Role of Macrophages in the Development of Pancreatic Islet Injury in Spontaneously Diabetic Torii Rats

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Spontaneously diabetic Torii (SDT) rats were established from Sprague-Dawley (SD) rat and are used as an animal model of type 2 diabetes mellitus. In the present study, the mechanism of the development of injury in the pancreas of these rats was examined focusing on the role of monocytes/macrophages. The number of lymphocytes and monocytes in the circulation of SDT rats increased with age, reaching a plateau at around 9 weeks of age and remaining at that level thereafter. The number of leukocytes in SDT rats was almost twice that of wild-type SD rats. Serum IL-18 levels began to increase at 8 weeks of age, forming a prominent peak at 9 weeks of age. In parallel with this, serum levels of NO₂/NO₃ showed an abrupt rise and decline. Spleen cells prepared from 9-week-old SDT rats expressed high levels of IFN-γ in response to IL-18, while those from 9-week-old wild-type SD rats did not. Immunohistochemical analysis revealed marked infiltration of CD68⁺ cells in the islets of SDT rats. Treatment of SDT rats with Cl₂MDP-liposomes reduced the number of monocytes as well as levels of NO₂/NO₃ in the circulation. Consistent with this, the number of infiltrated CD68⁺ cells in the islets was reduced in SDT rats treated with Cl₂MDP-liposomes. These results suggest that macrophages are involved in pancreatic islet injury in SDT rats through excess production of NO induced by IL-18 which increases transitorily at around 9 weeks of age.