Inhibition of immune-mediated low-dose streptozotocin diabetes by agents which reduce vascular permeability

E, Schwab; Burkart, Volker; Freytag, G; Kiesel, U; Kolb, Hubert

doi:10.1016/0162-3109(86)90047-0

Cited by 13 publications

(7 citation statements)

References 15 publications

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“…In low-dose STZ-treated mice, an almost complete suppression of macrophage infiltration into islets was seen after silica treatment. Concomitantly, the development of hyperglycemia was largely inhibited, which confirms two earlier reports (11,20). Thus, our immunocytochemical analysis of F4/80-positive cells in islet sections shows a clear correlation between presence or absence of macrophage infiltration and development or suppression of hyperglycemia.…”

Section: Discussionsupporting

confidence: 90%

Low-Dose Streptozocin-Induced Diabetes in Mice: Electron Microscopy Reveals Single-Cell Insulitis Before Diabetes Onset

Kolb-Bachofen

Epstein²,

Kiesel³

et al. 1988

Diabetes

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118

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We investigated the morphology of mouse islets 5 days after completion of low-dose streptozocin treatment of C57BL/6 mice by electron microscopy. At this stage, mice were still normoglycemic and light microscopy did not reveal massive islet infiltration. The electron-microscopic investigation revealed two characteristics indicative of ongoing islet cell destruction. In all islets investigated, lysed islet beta-cells were recognized by disrupted plasma membranes and concomitantly decreased plasma contrast. Many of the lysed islet beta-cells still contained numerous insulin granules. We also found immunocytes scattered throughout the islets, most of which could be identified as macrophages. Some were found engaged in phagocytosis of islet beta-cell debris. This early stage of islet lesion termed single-cell insulitis is followed by the well-known later stage of massive infiltration easily recognized in light microscopy. Administration of silica particles to mice treated with low-dose streptozocin inhibited macrophage infiltration of islets as shown by immunocytochemistry with macrophage-specific monoclonal antibody F4/80. In parallel, the development of hyperglycemia was suppressed. The observations favor a pathogenic role of macrophages in islet destruction.

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Section: Discussionsupporting

confidence: 90%

Low-Dose Streptozocin-Induced Diabetes in Mice: Electron Microscopy Reveals Single-Cell Insulitis Before Diabetes Onset

Kolb-Bachofen

Epstein²,

Kiesel³

et al. 1988

Diabetes

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118

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“…Ketotifen may not be able to inhibit or reverse peri-insular edema at a stage where physical damage of the islet vasculature may have occurred. Second, vasoactive amines have been shown to reduce peri-insular edema in animal models (8)(9)(10); however, a relevance of this finding in human diabetes has not yet been shown. Because vascular leakage in the presence of otherwise intact endothelia should quickly be inhibited by ketotifen, a beneficial effect should have been observed within a few weeks.…”

Section: Ketotifen and Insulin Secretion In Prediabetesmentioning

confidence: 96%

“…This has led to earlier attempts of an immune intervention therapy before the onset of the disease by immunosuppression (3,4), immunomodulation (5), and improving p-cell regeneration (6,7). The therapeutic approach described herein was based on the observation of vascular leakage in inflamed islets of animal models such as the BB rat (8) as well as the low-dose streptozocin diabetes mouse model (9,10). In the latter, an antiallergic therapy with a serotonin/ histamine antagonist (pizotifen) administered before the development of insulitis has been shown to suppress macrophage and T-cell infiltration and prevent diabetes manifestation (11).…”

mentioning

confidence: 99%

Linear Loss of Insulin Secretory Capacity During the Last Six Months Preceding IDDM: No effect of antiedematous therapy with ketotifen

et al. 1994

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“…Early during the inflammatory process morphological and functional changes in the microvascular system of the islets become apparent and increased permeability of the islet capillary bed appears to facilitate the extravasation of immune mediators and inflammatory cells [11]. Furthermore, experimental suppression of enhanced vascular permeability inhibits the development of diabetes [41].…”

Section: Discussionmentioning

confidence: 99%

A regulatory defect of constitutive no-synthase in islet endothelial cells correlates with probability of disease manifestation in BBdp rats

1999

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Type I (insulin-dependent) diabetes is an immune-mediated disease [1,2] characterised by early leucocyte accumulation around and then infiltration of pancreatic islets [3], concomitant with a progressive destruction of insulin-producing beta cells [4]. The mechanisms leading to the accumulation of circulating leucocytes at the sites of pancreatic islets are poorly characterised. Prior to this accumulation, circulating mononuclear cells must extravasate, a process dependent on leucocyte interaction with the local endothelium [5,6].It has been postulated that malfunction of the vascular endothelium represents an early pathological Diabetologia (1999) 42: 457±464 A regulatory defect of constitutive no-synthase in islet endothelial cells correlates with probability of disease manifestation in BBdp rats Abstract Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is characterised by leucocyte infiltration of pancreatic islets and a progressive destruction of insulin-producing beta cells. As endothelial nitric oxide production is known to regulate adhesion molecule expression and leucocyte permeation, we examined the activity and expression of the constitutive nitric oxide synthase (ecNOS) of islet endothelial cells from prediabetic BBdp rats. Methods. Cultures of aortic endothelial cells and islet capillary endothelial cells were established from young normoglycaemic BBdp rats, Wistar rats and diabetes-resistant BBdr rats, all matched for age. Nitrite and citrulline production was measured in all culture supernatants as indicators for ecNOS activities. Expression of ecNOS mRNA was assessed by reverse transcription-polymerase chain reaction.Results. In contrast to those of the aorta, the Wistar rat islet derived endothelial cells exhibited a strong positive correlation of ecNOS activity with the culture medium glucose concentration but none of the BB rat-derived islet endothelial cells showed a similar glucose-responsiveness. Furthermore, at physiological as well as at increased glucose concentrations islet endothelia from all BBdp rats exhibited a considerable decrease in ecNOS activity by a factor of 3 to 6, indicating a specific dysfunction which is also found for the inducible nitric oxide synthase activity after cytokine challenge but effects were less (2.5 to 3 times) dramatic. In contrast, aorta endothelia from all rats exhibited identical ecNOS activities and no glucose responsiveness. We also found a correlation between ecNOS activities and ecNOS-mRNA expression and can exclude the involvement of the inducible isoform. Conclusion/interpretation. A reproducible and highly significant dysfunction of islet ecNOS expression and activity in young normoglycaemic BBdp rats, which strongly correlates with the probability for disease manifestation is shown. [Diabetologia (1999) 42: 457±464]

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Inhibition of immune-mediated low-dose streptozotocin diabetes by agents which reduce vascular permeability

Cited by 13 publications

References 15 publications

Low-Dose Streptozocin-Induced Diabetes in Mice: Electron Microscopy Reveals Single-Cell Insulitis Before Diabetes Onset

Low-Dose Streptozocin-Induced Diabetes in Mice: Electron Microscopy Reveals Single-Cell Insulitis Before Diabetes Onset

Linear Loss of Insulin Secretory Capacity During the Last Six Months Preceding IDDM: No effect of antiedematous therapy with ketotifen

A regulatory defect of constitutive no-synthase in islet endothelial cells correlates with probability of disease manifestation in BBdp rats

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