Insulin resistance and increased pancreatic β-cell proliferation in mice expressing a mutant insulin receptor (P1195L)

• Published in: Journal of endocrinology Vol. 190; no. 3; pp. 739 - 747
• Main Authors: Ogino, J, Sakurai, K, Yoshiwara, K, Suzuki, Yoichi, Ishizuka, N, Seki, N, Suzuki, Yoshifumi, Koseki, H, Shirasawa, T, Hashimoto, N, Yagui, K, Saito, Y
• Format: Journal Article
• Language: English
• Published: Colchester BioScientifica 01.09.2006; Portland Press
• Subjects: Animals; Apoptosis; Biological and medical sciences; Blood Glucose - analysis; Blotting, Western - methods; Cell Proliferation; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Glucose - pharmacology; Immunohistochemistry - methods; Immunoprecipitation; Insulin Resistance; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Male; Medical sciences; Mice; Mice, Knockout; Models, Animal; Mutation; Phosphorylation; Receptor, Insulin - analysis; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Regular papers; Tumors. Hypoglycemia; Endocrinopathy; Cell proliferation; Diabetes mellitus; Rodentia; Male; In vitro; Vertebrata; Mammalia; Mouse; Adult animal; β Cell; Localization; Insulin receptor; Apoptosis
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1677/joe.1.06849

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 β-cell function affect each other under the expression of mutant IR. We investigated the response of pancreatic β-cells in mice carrying a mutation (P1195L) in the tyrosine kinase domain of IR β-subunit. Homozygous (IrP1195L/P1195L) mice showed severe ketoacidosis and died within 2 days after birth, and heterozygous (IrP1195L/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 (Irwt/wt) mice. There were no differences in the insulin receptor substrate (IRS)-2 expression and its phosphorylation levels in the liver between IrP1195L/wt and Irwt/wt mice, both before and after insulin injection. This result may indicate that IRS-2 signaling is not changed in IrP1195L/wt mice. The β-cell mass increased due to the increased numbers of β-cells in IrP1195L/wt mice. More proliferative β-cells were observed in IrP1195L/wt mice, but the number of apoptotic β-cells was almost the same as that in Irwt/wt mice, even after streptozotocin treatment. These data suggest that, in IrP1195L/wt mice, normal levels of plasma glucose were maintained due to high levels of plasma insulin resulting from increased numbers of β-cells, which in turn was due to increased β-cell proliferation rather than decreased β-cell apoptosis.