Destruction of pancreatic beta-cells by transgenic induction of prostaglandin E2 in the islets.
Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic beta-cells. Furthermore, the number of pancreatic beta-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E(2) (PGE(2)). To investigate whether high glucose-induced PGE(2) has an adverse effect on pancreatic beta-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their beta-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/-) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of beta-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/-) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because beta-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE(2) signaling thus contributes to the reduction of the pancreatic beta-cell mass through inhibition of proliferation, thereby aggravating diabetes further.
Oshima
Hiroko
H
Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan. oshimam@kenroku.kanazawa-u.ac.jp
Taketo
Makoto Mark
MM
Oshima
Masanobu
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics* / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051381:Rats; D019076:Transgenes
D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon; D051546:Cyclooxygenase 2; D015232:Dinoprostone