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Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
¹ Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
² Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
³ Department of Internal Medicine, Social Insurance Funabashi Central Hospital, 6-13-10 Kaijin, Funabashi 273-8556, Japan
⁴ Department of Internal Medicine, Matsudo Municipal Hospital, 4005 Kamihongo, Matsudo 271-8511, Japan
⁵ Laboratory for Developmental Genetics, Riken Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
⁶ Department of Molecular Embryology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
⁷ Department of Diabetes and Metabolic Disease, Asahi General Hospital, I-1136, Asahi 289-2511, Japan

(Requests for offprints should be addressed to K Sakurai; Email: sakuraik{at}faculty.chiba-u.jp)

Several mutations of the tyrosine kinase domain of insulin receptor (IR) have been clinically reported to lead insulin resistance and insulin hypersecretion in humans. However, it has not been completely clarified how insulin resistance and pancreatic ß-cell function affect each other under the expression of mutant IR. We investigated the response of pancreatic ß-cells in mice carrying a mutation (P1195L) in the tyrosine kinase domain of IR ß-subunit. Homozygous (Ir^{P1195L/P1195L}) mice showed severe ketoacidosis and died within 2 days after birth, and heterozygous (Ir^P1195L/wt) mice showed normal levels of plasma glucose, but high levels of plasma insulin in the fasted state and after glucose loading, and a reduced response of plasma glucose lowering effect to exogenously administered insulin compared with wild type (Ir^wt/wt) mice. There were no differences in the insulin receptor substrate (IRS)-2 expression and its phosphorylation levels in the liver between Ir^P1195L/wt and Ir^wt/wt mice, both before and after insulin injection. This result may indicate that IRS-2 signaling is not changed in Ir^P1195L/wt mice. The ß-cell mass increased due to the increased numbers of ß-cells in Ir^P1195L/wt mice. More proliferative ß-cells were observed in Ir^P1195L/wt mice, but the number of apoptotic ß-cells was almost the same as that in Ir^wt/wt mice, even after streptozotocin treatment. These data suggest that, in Ir^P1195L/wt mice, normal levels of plasma glucose were maintained due to high levels of plasma insulin resulting from increased numbers of ß-cells, which in turn was due to increased ß-cell proliferation rather than decreased ß-cell apoptosis.