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Biomedical subjects

R Gunnarsson

Publications and source records attributed to R Gunnarsson.

At least 91 records · Page 5Linked to original sources
PubMed1977

Effects of glucose on the "in vitro" synthesis of ribonucleic acid in pancreatic islets from mice homozygous for the mutation "diabetes" (db).

Isolated pancreatic islets obtained from spontaneously diabetic mice were recently shown to have a considerably reduced rate of insulin biosynthesis in response to glucose. This defect has now been further evaluated by in vitro measurements of the effects of glucose on the islet RNA metabolism. An increase of the glucose concentration from 3.3 mM to 16.7 mM more than doubled the incorporation of 3H-labelled uridine into the islet RNA in the normal mice. By contrast, no stimulation was observed in the diabetic mice. Electrophoretic separation, on polyacrylamide gels, of RNA from normal mouse islets indicated that glucose stimulated the incorporation mainly into RNA bigger than 4S. Furthermore the fraction of islet RNA which bound the poly (U) was stimulated in the normal mice but not in the diabetic animals. Taken together these findings indicate a deficient glucose regulation of the RNA metabolism in the diabetic mice which conforms to the previously reported low rate of insulin biosynthesis in response to glucose in these animals.

Animals↗
PubMed1977

Steroid diabetes after renal transplantation--a preliminary report.

The incidence of steroid diabetes mellitus was studied retrospectively in 84 renal transplant recipients with grafts which had functioned longer than 3 months. The observation time ranged between 3 and 36 months (mean 17 months). Overt diabetes necessitating treatment was found in 24 patients (29%). Another 14 patients had transient elevations in blood glucose. The incidence of steroid diabetes was found to correlate with increasing age and body weight and with the number of rejection episodes. In the majority of the patients with manifest diabetes it was diagnosed within three months after transplantation.

Adolescent↗
PubMed1976

Survival of isolated human islets of Langerhans maintained in tissue culture.

Transplantation of human pancreatic islets to diabetic patients may require that donor islets be kept viable in vitro for extended time periods before transfer to the recipient. We have maintained isolated pancreatic islets obtained from the human cadaveric pancreas in tissue culture for 1-3 wk, after which we studied the structure and function of the islets. Electron micrographs of the cultured islets showed a satisfactory preservation of both beta-cells and alpha 2-cells. After culture for 1 wk, the islet oxygen uptake proceeded at a constant rate at a low glucose concentration (3.3 mM) and was significantly enhanced by raising the glucose concentration to 16.7 mM. Likewise, after culture for 1 wk, the islets responded with an increased insulin release when exposed to 16.7 mM glucose with or without added theophylline (10 mM). Islets cultured for 1-3 wk were able to incorporate [3H]leucine into proinsulin, as judged by gel filtration of acid-alcohol extracts. Glucagon release from the cultured islets was reduced significantly by 16.7 mM glucose alone, but stimulated by glucose (16.7 mM) plus theophylline (10 MM). It is concluded that viable pancreatic islets can be isolated from the pancreas of adult human donors and maintained in tissue culture for at least 1 wk without loss of the specific functions of the alpha 2- and beta-cells. It remains to be established whether such islets will survive and remain functionally competent after transplantation to human recipients.

Culture Techniques↗
PubMed1976

Long-term effects of a low extracellular glucose concentration on glucose metabolism and insulin biosynthesis and release of mouse pancreatic islets maintained in tissue culture.

In order to study the long-term effects of a low extracellular glucose concentration on the metabolism and insulin production of the pancreatic B-cells a tissue culture system was applied in which isolated mouse pancreatic islets were maintained for 1 week in vitro at a glucose concentration of 0.6 mg/ml. Short-term experiments at the end of the culture period showed that both the oxygen uptake and the glucose oxidation were depressed but could be stimulated by increasing the glucose concentration of the incubation medium. Although incorporation of [3H]leucine into proinsulin and insulin was markedly depressed it could still be enhanced by increasing the glucose concentration of the incubation medium. By contrast, the insulin release could not be stimulated with glucose alone but with glucose plus theophylline a subnormal stimulation was achieved. The insulin response to glucose was, however, maintained when the glucose concentration of the culture medium was equal to or above 0.75 mg/ml. Similarly, the glucose sensitivity of the low-glucose cultured B-cells could be restored by raising the glucose concentration of the culture medium to 1.1 or 3.0 mg/ml during the last 2 days of culture. The results suggest that the insulin biosynthesis remains sensitive to glucose even when islets have been previously exposed to a low-glucose concentration for a prolonged period of time. The observations also support the view that the impaired insulin release in response to glucose observed during fasting reflects a lack of glycaemic stimulus to the B-cell.

Animals↗
PubMed1976

Morphology of experimental, organ-specific insulitis of the mouse pancreas.

The morphologic and metabolic effect of a single intracutaneous injection of homologous endocrine pancreas in Freund's complete adjuvant (CFA) was studied in 100 mice and compared with control groups which had been (1) immunized with murine insulin in CFA, (2) injected with CFA alone, or had (3) received no treatment. There were no differences between the control groups as regards the morphology of the pancreatic islets, and the glucose tolerance was normal. Mice immunized with islet homogenate exhibited morphological changes in the form of degranulation and cytoplasmic disintegration. These changes involved B-cells as well as A2-cells and were present from 7 to 18 days after the immunization. A significant reduction in glucose tolerance was observed 14 days after the immunization. Another characteristic finding in the islets from the immunized mice was the extra-vascular presence of mononuclear, agranular cells which on the basis of their morphological criteria appeared to represent lymphocytes.

Animals↗
PubMed1976

Regeneration of islet cells.

The number of functionally intact B-cells in the islet organ is of decisive importance for the development, course and outcome of diabetes mellitus. Generally speaking, the total B-cell mass reflects the balance between the renewal and loss of these cells. While factors resulting in damage and degeneration of the B-cells have attracted much attention there has been relatively little interest in the kinetics and regulation of B-cell proliferation. This paper briefly reviews the literature in the latter field with special attention to B-cell renewal in various kinds of diabetes. In early fetal life both the endocrine and exocrine pancreatic cells probably arise from a common "protodifferentiated" cell type. The islets subsequently grow according to a regular pattern characterized by a symmetrical distribution of the islet volume in relation to islet diameter. The growth of the islets reflects the replication of both B-, A1- and A2-cells in individual islets. Whether new islet cells are derived also from duct epithelium or by transformation of differentiated acinar cells remains a matter of controversy. The ability of the differentiated B-cell to replicate in adult life has been confirmed in many studies. Factors believed to increase the rate of replication in vivo include a high caloric intake, hypoglycemic sulfonylureas, various hormones and hyperglycemia. Recent studies in vitro have so far confirmed the mitogenic action of a high extracellular glucose concentration. The renewal of B-cells in diabetes has been studied in several animal models. Both in experimental diabetes, such as that induced by alloxan, and in hereditary diabetes, exemplified by the diabetic mutant mouse (gene symbol db), there is initial stimulation of the mitotic rate during development of hyperglycemia followed by a notable decrease in the B-cell renewal. In the diabetic mouse the decreased proliferation of B-cells is paralleled by the appearance of fulminant diabetes. These and other data suggest a limited capacity for B-cell proliferation, which may differ between species. According to this hypothesis, there is an increased risk of developing diabetes once the predetermined potential for B-cell division has been exhausted.

Animals↗
PubMed1975

Function of the pancreatic B-cell during the development of hyperglycaemia in mice homozygous for the mutations "diabetes" (db) and "misty" (m).

The function of the pancreatic B-cell was studied in relation to the development of the diabetic syndrome in a new variety of the diabetic mutant mouse, which was produced at The Jackson Laboratory, Bar Harbor, Maine, U.S.A. by outcrossing of a c57bl/ksJ-db stock with C57BL/6J mice. The expression of the db-gene in the resulting strain was evaluated by measurements of the body weights and the concentrations of serum glucose and serum insulin at different ages of the animals. In the diabetic mice the body weights increased rapidly between 5 and 25 weeks of age to a weight twice that of the lean controls. During the same time hyperglycaemia and hyperinsulinaemia occurred, the maximal serum glucose and insulin values being observed between 17 and 25 weeks of age. Later on the serum glucose and serum insulin concentrations gradually decreased. Islets were isolated with collagenase from animals 5, 10 or 20 weeks old, and studied with respect to insulin content, glucose oxidation and the secretion and synthesis of insulin. The results were compared with data from control experiments with islets isolated from non-diabetic littermates. No major differences were found between islets from diabetic and control mice with regard to the glucose oxidation rate, whereas an exaggerated insulin response to glucose was observed in islets from 5 weeks old diabetic mice. In the 20 weeks old diabetic animals there was a significantly decreased islet insulin content and a considerably lowered insulin biosynthesis.

Age Factors↗
PubMed1975

Diabetogenic effects of n-nitrosomethylurea in the chinese hamster.

To evaluate the role of the glucose residue of the diabetogenic substance streptozotocin, the effect of its aglucone derivate N-nitrosomethylurea was tested in Chinese hamsters. At a dose of 50 mg/kg body weight of N-nitrosomethylurea a triphasic blood glucose curve was recorded with an initial hyperglycaemic peak after 3 hours followed by a decrease at 6 hours. After 24 hours and during the following days the values were moderately elevated. There was a high mortality in the diabetic animals, about 80 per cent of them dying within one week. The approximate L.D. 50 of N-nitrosomethylurea injected intraperitoneally in non-fasting adult animals was about 125 mg/kg body weight at an observation time of 48 hours. On light microscopy, degenerative changes with nuclear pyknosis were seen after 3 hours in the pancreatic islet cells, followed by cellular disintegration. Both beta-, alpha2- and alpha1-cells were obviously affected. Pretreatment with 500 mg nicotinamide/kg body weight given intraperitoneally 10 minutes before the injection of N-nitrosomethylurea inhibited and hyperglycaemia and seemed to prevent the injurious effects of N-nitrosomethylurea on the islet cells. The results show that the glucose residue of the streptozotocin molecule is not necessary for the induction of diabetes in Chinese hamsters, but it seems to increase the selectivity of the toxic effects for the islet cells. This is a clear advantage in studies of experimental diabetes, especially when longer observation periods are desired.

Animals↗
PubMed1974

Cytotoxic effects of streptozotocin and N-nitrosomethylurea on the pancreatic B cells with special regard to the role of nicotinamide-adenine dinucleotide.

The effects on the pancreatic B cell of streptozotocin and its aglucone derivative N-nitrosomethylurea were investigated in obese-hyperglycaemic mice and their lean littermates. Both streptozotocin and N-nitrosomethylurea were found to be B-cytotoxic although N-nitrosomethylurea produced less islet damage. Both substances decreased the concentrations of NAD(+) in the islet cells to about 10% of the control values within 2h after injection. This NAD(+) depletion was prevented by injection of nicotinamide 10min after the administration of streptozotocin or N-nitrosomethylurea. In islets taken from animals 10min after injection of streptozotocin or N-nitrosomethylurea there was no stimulatory effect of glucose on the respiration or insulin release and the oxidation of glucose was markedly decreased. Addition of nicotinamide (10mm) to the incubated islets restored glucose stimulation of both the oxygen consumption and insulin release. It is concluded that islet NAD(+) depletion is probably important for the B-cytotoxin action of N-nitrosomethylurea and streptozotocin. The glucose residue in the streptozotocin molecule may potentiate the B-cytotoxic action of this drug in mice.

Adenosine Triphosphate↗