Role of macrophages in the development of pancreatic islet injury in spontaneously diabetic torii rats.
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-gamma 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.
Inokuchi
Chie
C
Division of Diabetes and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, hyogo, Japan.
Ueda
Haruyasu
H
Hamaguchi
Tomoya
T
Miyagawa
Jun-Ichiro
J
Shinohara
Masami
M
Okamura
Haruki
H
Namba
Mitsuyoshi
M
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002452:Cell Count; D002469:Cell Separation; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008081:Liposomes / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D050071:Bone Density Conservation Agents; D004002:Clodronic Acid; D007371:Interferon-gamma; D020382:Interleukin-18; D008081:Liposomes; D009566:Nitrates; D009573:Nitrites; C539355:CD68 protein, rat; D000097382:CD68 Molecule