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D L Eizirik

Publications and source records attributed to D L Eizirik.

At least 19 recordsLinked to original sources
PubMed1999

Contribution of ductal cells to cytokine responses by human pancreatic islets.

In type 1 diabetes, autoimmune destruction of pancreatic beta-cells has been attributed to cytokines released from infiltrating immunocytes. Exposure of isolated islets to cytokines leads to nitric oxide (NO) production, which can damage beta-cells. Because ductal cells are closely associated with human beta-cells, we examined whether they can contribute to this process. Isolated human ductal cells were cultured for 48 h with various cytokines. The combination of interleukin-1beta (IL-1beta) plus interferon-gamma (IFN-gamma) increased nitric oxide production 12-fold while stimulating mRNA expression of inducible nitric oxide synthase (iNOS). In this condition, 10-20% of cells positive for the cytokeratin-19 duct marker also stained positive for iNOS protein, whereas no positive cells were found in control preparations. Comparison of the magnitude of iNOS mRNA expression and nitric oxide production in these cells with that in isolated human islets suggests that >50% of total islet nitric oxide production might originate from associated ductal cells. It is concluded that ductal cells are a potential source of nitric oxide production in human islets infiltrated by cytokine-releasing immunocytes.

Adolescent↗
PubMed1999

Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes.

Nitric oxide (NO), synthesized by the inducible isoform of nitric oxide synthase (iNOS), has been proposed as a mediator of immune-induced beta-cell destruction in type 1 diabetes. To evaluate the role of iNOS for beta-cell dysfunction and death, we investigated the sensitivity of beta-cells from mice genetically deficient in this enzyme (iNOS-/-, background C57BL/6x129SvEv, H-2b) both to interleukin (IL)-1beta-induced beta-cell dysfunction in vitro and to multiple low-dose streptozotocin (MLDS)-induced diabetes in vivo. Exposure of islets isolated from C57BL/6 mice to IL-1beta for 24 h in vitro resulted in an induction of iNOS mRNA expression, an increase in nitrite formation, and a decrease in insulin release and proinsulin biosynthesis as compared with untreated C57BL/6 islets. IL-1beta failed to induce iNOS mRNA expression and increase nitrite formation by islets isolated from iNOS knockout mice (iNOS-/-), and no impairment in islet function was observed. The iNOS-/- mice showed a reduced incidence of hyperglycemia after treatment with MLDS as compared with wild-type C57BL/6 (H-2b) and 129 SvEv (H-2b) mice. On day 21 after the first streptozotocin (STZ) injection, 75% of the C57BL/6 mice and 100% of the 129SvEv mice had blood glucose levels >11 mmol/l, whereas the corresponding number for iNOS-/- mice was only 23%. This protection was not due to a delay in the onset of hyperglycemia, since no increase in number of hyperglycemic iNOS-/- mice was observed when the animals were followed up to 42 days. Moreover, islets isolated from iNOS-/- mice were susceptible to the in vitro deleterious effects of STZ. In conclusion, the present study provides evidence that iNOS may contribute to beta-cell damage after exposure to IL-1beta in vitro and treatment with MLDS in vivo.

Animals↗
PubMed1998

Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells.

Cytokines could contribute to beta-cell damage in Type I diabetes mellitus. The radical nitric oxide, generated by the inducible form of nitric oxide synthase (iNOS), is a potential mediator of cytokine-induced beta-cell dysfunction. In rat pancreatic islets and insulin-producing cell lines, interleukin-1beta (IL-1beta) induces expression of iNOS mRNA and increases NO production, an effect potentiated by interferon-gamma (IFN-gamma). In human islet cells both IL-1beta and IFN-gamma are required for iNOS expression. We have shown previously that both the transcription factors nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor-1 (IRF-1) are activated by cytokines in rodent and human islets but there is no direct information on the regulation of the iNOS promoter in insulin-producing cells. We presently investigated the effects of cytokines on iNOS transcriptional regulation in both rat insulin-producing RINm5F cells and in primary FACS-purified rat beta cells. Transient transfection experiments with the 1.5-kb rat promoter region and 5' deletants of it showed that a distal region extending up to -1002 bp, and containing a distal and a proximal nuclear factor-kappaB (NF-kappaB) binding site, a gamma-interferon activated site (GAS) and two adjacent IFN-stimulated response elements (ISRE), is required for IL-1beta induction and IFN-gamma potentiation of iNOS activation. Site-mutation analysis showed that both the distal and proximal NF-kappaB and GAS are necessary for IL-1beta-induced iNOS expression in RINm5F cells. In these cells IFN-gamma potentiation is mostly mediated by GAS and ISRE, suggesting a role for the IFN-gamma-induced transcription factors Stat1alpha (which binds GAS) and IRF-1 (which binds ISRE), which may cooperate with NF-kappaB induced by IL-1beta for iNOS activation. In primary beta cells both NF-kappaB binding sites are required for IL-1beta-induced iNOS promoter activation. In these cells IFN-gamma neither increased IL-1beta-induced iNOS promoter activity nor iNOS mRNA expression but it induced a twofold increase in NO production. The present results unveiled the nature of the promoter binding sites necessary for iNOS expression in rodent beta cells. This information could be relevant for the development of new strategies aimed at preventing cytokine-induced iNOS expression and consequent beta-cell damage.

Animals↗
PubMed1998

Intercellular differences in interleukin 1beta-induced suppression of insulin synthesis and stimulation of noninsulin protein synthesis by rat pancreatic beta-cells.

The normal pancreatic beta-cell population exhibits intercellular differences in its responsiveness to glucose. This cellular heterogeneity allows glucose to regulate, in a dose-dependent manner, total rates of insulin synthesis and release. It may also predispose to intercellular differences in susceptibility to dysregulating agents. The present study examines whether this is the case for interleukin 1beta (IL-1beta), which is known to suppress glucose-induced insulin synthesis and release. The effects of the cytokine were compared on beta-cell subpopulations with, respectively, high and low sensitivity to glucose. These subpopulations were separated on the basis of differences in the cellular metabolic responsiveness to an intermediate glucose concentration (7.5 mmol/liter) and then cultured for 20 h at 5 or 20 mmol/liter with or without IL-1beta. The suppressive action of IL-1beta (0.1 ng/ml) occurred predominantly in glucose-activated beta cells, reducing their high rates of insulin synthesis and release by more than 80%. Glucose-unresponsive cells became subject to a similar inhibition after their activation during culture at 20 mmol/liter glucose. On the other hand, IL-1beta induced or enhanced the expression of several noninsulin proteins in both subpopulations. The IL-1beta-stimulated expression of inducible nitric oxide synthase (iNOS) and heat shock protein 70 was more marked in the glucose-responsive subpopulation; that of heme oxygenase and Mn superoxide dismutase was comparable in the two subpopulations. Exposure to IL-1beta resulted in 10-fold higher medium nitrite levels in both subpopulations; this effect was prevented by the iNOS blocker, N(G)-methyl-L-arginine, which also prevented the IL-1beta-induced suppression in the glucose-responsive subpopulation. This study demonstrates that the cellular heterogeneity in glucose responsiveness predisposes to intercellular differences in the IL-1-induced suppression of insulin synthesis and release. While the cytokine induces the expression of noninsulin proteins such as iNOS in both glucose responsive and unresponsive cells, the subsequent nitric oxide production appears to predominantly affect glucose-stimulated functions in the glucose-activated cells.

Animals↗
PubMed1997

Assessment of insulin secretion in vitro from microencapsulated fetal porcine islet-like cell clusters and rat, mouse, and human pancreatic islets.

BACKGROUND: The possibility of transplanting microencapsulated pancreatic islets into patients with insulin-dependent diabetes mellitus, either as allografts or xenografts, has attracted great interest. A critical evaluation of the results obtained reveals that the success has been very limited. The aim of the present study was to compare the in vitro function of microencapsulated islets obtained from adult humans, adult mice, adult rats, and fetal pigs. METHODS: Human pancreatic islets were isolated at beta-Cell Transplant in Brussels, Belgium, and sent to the Department of Medical Cell Biology, Uppsala University in Uppsala, Sweden. Rat and mouse pancreatic islets and fetal porcine islet-like cell clusters (ICC) were prepared in Uppsala. All groups of islets were subsequently sent to the Department of Biotechnology, Norwegian Institute of Biotechnology, University of Trondheim, Trondheim, Norway. After 1 day in tissue culture, the islets were microencapsulated in alginate then cultured and sent back to Uppsala the next day. After either overnight culture (day 1) or 6 days of culture (day 6), the microencapsulated islets were examined for their insulin content and insulin release. Nonencapsulated islets from the same isolations were used as controls. RESULTS: The insulin content of rodent and human islets was not affected by microencapsulation, whereas porcine ICC showed a diminished insulin content. Microencapsulated porcine ICC also had a marked reduction in their insulin secretion in response to stimulation with glucose or glucose + theophylline both on days 1 and 6 in tissue culture. Mouse islets showed a reduced insulin response at both time points. Rat islets exhibited an inhibition of insulin secretion on day 1, but this had been restored by day 6. Human islets had well-preserved insulin secretion after both days 1 and 6. Microencapsulated human islets showed a normal morphology 3-4 weeks after intraperitoneal transplantation to nude mice. CONCLUSIONS: Pancreatic islets isolated from human, rat, and mouse donors show a glucose-stimulated insulin release in vitro after microencapsulation and repeated transports between laboratories. The insulin secretory capacity of microencapsulated human and rat islets was preserved best, whereas mouse islets and particularly fetal porcine ICC were impaired by microencapsulation.

Adult↗
PubMed1997

IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice.

The effect of an IL-1 receptor antagonist on recurrence of hyperglycaemia after syngeneic pancreatic islet transplantation to spontaneously diabetic female NOD mice was investigated. The transplanted animals were treated with either the receptor antagonist (8.0 mg/kg body weight per day for 12-14 days) or PBS, delivered by subcutaneously implanted osmotic pumps. In the control animals, a transient normoglycaemia was achieved, but hyperglycaemia was generally observed 6 days after islet transplantation. Administration of IL-1 receptor antagonist had a clear protective effect against recurrence of hyperglycaemia until day 14, but after cessation of drug delivery hyperglycaemia re-appeared. The results indicate that continuous administration of the IL-1 receptor antagonist can prevent recurrence of the diabetogenic process in NOD mice. IL-1 receptor antagonist may therefore become a useful adjuvant immunomodulating therapy after human islet transplantation in insulin-dependent diabetes mellitus.

Animals↗
PubMed1997

Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells.

We have previously observed that a 6-day exposure of human pancreatic islets to a combination of cytokines (interleukin-1beta 50 U/ml + tumour necrosis factor-alpha 1000 U/ml + interferon-gamma 1000 U/ml) severely impairs beta-cell functions. In the present study, we examined whether this condition affects DNA integrity and viability of human islet cells. Cells were studied after 3, 6, and 9 days of cytokine treatment by both single cell gel electrophoresis (the "comet assay," a sensitive method for detection of DNA strand breaks) and by a cytotoxicity assay using the DNA binding dyes Hoechst 33342 and propidium iodide as indices for the number of viable, necrotic, and apoptotic cells. Cytokine treatment for 6 and 9 days resulted in a 50% increase in comet length (P < 0.01 vs. controls), indicating DNA strand breaks, as well as in a significant increase in the number of apoptotic cells (P < 0.02 vs. controls), but not in the number of necrotic cells. The arginine analogs N(G)-nitro-L-arginine and N(G)-monomethyl-L-arginine prevented nitric oxide formation by the cytokines but did not interfere with cytokine-induced DNA strand breaks and apoptosis. The present data suggest that prolonged (6-9 days) exposure of human pancreatic islets to a mixture of cytokines induces DNA strand breaks and cell death by apoptosis. These deleterious effects of cytokines appear to be independent of nitric oxide generation.

Analysis of Variance↗
PubMed1997

Interferon-gamma-induced interferon regulatory factor-1 (IRF-1) expression in rodent and human islet cells precedes nitric oxide production.

The radical nitric oxide (NO) may be a mediator of beta-cell damage in IDDM. The cytokines IFN-gamma and IL-1beta are required for expression of the enzyme nitric oxide synthase (iNOS), and NO production by human pancreatic islets. In this study, possible mechanisms by which IFN-gamma participates in iNOS messenger RNA (mRNA) expression were evaluated in both rodent and human islets cells. Addition of IFN-gamma, before or after arrest of IL-1beta-induced iNOS gene transcription by actinomycin D, did not prolong iNOS mRNA half life in the rat insulin-producing cell line RINm5F (RIN cells). IFN-gamma also failed to modify IL-1beta-induced activation of the transcription factor kappaB (NF-kappaB) in RIN cells, as determined by electrophoretic mobility shift assay. However, IFN-gamma induced an early (30 min(-1) h) increase in interferon regulatory factor-1 (IRF-1) mRNA expression and a later (2 h) 19-fold increase in RIN cell nuclear IRF-1 protein content, an effect further potentiated by IL-1beta. The total cellular content of IRF-1 protein increased by 30- to 50-fold in human islets exposed for 2-8h to IFN-gamma or IFN-gamma + IL-1beta. IL-1beta alone induced a marginal and transient increase in IRF-1. It has been previously reported that nicotinamide prevents IL-1beta-induced IRF-1 expression in rat pancreatic islets. However, nicotinamide (20 mM) presently failed to prevent IL-1beta + IFN-gamma-induced IRF-1 protein expression in human pancreatic islets. In conclusion, the effects of IFN-gamma on iNOS expression can neither be explained by iNOS mRNA stabilization nor increased NF-kappaB activation. However, IFN-gamma induces an early increase in cellular IRF-1 content, and this may contribute to increased iNOS mRNA expression.

Adolescent↗
PubMed1997

Mechanisms of defective glucose-induced insulin release in human pancreatic islets transplanted to diabetic nude mice.

We have previously observed that human islets, transplanted under the kidney capsule of hyperglycemic nude mice, show a longlasting impairment in glucose-induced insulin release. To investigate the cause(s) of this phenomenon, we transplanted human islets into normoglycemic or alloxan-diabetic nude mice for a 4- to 6-week period. In a third experimental group, aimed at evaluating reversibility of hyperglycemia effects, diabetic nude mice bearing a human islet graft were cured by a second intrasplenic transplant of mouse islets, and the human islets were exposed to a further 2 weeks of normoglycemia. Four to 6 weeks of hyperglycemia induced a severe impairment of glucose- and arginine-induced insulin release, as demonstrated by perfusion of the graft-bearing kidney. This defective release was not restored by a subsequent 2-week period of normoglycemia, and it was accompanied by normal (pro)insulin biosynthesis, glucose oxidation, and expression of insulin messenger RNA. Taken together with our previous study, these observations indicate that impaired glucose metabolism, depletion of insulin messenger RNA, decreased (pro)insulin biosynthesis, increased glycogen accumulation, and depletion of insulin reserves cannot explain the deleterious effects of the diabetic state on human islet insulin release. This, and the similar inhibition of glucose- and arginine-induced insulin release, suggest that prolonged hyperglycemia may exert its deleterious effect on insulin release at a step distal to closure of ATP-sensitive K-channels.

Adult↗
PubMed1996

Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells.

Interleukin-1 (IL-1) may be a mediator of beta-cell damage in insulin-dependent diabetes mellitus (IDDM). The IL-1 mechanism of action on insulin-producing cells probably includes activation of the transcription nuclear factor kappa B (NF-kappa B), increased transcription of the inducible form of nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Reactive oxygen intermediates, particularly H2O2, have been proposed as second messengers for NF-kappa B activation. In the present study, we tested whether ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a glutathione peroxidase mimicking compound, could counteract the effects of IL-1 beta, H2O2 and alloxan in rat pancreatic islets and in the rat insulinoma cell line RINm5F (RIN cells). Some of these experiments were also reproduced in human pancreatic islets. Ebselen (20 microM) prevented the increase in nitrite production by rat islets exposed to IL-1 beta for 6 hr and induced significant protection against the acute inhibitory effects of alloxan or H2O2 exposure, as judged by the preserved glucose oxidation rates. However, ebselen failed to prevent the increase in nitrite production and the decrease in glucose oxidation and insulin release by rat islets exposed to IL-1 beta for 24 hr. Ebselen prevented the increase in nitrite production by human islets exposed for 14 hr to a combination of cytokines (IL-1 beta, tumor necrosis factor-alpha and interferon-gamma). In RIN cells, ebselen counteracted both the expression of iNOS mRNA and the increase in nitrite production induced by 6 hr exposure to IL-beta but failed to block IL-1 beta-induced iNOS expression following 24 hr exposure to the cytokine. Moreover, ebselen did not prevent IL-1 beta-induced NF-kappa B activation. As a whole, these data indicate that ebselen partially counteracts cytokine-induced NOS activation in pancreatic beta-cells, an effect not associated with inhibition of NF-kappa B activation.

Alloxan↗
PubMed1996

Sensitivity of human pancreatic islets to peroxynitrite-induced cell dysfunction and death.

Nitric oxide and peroxynitrite (generated by the reaction of nitric oxide with the superoxide anion) may both be mediators of beta-cell damage in early insulin-dependent diabetes mellitus. We observed that acute exposure of primary cultured human pancreatic islets to peroxynitrite results in a significant decrease in glucose oxidation and islet retrieval. DNA strand breaks in single human and rat islet cells are detectable after acute peroxynitrite exposure, followed by a decrease in islet cell survival after 1 h and 24 h. Cell death appeared to occur via a toxic cell death mechanism (necrosis) rather than apoptosis, as suggested by vital staining and ultrastructural evidence of early membrane and organelle degradation, mitochondrial swelling and loss of matrix. This study demonstrates for the first time that cultured human pancreatic islets are susceptible to the noxious effects of peroxynitrite.

Animals↗
PubMed1996

Potential role of environmental genotoxic agents in diabetes mellitus and neurodegenerative diseases.

Epidemiological data suggest that environmental genotoxins are risk factors for some forms of diabetes mellitus and neurodegenerative diseases. The present commentary focuses on mechanisms involved in genotoxin-induced pancreatic beta-cell and neuronal damage. These two cell types seem to share a similar vulnerability to different forms of DNA damage, and the long-term consequences of repeated genotoxic insults to post-mitotic neurons or slowly proliferating beta-cells remain to be clarified. One intriguing possibility is that genotoxins could act as "slow" toxins in these cells, triggering a cascade of cellular events, which culminates in progressive cell dysfunction and loss. Indeed, exposure to mutagenic nitroso agents such as streptozotocin and cycasin induces long-lasting damage to both beta -cells and neurons. These data on cycasin, a toxin obtained from the cycad plant (Cycas spp.), are of special interest, since this agent may be implicated in both amyotrophic lateral sclerosis/Parkinson dementia complex and diabetes mellitus in the western Pacific area. Future studies are required to sort out the interactions between different genotoxic agents, viral infections, and cellular repair mechanisms on cellular survival and function. Moreover, further epidemiological studies are needed to clarify the role of N-nitrosoureas in diabetes mellitus and neurodegenerative diseases in populations with different genetic backgrounds. Answers to these questions may provide useful information on the pathogenesis of these devastating diseases, and open the possibility for their primary prevention.

Diabetes Mellitus↗
PubMed1996

Cytokines activate the nuclear factor kappa B (NF-kappa B) and induce nitric oxide production in human pancreatic islets.

We studied the ability of cytokines to activate the nuclear transcription factor NF-kappaB in human pancreatic islets and the putative role of NF-kappaB for cytokine-induced NO production. Brief exposure (20 min) of human islets of Langerhans to a combination of interleukin-1beta + interferon-gamma + tumor necrosis factor-alpha induced a 2.6-fold increase in nuclear NF-kappaB activity in gel shift analysis. This increase was prevented by the NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), which also counteracted NO production by human islets exposed for 14 h to the cytokine combination. High concentrations of interleukin-1beta alone (150 and 250 U/ml) increased NF-kappaB nuclear binding but failed to induce NO formation in human islets. The present data are the first to demonstrate that cytokines activate NF-kappaB in primary adult human pancreatic islets and suggest that activation of NF-kappaB may be a necessary but not sufficient signal for cytokine-induced iNOS expression in human islets of Langerhans.

Adolescent↗
PubMed1996

Nitric oxide donors decrease the function and survival of human pancreatic islets.

Nitric oxide (NO) has been proposed as a possible mediator of beta-cell damage in human IDDM. This hypothesis is based on in vitro studies with rodent pancreatic islets. In the present study we examined whether human beta-cells are affected by NO. In view of species differences in beta-cell sensitivity to damaging agents, rat islets were investigated in parallel. Isolated islets were exposed for 90 min to different concentrations of three chemically unrelated NO donors, SIN-1, GSNO or RBS. At the end of this incubation, human insulin release was mostly similar in control and NO-treated islets but, 48 h later, islet retrieval, islet DNA and insulin content, and glucose-induced insulin release were markedly lower in islets exposed to NO donors. Rat islets were already inhibited during the initial 90 min; 48 h later their loss in beta-cell function was similar to that in human islets. Nicotinamide or succinic acid monomethyl ester partially protected against SIN-1 induced islet cell loss, but not against the functional inhibition of human pancreatic islets. Exposure of human or rat islets to RBS was associated with significant DNA strand breakage, as judged by the comet assay (single cell gel electrophoresis) and by ultrastructural signs of cell damage. DNA damage was more severe in rat islet cells exposed to similar amounts of RBS. It is concluded that NO donors can damage human pancreatic islets, an effect paralleled by induction of nuclear DNA strand breaks.

Adolescent↗
PubMed1996

Role of the citrulline-nitric oxide cycle in the functional response of adult human and rodent pancreatic islets to cytokines.

The present study aims to characterize the role of the citrulline-nitric oxide cycle in the response of adult human and rat pancreatic islets to cytokines. Citrulline (0.1-1.0 mM) or arginine (0.1-1.0 mM) led to a similar dose dependent nitric oxide (NO) production by rat islets exposed to interleukin 1 beta (IL-1 beta) or human islets exposed to IL-1 beta + tumour necrosis factor alpha (TNF-alpha) + interferon gamma (IFN-gamma). In the absence of citrulline or arginine cytokines failed to induce NO production. Cytokines induced argininosuccinate synthetase activity in both species. Studies of IL-1 beta exposed rat islets revealed both NO-dependent and NO-independent effects: (1) IL-1 beta inhibits glucose-induced insulin release even in the absence of NO synthesis, but this inhibition is more severe when the presence of citrulline or arginine enables NO production; (2) NO formation in the presence of arginine or citrulline is necessary for cytokine-induced inhibition of protein biosynthesis. In conclusion, the citrulline-NO cycle enables rodent and human islet of Langerhans to regenerate arginine from citrulline and maintain NO production, thus contributing to islet functional inhibition. Considering that arginine availability may be limiting for NO production in vivo, the citrulline-NO cycle may be important for the regulation of NO production during insulitis in early insulin-dependent diabetes mellitus.

Adult↗
PubMed1996

The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells.

The radical nitric oxide (NO) is a possible mediator of pancreatic beta-cell damage in insulin-dependent diabetes mellitus (IDDM). NO is produced by the enzyme nitric oxide synthase (NOS), in a reaction where arginine is the main substrate. There are different isoforms of NOS, but in the context of immune mediated beta-cell damage the inducible form of NOS (iNOS) is the most relevant. The beta-cell iNOS is similar and encoded by the same gene on chromosome 17 as the iNOS expressed in macrophages and other nucleated cells. iNOS activation depends on gene transcription and de novo enzyme synthesis, and NO seems to induce a negative feedback on iNOS expression. While iNOS mRNA is induced by interleukin-1 beta (IL-1 beta) alone in rodent insulin-producing cells, a combination of two (IL-1 beta + interferon gamma) (IFN-gamma) or three (IL-1 beta + IFN gamma + tumour necrosis factor alpha) cytokines is required for iNOS activation in human pancreatic islets. The promoter region of the murine iNOS gene has at least 25 binding sites for different transcription factors, and the nuclear transcription factor kappa B is necessary for cytokine-induced iNOS transcription in both rodent and human pancreatic islets. The nature of other transcription factors relevant for iNOS regulation in these cells remains to be determined. Induction of iNOS is paralleled by induction of several other cytokine-dependent genes in beta cells, including argininosuccinate synthetase, cyclooxygenase and manganese superoxide dismutase. Some of these genes may contribute to beta-cell damage, while others are probably involved in beta-cell defence and/or repair. Regulation of iNOS and other related genes in beta cells is complex, and differs in several aspects from that observed in macrophages. There are also important differences in iNOS regulation between rodent and human pancreatic islets. A detailed knowledge of the molecular regulation of these genes in beta cells may be instrumental in the development of new approaches to prevent beta-cell destruction in early IDDM.

Animals↗
PubMed1996

Beta-cell defence and repair mechanisms in human pancreatic islets.

In vivo and in vitro data obtained in rodents indicate that beta-cells can trigger efficient repair mechanisms following non-lethal injury. Recent observations suggest that human pancreatic islets are more resistant than rodent islets to damage by alkylating agents, free oxygen radicals, nitric oxide and cytokines. This increased resistance to injury is associated with higher expression of heat shock protein 70, catalase and superoxide dismutase. These findings emphasise the potential relevance of beta-cell repair and/or defence mechanisms in the development of human IDDM.

Animals↗