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S Sandler

Publications and source records attributed to S Sandler.

At least 91 records · Page 5Linked to original sources
PubMed1993

Nicotinamide and dexamethasone inhibit interleukin-1-induced nitric oxide production by RINm5F cells without decreasing messenger ribonucleic acid expression for nitric oxide synthase.

Nitric oxide (NO) generation may be a final common pathway for beta-cell damage in early insulin-dependent diabetes mellitus. Insulin-producing cells express an inducible form of NO synthase (iNOS), which is similar to that observed in activated macrophages. Induction of iNOS mRNA in these cells depends on protein synthesis. To further characterize the regulation of iNOS induction in insulin-producing cells, RINm5F cells (RIN cells) were exposed for 6 h to human recombinant interleukin-1 beta (rIL-1 beta; 1 ng/ml) alone or in combination with either nicotinamide (10, 20, or 50 mM) or dexamethasone (1 or 5 microM). These agents have been previously shown to prevent activation of iNOS in macrophages, fibroblasts, and hepatocytes. rIL-1 beta induced the expression of iNOS mRNA in RIN cells and a 12- to 13-fold increase in medium nitrite accumulation, the latter indicating NO production. Nicotinamide decreased nitrite production in a dose-dependent way. Thus, 10 mM nicotinamide decreased rIL-1 beta-induced nitrite formation by 30%, 20 mM by 60%, and 50 mM by 90%. The highest concentration of nicotinamide also prevented rIL-1 beta-induced iNOS mRNA, an effect associated with inhibition of total protein biosynthesis. However, 10 or 20 mM nicotinamide did not modify rIL-1 beta-induced iNOS mRNA expression or inhibit protein biosynthesis. Dexamethasone also decreased rIL-1 beta-induced nitrite production without affecting iNOS mRNA expression. As a whole, these data suggest that both nicotinamide and dexamethasone may prevent NO accumulation in insulin-producing cells by posttranscriptional mechanisms. It is also possible that these drugs induce direct inhibition of iNOS enzymatic activity and/or scavenge NO. Higher concentrations of nicotinamide might also inhibit iNOS mRNA expression, possibly by blocking protein biosynthesis.

Amino Acid Oxidoreductases↗
PubMed1993

Effects of nicotinamide supplementation on human pancreatic islet function in tissue culture.

Nicotinamide currently attracts considerable interest as a compound that might prevent the development of human insulin-dependent diabetes mellitus. The present study investigated the direct actions of nicotinamide on human pancreatic beta-cells. For this purpose, islets were isolated from 11 adult cadaveric donors. The human islets were subsequently precultured in RPMI-1640 (5.6 mmol/L glucose) and 10% fetal calf serum for 3-4 days. The islets were cultured for another 6 days in the same medium in either the presence or absence of 10 mmol/L nicotinamide, and subsequently, islet function was examined. After culture, both groups of islets contained similar amounts of DNA, and DNA synthesis, determined by the tritiated thymidine incorporation rate, was unchanged. The insulin content both on a per islet basis and per DNA was similar in both groups as was the islet glucose oxidation rate. Insulin accumulation into the culture medium was sustained over the entire culture period and did not differ at any time point between the nicotinamide and the control group. Nicotinamide affected neither basal and glucose-stimulated insulin secretion nor (pro)insulin and total protein biosynthesis rates after culture. The insulin response to glucose of the human islets was about 5-fold. In conclusion, the present study shows that nicotinamide does not directly affect human beta-cell function or the cell replicatory rate. This would suggest that any potential beneficial effects observed after treatment with nicotinamide in patients with insulin-dependent diabetes mellitus may not necessarily reflect an action at the beta-cell level.

Adolescent↗
PubMed1993

Lack of long-term beta-cell glucotoxicity in vitro in pancreatic islets isolated from two mouse strains (C57BL/6J; C57BL/KsJ) with different sensitivities of the beta-cells to hyperglycaemia in vivo.

Previous studies have shown that 4 weeks after syngeneic transplantation of a suboptimal number of islets into either C57BL/6J (BL/6J) or C57BL/KsJ (BL/KsJ) diabetic mice there is an impaired insulin secretion by the perfused grafts. After normalization of the blood glucose level with a second islet graft, the BL/6J strain showed restored insulin secretion whilst that of the BL/KsJ strain remained impaired. The aim of the present work was to study the effects of glucose on the in-vitro function of islet beta-cells from these two mouse strains, with different sensitivities of their beta-cells to glucose in vivo. Isolated pancreatic islets from each strain were kept for 1 week in tissue culture at 5.6, 11, 28 or 56 mmol glucose/l and were subsequently analysed with regard to insulin release, (pro)-insulin and total protein biosynthesis, insulin, DNA and insulin mRNA contents and glucose metabolism. Islets from both strains cultured at 28 or 56 mmol glucose/l showed an increased accumulation of insulin in the culture medium and an enhanced glucose-stimulated insulin release compared with corresponding control islets cultured at 11 mmol glucose/l. After culture at either 5.6 or 56 mmol/l, rates of (pro)insulin biosynthesis were decreased in BL/KsJ islets in short-term incubations at 17 mmol glucose/l, whereas islets cultured at 56 mmol glucose/l showed a marked increase at 1.7 mmol glucose/l. In BL/6J islets, the (pro)insulin biosynthesis rates were similar to those of the BL/KsJ islets with one exception, namely that no decrease was observed at 56 mmol glucose/l. Islets of both strains showed a decreased insulin content after culture with 56 mmol glucose/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Repair of pancreatic beta-cells. A relevant phenomenon in early IDDM?

Most studies dealing with the pathogenesis of IDDM have emphasized the immune assault against beta-cells. In this perspective, we review the data that suggest that the beta-cell destruction of IDDM depends on a balance between beta-cell damage and repair. The progressive beta-cell damage leading to IDDM seems to follow markedly different temporal courses in individual patients. Some individuals at high risk for developing IDDM, and presenting with impaired beta-cell function, appear to recover beta-cell function when followed prospectively. Moreover, after the clinical onset of IDDM, most patients experience a transitory period of improved insulin secretion. In vitro and in vivo experimental data suggest that beta-cells are indeed able to repair themselves after damage. Dispersed beta-cells or whole islets can survive and regain their function after a toxic assault. Furthermore, the abnormal insulin release and glucose oxidation of islets isolated from NOD mice during the prediabetic period is completely restored after 1 wk in tissue culture. Finally, treatment of NOD mice with monoclonal antibodies directed against infiltrating T-cells reverses the altered glucose metabolism of beta-cells. Note that beta-cell repair after exposure to different toxic agents can be enhanced both in vivo and in vitro. Potential enhancers of beta-cell repair are nicotinamide, glucose, protein-rich diets, and branched chain amino acids. A basic question that remains to be answered is the nature of the repair mechanisms triggered by beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Treatment with an interleukin-1 receptor antagonist protein prolongs mouse islet allograft survival.

An interleukin-1 receptor antagonist protein was evaluated with regard to its efficacy in allogeneic and xenogeneic islet transplantation. Alloxan-induced diabetic C57BL/6 (H-2b) mice were transplanted under the kidney capsule with 500 C57BL/Ks (H-2d) mouse islets. Alzet osmotic pumps, which release their content over an 11- to 13-day period, were implanted subcutaneously for continuous infusion of interleukin-1 receptor antagonist protein (1.0, 5.0, 8.0 mg.kg-1 x day-1) or phosphate-buffered saline. Blood glucose determinations were performed every second or third day; at death, the islet-bearing kidneys were morphologically evaluated. Mice treated initially with the higher interleukin-1 receptor antagonist protein concentrations were followed for an additional period after cessation of the drug release to evaluate whether a transitory interleukin-1 receptor antagonist protein treatment would induce tolerance to the graft. All phosphate-buffered saline-treated mice were hyperglycemic 11 days after islet allotransplantation. Most of their grafts were heavily infiltrated with mononuclear cells. In the various interleukin-1 receptor antagonist protein-treated groups, 60-80% of the mice were normoglycemic after 11 days. Moreover, light microscopic examinations showed that most mice treated with interleukin-1 receptor antagonist protein had normal islet grafts or grafts infiltrated with only a few mononuclear cells. After interruption of interleukin-1 receptor antagonist protein infusion (8.0 mg.kg-1 x day-1), all animals developed hyperglycemia within 2-9 days. In xenogeneic experiments, 500-750 fetal porcine islet-like cell clusters were transplanted under the kidney capsule of normoglycemic C57BL/6 mice. These animals were treated either with interleukin-1 receptor antagonist protein (8.0 mg.kg-1 x day-1) or phosphate-buffered saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

In vitro screening of putative compounds inducing fetal porcine pancreatic beta-cell differentiation: implications for cell transplantation in insulin-dependent diabetes mellitus.

Successful transplantation of fetal pancreatic beta-cells to diabetic recipients requires that differentiation of the immature beta-cells is achieved. Animal experiments have shown that this can occur in vivo, but it would be desirable to induce beta-cell maturation in vitro prior to transplantation. For that purpose the effect of several putative inducers of beta-cell differentiation and/or replication in explant cultures of fetal porcine pancreatic islet-like cell clusters (ICC) were investigated. Initial screening experiments indicated that dexamethasone (DEX; 200 ng/ml) and sodium butyrate (BUT; 2 mM) might promote beta-cell differentiation as evidenced by increased insulin/DNA contents in the ICC. In subsequent experiments these two substances, and also nicotinamide (NIC; 10 mM) which previously has been found to promote fetal beta-cell differentiation, were added alone or in combinations to the basal control medium consisting of RPMI 1640 + 1% human serum. All three test agents alone or in combinations increased the insulin content/DNA of the ICC compared with that of the control group. The combination of NIC+DEX increased the insulin mRNA levels of the ICC. No significant stimulation of insulin release was observed in any test group after short-term incubation with high glucose alone. Addition of 5 mM theophylline to high glucose stimulation, however, increased the insulin secretion in most groups of ICC. Finally, ICC in groups of about 600, which had developed in the presence of NIC or NIC+DEX, were transplanted under the kidney capsule of alloxan-diabetic nude mice. However, neither the time for reversal of diabetes (4 weeks) nor the amount of insulin secretion during perfusion from the grafted ICC were further affected by adding DEX to the NIC supplemented medium. The marked increase of the insulin content of the ICC cultured with DEX supplementation, appeared transient and was not manifested after transplantation. In conclusion, the present study demonstrated that some compounds can stimulate porcine fetal beta-cells in an in vitro system, but in order to attain terminal differentiation of the beta-cells including glucose-sensitive insulin secretion, longer observation periods might be required than used herein. Alternatively, an in vivo environment like that after transplantation is mandatory for this process.

Animals↗
PubMed1993

Aminoguanidine, an inhibitor of nitric oxide formation, fails to protect against insulitis and hyperglycemia induced by multiple low dose streptozotocin injections in mice.

It has been suggested that pancreatic beta-cell destruction occurring during the process leading to insulin-dependent diabetes mellitus (IDDM) involves formation of nitric oxide (NO). We have presently studied the effect of aminoguanidine (AG), which has recently been reported to inhibit generation of NO induced by the cytokine interleukin-1 beta. AG currently counteracted IL-1 beta induced impairment of the glucose oxidation rate in rat pancreatic islets. Then we studied the effect of AG on the development of hyperglycemia and pancreatic insulitis in mice treated with multiple low dose injections of streptozotocin (40 mg/kg body-weight for five consecutive days). It was found that one daily intraperitoneal injection of AG (50 mg/kg body-weight) for 14 days failed to prevent the development of diabetes as well as insulitis following the streptozotocin injections. Furthermore, the mice treated with streptozotocin plus AG showed an increased mortality compared to mice treated with streptozotocin plus saline. Although the present data do not exclude a role for NO in IDDM, it raises concerns about the use of testing AG as therapeutic agent in IDDM.

Animals↗
PubMed1993

Pretreatment of fetal porcine pancreas in culture with nicotinamide accelerates reversal of diabetes after transplantation to nude mice.

Successful transplantation of fetal pancreatic beta-cells to recipients with diabetes requires that differentiation of the immature beta-cells is induced. In this study isletlike cell clusters (ICC) were produced from fetal porcine pancreas in tissue culture, in medium RPMI-1640 supplemented with 10% human serum and in the presence or absence of 10 mmol/L nicotinamide. Light microscopy of immunostained ICC on day 4 of culture showed that nicotinamide caused a more than doubling in the frequency of insulin-positive cells, whereas no stimulatory effect by nicotinamide on DNA replication was found. Transplantation of ICC into nude mice with alloxan diabetes revealed that ICC formed in nicotinamide normalized the hyperglycemia faster than did control ICC (3 to 4 weeks compared with 6 to 8 weeks). The DNA content of the transplanted ICC increased two to three times over an 8-week period, whereas the insulin content increased 100-fold. The total insulin, total DNA content, and the insulin concentration of the grafts were significantly higher in the nicotinamide grafts in comparison with control grafts. In fact, the insulin concentration in the nicotinamide grafts was almost identical to that normally observed in fully differentiated mouse islets. Furthermore, perfusion in vitro of the graft-bearing kidneys 18 weeks after transplantation showed that the total amount of insulin released from the nicotinamide grafts on stimulation with glucose was more than five times higher than the amount from the control grafts. The perfusion of grafts from the nicotinamide group revealed a marked biphasic insulin response to glucose, which was less obvious in the control grafts. We conclude that nicotinamide induces beta-cell differentiation in porcine ICC and that this effect is beneficial when such explants are used for transplantation to recipients with diabetes.

Alloxan↗
PubMed1992

Interleukin-1 beta induces nitric oxide production and inhibits the activity of aconitase without decreasing glucose oxidation rates in isolated mouse pancreatic islets.

The aim of this investigation was to further characterize the process of interleukin-1 beta (IL-1 beta) induced nitric oxide production in isolated pancreatic islets. It was found that both IL-1 beta and nitroprusside increased islet nitrite production. This effect was paralleled by inhibition of islet aconitase activity and glucose oxidation rates. Neither trifluoroperazinen or aminopterin could prevent the IL-1 beta induced increase in nitrite production, aconitase inhibition and decrease in glucose oxidation rates. In a second series of experiments, isolated mouse pancreatic islets were exposed to IL-1 beta for 24 h and subsequently used for nitrite production, aconitase activity and glucose oxidation determinations. The islets responded to IL-1 beta with an increased nitrite production and a decreased activity of aconitase, whereas the islet glucose oxidation rates were not decreased. It is concluded that IL-1 beta in both rat and mouse islets induces nitric oxide formation and that this induction leads to the inhibition of the Krebs cycle enzyme aconitase. In rat islets this probably leads to an inhibited insulin secretion, whereas IL-1 beta in mouse islets suppresses insulin secretion by a non-mitochondrial mechanism.

Aconitate Hydratase↗
PubMed1992

Role of infiltrating T cells for impaired glucose metabolism in pancreatic islets isolated from non-obese diabetic mice.

Pancreatic islets isolated from non-obese diabetic (NOD) mice, all of which have insulitis, exhibit an impaired glucose metabolism. In order to investigate the role of infiltrating lymphocytes for this altered metabolism, we injected 12- to 13-week-old female NOD mice with monoclonal antibodies directed against either the alpha beta-T cell receptor, CD4+ or CD8+ T cells. Control NOD mice were injected with normal rat IgG or with the vehicle (phosphate buffered saline) alone. Injection of the three different monoclonal antibodies markedly reduced the mononuclear cell infiltration. An intravenous glucose tolerance test showed no differences between the groups. Islet insulin release in response to glucose was similar in all groups. In contrast, islets isolated from the control NOD mice with insulitis showed a high basal (1.7 mmol/l glucose) glucose oxidation rate and a small increase in the glucose oxidation rate in response to a high glucose concentration (16.7 mmol/l glucose). The monoclonal antibodies counteracted the elevated basal glucose oxidation rate of the islets. Parallel studies of stimulated mononuclear cells suggested that the contribution of glucose oxidized by islet-infiltrating lymphocytes could only partially explain the observed alterations in NOD mouse islet metabolism. Culture of islets obtained from NOD mice in the presence of the cytokine interleukin-1 beta induced a similar pattern of glucose metabolism as seen earlier in IgG or phosphate-buffered saline treated control NOD mice. In conclusion, alterations in the glucose oxidation rates seem to be an early sign of disturbance in islets isolated from NOD mice. These early alterations in glucose metabolism can be reversed in vivo by monoclonal antibodies directed against effector lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Induction of intercellular adhesion molecule-1 (CD54) on isolated mouse pancreatic beta cells by inflammatory cytokines.

Insulin-dependent diabetes mellitus (IDDM) results from a T cell-dependent autoimmune destruction of insulin-producing pancreatic beta cells. In the present study, expression of adhesion molecule ICAM-1 (CD54) on pancreatic beta cells was studied in normal, obese hyperglycemic (ob/ob), and nonobese diabetic (NOD) mice. Freshly isolated pancreatic beta cells from ob/ob mice did not express ICAM-1, but treatment of the cells with IL-1-beta, TNF-alpha, or INF-gamma strongly induced its expression as measured by immunofluorescence flow cytometry. The cytokines acted in a dose- and time-dependent manner. Maximal induction by either cytokine occurred at 24 hr and thereafter expression decreased, except for INF-gamma. Immunoprecipitation from IL-1-beta-treated beta cells demonstrated a cell-surface glycoprotein with an apparent molecular weight of 95 kDa. ICAM-1 expression was undetectable on pancreatic beta cells of normal and ob/ob mice as measured by immunohistochemistry. In NOD mice at different ages (1 to 6 months) ICAM-1 was also undetectable on beta cells, in contrast to the strong expression on infiltrating mononuclear cells. The present study indicates that mouse pancreatic beta cells, under certain conditions, can express ICAM-1.

Animals↗
PubMed1992

Adaptive response in beta-cell function in pancreatic islets isolated from partially pancreatectomized rats.

Before clinical onset of insulin-dependent diabetes mellitus a decreasing pancreatic beta-cell mass maintains glucose homeostasis. We currently aimed to study the function of pancreatic islets isolated 2 weeks after a 60% partial pancreatectomy (P) or after a sham operation (S) on adult rats. Experiments on the islets were subsequently performed acutely (day 0) and after 1 week (day 7) of tissue culture in medium RPMI 1640 (11.1 mM glucose) + 10% calf serum. There was no difference in the body weight 2 weeks after surgery. The pancreatic remnant weight of the P rats was 35% less than the pancreatic weight in the S rats. The islet DNA content was 25% higher in the islets of the P rats on day 0, indicating a stimulated islet growth. However, this difference did not remain after culture for 7 days. Islet proinsulin mRNA content and (pro)insulin biosynthesis rates were slightly increased in the islets of P rats on day 0, which could be due to the increased islet mass. The islet insulin content was not different on day 0, but was higher after culture in the islets of the P rats. The islet rates of glucose oxidation and insulin release were markedly higher in the P rats on day 0, suggesting a selective effect on these processes. A higher glucose oxidation rate was, however, not evident on day 7. The relative fraction of insulin-positive cells was slightly lowered in the islets of the P rats on day 0.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1992

Dissociation between the blood flow response of transplanted pancreatic islets and that of the implantation organ.

The aim of this study was to investigate if the blood flow of transplanted islets is affected by the implantation organ or regulated by the grafted islets themselves. For this purpose adult rats were partially depancreatized and islets were isolated from the excised pancreatic tissue, maintained in tissue culture for 7 days, and subsequently 500 islets were implanted into the same animal beneath the renal capsule. Four weeks after transplantation, the rats were given an i.v. injection of either saline or furosemide (7.5 mg/kg body weight). Fifteen minutes later the blood perfusion of the whole left kidney and its islet grafts were measured separately with a microsphere technique. Also, the blood flow values of the pancreatic remnant were determined. Rats that were partially pancreatectomized and transplanted showed a decreased whole pancreatic blood flow in the pancreatic remnant after furosemide injection, whereas the blood flow to the islets was not significantly affected. Furosemide also increased the blood flow to the kidney but had no effect on the blood perfusion of the pancreatic islets grafted into the same kidney. These results suggest that the blood flow of an islet graft does not necessarily change in concert with the blood flow of the implantation organ. This may reflect differences in the blood flow regulation between the grafted islets and the implantation organ. In addition, it could be that the vascular system developing in the transplanted islets originates from either the islets or the kidney capsule, rather than from the kidney parenchyma. This may account for a different blood flow regulation.

Animals↗
PubMed1992

Alloxan, but not streptozotocin, increases blood perfusion of pancreatic islets in rats.

It has recently been shown that selective B-cell toxins alloxan and streptozotocin (STZ) possess marked effects also on the vascular system. To evaluate to what extent changes in blood perfusion of islets induced by alloxan or STZ could be of importance for diabetogenic action of these compounds, we first investigated acute effects of alloxan (75 mg/kg body wt iv) and STZ (40 mg/kg body wt iv) on both whole pancreatic blood flow (PBF) and islet blood flow (IBF) in adult rats. Alloxan caused a marked increase in IBF, which was most pronounced 3 min after administration and remained for 30 min. PBF, however, was decreased 3 min after alloxan administration but was similar to that of control animals from 10 min and onward. These two opposite effects on IBF and PBF caused the fraction of whole PBF diverted through islets to increase from approximately 10 to 50%. Pretreatment with glucose (2 g/kg body wt iv), indomethacin (3.5 mg/kg body wt iv), dimethyl sulfoxide (10 ml/kg body wt ip of a 33% solution), superoxide dismutase (SOD, 1,000 kU/kg body wt iv), NG-methyl-L-arginine (30 mg/kg body wt iv), theophylline (7 mg/kg body wt iv), or terbutaline (1 mg/kg body wt iv) failed to affect stimulation of IBF by alloxan observed at 3 min. SOD was found to exert a marked stimulation of IBF both when given alone and together with alloxan. Alloxan increased IBF and decreased PBF also in a syngeneic pancreaticoduodenal graft in rats but did not affect flow distribution in a perfused pancreas-duodenum preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Alloxan↗
PubMed1992

Interleukin-1 beta increases the activity of superoxide dismutase in rat pancreatic islets.

The suppressive effects of interleukin-1 beta (IL-1 beta) on the function of pancreatic islets may be related to induction of gene transcription and protein synthesis. Presently, the effects of human recombinant IL-1 beta (rIL-1 beta) on the activities of superoxide dismutase (SOD) and the expression of corresponding genes were studied in rat pancreatic islets. Islets that were exposed to rIL-1 beta for 48 h showed a 2.6-fold greater activity of mitochondrial manganese containing SOD (MnSOD) than control islets. The cytosolic copper- and zinc-containing SOD (CuZnSOD) was, however, less affected by rIL-1 beta. Also, brief exposure of the islets to rIL-beta induced an increase in SOD activities. Hence, 12 h after a 1-h exposure of the islets to rIL-1 beta, there was a 1.4-fold increase in the activity of both MnSOD and CuZnSOD. The early induction of SOD by rIL-1 beta was inhibited by an interleukin-1 receptor antagonist protein and actinomycin-D, which is a blocker of gene transcription. This suggests that the effects of rIL-1 beta on the islet SOD activities are dependent on binding to membrane receptors and activation of gene transcription. Northern blot analysis showed a 4-fold increase in islet MnSOD mRNA content after a 90-min incubation and a 10-fold increase after a 180-min incubation with rIL-1 beta. Thus, the enhanced MnSOD activity in the islets reflects increased gene expression. To evaluate a possible role for free oxygen radicals as mediators of the early action of rIL-1 beta on the pancreatic B-cells, isolated islets were exposed to rIL-1 beta only or to rIL-1 beta plus various free radical scavengers. None of the scavengers, single or in combinations, could counteract the suppressive action of rIL-1 beta on islet insulin secretion. The present data suggest that rIL-1 beta induces increased activity of SOD, in particular MnSOD, in pancreatic islets. This may be due to a direct action of rIL-1 beta that is mediated by an increase in gene transcription.

Actins↗
PubMed1992

Protection against hyperglycemia in female nonobese diabetic mice treated with 15-deoxyspergualin.

The effects of 15-deoxyspergualin (15-DS), a newly described immunosuppressive agent, have been studied on the development of diabetes in female NOD mice. 15-DS treatment was started two weeks after weaning i.e. at five weeks of age. The mice received either one daily intraperitoneal injection of 15-DS (2.5 mg/kg body weight) or saline for two weeks. The mice were then injected every third day up to eight months of age for evaluation of the diabetes incidence. In another set of experiments the mice were treated up to three months of age, whereafter islet insulin release, islet insulin content and DNA content was measured together with an evaluation of spleen cell proliferation rates. Different spleen cell subsets were studied directly after the two weeks of daily injections. In the saline group 8 out of 9 mice developed diabetes, whereas only 4 out of 11 of the 15-DS treated mice became diabetic (p < 0.05). There was no difference between the groups in islet insulin release in response to glucose, however, the islet insulin release increased after one week in culture. The 15-DS treatment did not affect the insulin or DNA content of the isolated islets or the insulin concentration in the pancreas. No detectable changes in the relative number of CD4+ and CD8+ T-cell subsets in the spleen were seen and there were no obvious differences in splenocyte proliferation rates. The histological examinations of the pancreatic glands showed gradual increasing signs of islet inflammation with age and 15-DS could apparently not prevent this.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗