of the radio efflux was inhibited by the addition of nicotinamide. The inability of nicotinamide to prevent the alloxan-induced impairment of proinsulin biosynthesis, insulin release, and oxygen uptake, together with the failure of nicotinamide to prevent the development of diabetes when given after alloxan, does not support a current hypothesis that the major cytotoxic effect of alloxan is primarily due to DNA damage. The present data suggest that organelles other than the nuclei, e.g., the mitochondria or the plasma membrane, are the primary sites of B-cell injury by alloxan.(ABSTRACT TRUNCATED AT 250 WORDS)

Alloxan↗
PubMed1984

The Langerhans cells in healed patch tests reactions, before and after oral administration of nickel.

Langerhans cells (LC) were studied at the light and electron microscopic levels in normal skin and in positive patch test areas after long-term healing before and after the flare-up reaction induced by oral administration of nickel. A number of reactive changes indicating increased cell activity, similar to those found in positive patch tests 72 hours after allergen application, were registered in the test areas. Thus, strong reactive changes persist in the LC system after a fulminant contact allergic dermatitis, even beyond clinical healing. Some cellular reactions, especially pronounced after oral nickel provocation, indicate that much of the LC activity takes place on a superficial level of the epidermis. Oral nickel administration induced, among other things, an intense formation of lipid-like inclusions in the LC, formerly observed only in contact allergic reaction to nickel. Goniometric analysis of the LC cytomembrane showed that the concept "spotty damage" is probably erroneous and that the LC are not targets of destruction in contact allergy. Keratinocytes adjacent to LC exhibited membrane and cytoplasmic changes indicative of interaction between these two cell types. Combined fluorescence and electron microscopic analyses of contact allergic dermatitis using long series of sections have disclosed a variety of reactive changes in, and an increased activity of, the Langerhans cell system (1, 2). In the present study Langerhans cells (LC) have been scrutinized for reactive changes after long-term healing of challenged epidermis and after oral nickel provocation causing a flare-up reaction of healed patch test areas.

Administration, Oral↗
PubMed1984

Glucose induced inhibition of radioactive nucleotide efflux from mouse pancreatic islets is dissociated from an increase in islet oxygen uptake.

Glucose at 1.7 and 5.6 mmol/l, pyruvate (30 mmol/l) and glutamine (10 mmol/l) all stimulated islet respiration slightly. More marked stimulation was achieved with glucose 8.3 mmol/l. When pyruvate (30 mmol/l) was added to islets respiring in the presence of different concentrations of glucose (1.7, 3.3 or 5.6 mmol/l), a stimulatory effect was only observed at the highest glucose concentration. Stimulation of islet oxygen uptake was also achieved when glucose 8.3 (but not 5.6) mmol/l was added to islets respiring in glutamine 10 mmol/l. Radioactive nucleotide efflux was, however, progressively inhibited by increasing the glucose concentration up to 5.6 mmol/l both in the absence or presence of glutamine 10 mmol/l. It is concluded that the glucose-induced inhibition of radioactive nucleotide efflux is not obligatorily linked to respiration.

Adenine Nucleotides↗
PubMed1984

Effects of starvation on phospholipid metabolism of pancreatic islets.

It was the aim of the present study to examine the extent to which starvation-induced impairment of glucose-stimulated insulin secretion is linked to changes of islet phospholipid metabolism. For this purpose both islets isolated from mice starved for 60 hr and islets maintained in culture for 1 week in a low (3.3 mM) glucose medium were studied together with relevant control islets. When challenged with a high glucose concentration the insulin response of both groups of islets was totally blunted. The effect of food restriction on 14C-glucose incorporation into different phospholipid classes was less prominent. On a percentage basis phosphatidylserine biosynthesis of islets isolated from starved mice was most affected, whereas the biosynthesis of phosphatidylcholine was only marginally impaired. Culture of islets for 1 week at the low glucose concentration affected the phospholipid biosynthesis even less and there was only a small decrease of 14C-glucose incorporation into phosphatidylcholine. In general, cultured islets synthesized more phospholipids than the freshly isolated ones. No dose-response relationship was found between various degrees of glucose-stimulated insulin secretion and 14C-glucose incorporation into different phospholipid classes of islets isolated from fed mice. The present data thus provided no evidence that an impairment of the islet phospholipid turnover contributes to the starvation-induced impairment of insulin secretion. There was also no close correlation between phospholipid biosynthesis in terms of 14C-glucose incorporation and glucose-stimulated insulin secretion.

Animals↗
PubMed1983

A 113Cd and 1H NMR study of the interaction of calmodulin with D600, trifluoperazine and some other hydrophobic drugs.

The interaction of calmodulin with D600 (a methoxy derivative of verapamil), trifluoperazine and some other drugs was studied by 113Cd and 1H NMR. All four cation binding sites of calmodulin were found to be affected by the binding of the drugs to calmodulin. The physiologically active and inactive forms of felodipine were found to give qualitatively the same changes in the 113Cd NMR spectra of calmodulin. The interpretation of this observation in terms of the physiological relevance of the binding to calmodulin is discussed. The binding constants for the two strongly bound trifluoperazine molecules were found to differ by one or two orders of magnitude. A competition study showed that trifluoperazine replaces D600 from at least one binding site on calmodulin. Moreover the binding of D600 was found to be calcium dependent. The data indicate that two calcium ions bound to calmodulin are sufficient to render the binding site(s) accessible for D600.

Animals↗
PubMed1983

Cadmium-113 nuclear magnetic resonance studies of proteolytic fragments of calmodulin: assignment of strong and weak cation binding sites.

Proteolytic fragments of bovine testis calmodulin were obtained by limited proteolysis with trypsin or thrombin. Cadmium-113 NMR studies showed that the tryptic fragment encompassing Ca2+ binding domains III and IV (TR2C) gave rise to a spectrum identical with that of the native protein. Two thrombic fragments containing either domains I, II, and III [TM1-(1-106)] or the single domain IV [TM2-(107-148)] both gave rise to one broad resonance only. These data indicate that domains III and IV comprise the two high-affinity Ca2+ binding sites in intact calmodulin and that disturbance of the structural relationship between domain III and domain IV markedly reduces the affinity of these two sites for Ca2+ ions. These observations are discussed with respect to other published accounts concerning the sequence in which the four calcium domains in calmodulin are filled.

Animals↗
PubMed1983

The influence of hyperglycaemia, hyperinsulinaemia and genetic background on the fate of intrasplenically implanted mouse islets.

We reported recently that intrasplenic transplantation of syngeneic pancreatic islets failed to cure obese-hyperglycaemic mice, despite a considerable growth of the grafted islets. In the present study, the role of sustained hyperglycaemia and hyperinsulinaemia for regeneration of transplanted islet cells was evaluated in these animals. Islets implanted into alloxan-diabetic C57BL/6J mice in numbers insufficient to restore normoglycaemia did not grow. There was, however, a statistically significant correlation between the mean volume of implanted islets and the degree of normalization of hyperglycaemia. Insulin treatment of these suboptimally islet-implanted C57BL/6J mice resulted in a volume increase of the implanted islets. When corresponding experiments were undertaken with alloxan-diabetic C57BL/KsJ mice, no effect was noted on hyperglycaemia and there was a drastic decrease in the volume of implanted islets. Islets implanted into old obese-hyperglycaemic mice that had returned to normoglycaemia but still were hyperinsulinaemic, decreased markedly in size. The present data suggest that neither hyperglycaemia nor hyperinsulinaemia per se are primarily responsible for the growth of islets in obese-hyperglycaemic mice. Furthermore, it is obvious that the genetic background is very important for morphological and functional responses of the islets to a prolonged period of hyperglycaemic stress.

Animals↗
PubMed1983

Viability tests of cryopreserved endocrine pancreatic cells.

Collagenase-isolated islets, which had been cultured for 1 week, were frozen at two different cooling rates. Islets frozen at 5 degrees C/min behaved from a functional point of view very similarly to that of nonfrozen, cultured control islets, except for a reduced maximal insulin secretory capacity and a reduced insulin content. Slowly frozen islets (0.5 degrees C/min), however, displayed reduced rates of both proinsulin biosynthesis and glucose oxidation. It is concluded that isolated islets can be cryopreserved with great success and that the methods of choice for viability tests are those characterizing the dynamics of insulin secretory capacity of the cryopreserved islets.

Animals↗
PubMed1983

Effects of glucose, leucine and adenosine on insulin release, 45Ca2+ net uptake, NADH/NAD ratios and oxygen consumption of islets isolated from fed and starved mice.

In order to elucidate further the effects of starvation on islet metabolism and insulin release, pancreatic islets of mice were isolated and incubated in the presence of various nutrient secretagogues. Starvation for 60 h completely blocked the insulin release in response to either 16.7 mM glucose or 10 mM leucine. The further addition of 20 mM adenosine partly restored the insulin response. Glucose, adenosine, glucose + adenosine, glucose + leucine or leucine + adenosine all increased the NADH/NAD ratios over basal values in islets from both fed and starved mice. No effects of starvation were observed on islet NADH/NAD ratios in any of the above media, but when islets of starved animals were incubated in the absence of any metabolic substrates the NADH/NAD ratios were decreased. In the absence of exogenous substrates the respiratory rate was also lower in islets from starved animals. Respiratory stimulation evoked by either 16.7 mM glucose or 10 mM leucine + 10 mM glutamine was lower after starvation, whereas glucose + adenosine, glucose + leucine and adenosine all induced normal respiratory responses. No differences between the 45Ca2+ uptake of islets from either starved or fed mice were observed under any conditions. It is concluded that, in starvation, a dissociation between islet insulin release and metabolism (measured as NADH/NAD ratios, oxygen consumption and 45Ca2+ uptake) may exist in the presence of certain nutrient secretagogues.

Adenosine↗
PubMed1983

Streptozotocin-induced impairment of islet B-cell metabolism and its prevention by a hydroxyl radical scavenger and inhibitors of poly(ADP-ribose) synthetase.

The possible protective effects in vitro of the hydroxyl radical scavenger dimethyl urea (6 mg/ml) and the poly(ADP-ribose)synthetase inhibitors theophylline (5 mM) and nicotinamide (0.75 mg/ml) against streptozotocin (SZ) induced deterioration of islet metabolism were investigated using isolated mouse pancreatic islets. All these compounds counteracted to different extents the deleterious effects of SZ (4.4 mM) on glucose-stimulated (pro)insulin biosynthesis, dimethyl urea protecting least. No protective effects against SZ were obtained by adding 16.7 mM glucose or 5 mM dibuturyl cAMP. The islet NADH + NAD content decreased drastically when exposed to SZ. Again, nicotinamide and theophylline protected better against the SZ-effects on pyridine nucleotides than dimethyl urea. Furthermore, the maintenance of a linear rate of oxygen uptake was lost after SZ-exposure of the islets, and there was no increase of the respiratory rate when these islets were challenged with high glucose. Also in these islet respiratory studies a partial or total protection by dimethyl urea, theophylline and nicotinamide against SZ was observed. In perifusion experiments SZ rapidly decreased insulin release together with a slightly delayed increased radioactive nucleotide efflux. Later (about 20 min.) a massive leakage of both radioactive nucleotides and insulin occurred in most of the experiments. It is concluded that all the observed impairments of islet metabolism after SZ-exposure can be related to islet NAD depletion, which may depend on poly(ADP-ribose)synthetase activation due to DNA damage. The SZ-induced DNA injury may be mediated by free radicals as suggested by the protective effects of dimethyl urea.

Animals↗
PubMed1983

Effects of pancreatic islet implantation on the morphology of retinal capillaries in alloxan diabetic mice.

Intrasplenic implantation of syngeneic islets normalized the hyperglycaemia of alloxan-diabetic mice irrespective of whether the implantation was performed 2 weeks or 4 months after the induction of diabetes. Islet implantation soon after the onset of diabetes prevented the development of retinal capillary disease as evidenced by a normal ratio between endothelial cells and pericytes. The increase of the cell count ratio (endothelial cells/pericytes) induced by long-term diabetes could not, however, be restored by islet implantation. The present results further underline the importance of optimal treatment for prevention of diabetic retinopathy.

Animals↗
PubMed1982

Respiration and insulin release in mouse pancreatic islets. Effects of L-leucine and 2-ketoisocaproate in combination with D-glucose and L-glutamine.

In order to further evaluate the importance of B-cell metabolism for the stimulation of insulin release, respiration and insulin release were studied in mouse pancreatic islets. Leucine and 2-ketoisocaproate stimulated insulin release during an initial 1-h period, whereas there was no stimulation during two subsequent 1-h periods. This effect was in contrast to that of 16.7 mM glucose, which was a potent stimulator through all the 3 h. Furthermore, the presence of glucose (5.6 mM) or glutamine together with either leucine or 2-ketoisocaproate enhanced the insulin release and prolonged the stimulation. When the kinetics of islet respiration were studied both leucine and 2-ketoisocaproate exerted an initial stimulation on the O2 uptake which, however, was short-lived (less than 30 min). The presence of 5.6 mM glucose strongly delayed the respiratory retardation seen after the initial stimulation. Similarly, glutamine enhanced the leucine- and 2-ketoisocaproate-stimulated respiratory rates and prevented the respiratory retardation otherwise observed. Leucine (20 mM) and 2-ketoisocaproate (10 and 20 mM) stimulated the oxidation of glucose (5.6 mM). It is concluded that there is a strong correlation between respiratory stimulation and the enhancement of insulin release and that leucine and 2-ketoisocaproate depend on the presence of endogenous fuels for their ability to stimulate islet functions in vitro.

Animals↗
PubMed1982

Release of fibrinolytic activators from the cornea and conjunctiva.

The authors studied the release of fibrinolytic activators from in vitro cultures of human and animal cornea with the following main findings: (1) the epithelium is the main activator source; (2) the addition of tripeptide, salicylate, chloroquine and phorbolester to the culture medium increases the fibrinolytic activity of the cultures; (3) corticosteroids depress the fibrinolytic activity; (4) explants of human conjunctiva also release fibrinolytic activators. The pathophysiological role of this activator is unknown. Hypothetically, besides preventing fibrin deposition on the surface of the eye, this activator may also stimulate leucocyte migration, activate procollagenase, protect the endothelial pump, and regulate vascular permeability and angiogenesis in the cornea.

Animals↗
PubMed1982

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro.

The protective effect on streptozotocin-induced diabetes of dimethyl urea, a hydroxyl radical scavenger, has been evaluated in vivo and in vitro. Pretreatment with dimethyl urea before a single diabetogenic dose of streptozotocin partially protected NMRI mice from hyperglycaemia, whereas the serum glucose of C57BL/KsJ mice increased during week 2 of observation. When the pancreases of these latter mice were examined histologically, insulitis was found in 15 out of 22 animals. The protective effect of dimethyl urea in the NMRI mice was not due to short-term hyperglycaemia induced by the drug, since pretreatment with glucose did not protect from streptozotocin but potentiated its diabetogenic effect. Dimethyl urea reduced the inhibition caused by streptozotocin on proinsulin biosynthesis of NMRI islets in vitro. It is suggested that streptozotocin-induced diabetes in mice may involve generation of hydroxyl radicals which are toxic to islet B cells. If this immediate cytoxicity is reduced by a scavenger, a more slowly developing hyperglycaemia and an accompanying insulitis may occur in particularly susceptible animals.

Animals↗