Research Article: Betacellulin-Induced Beta Cell Proliferation and Regeneration Is Mediated by Activation of ErbB-1 and ErbB-2 Receptors

Date Published: August 29, 2011

Publisher: Public Library of Science

Author(s): Yoon Sin Oh, Seungjin Shin, Youn-Jung Lee, Eung Hwi Kim, Hee-Sook Jun, Kathrin Maedler.

Abstract: Betacellulin (BTC), a member of the epidermal growth factor family, is known to play an important role in regulating growth and differentiation of pancreatic beta cells. Growth-promoting actions of BTC are mediated by epidermal growth factor receptors (ErbBs), namely ErbB-1, ErbB-2, ErbB-3 and ErbB-4; however, the exact mechanism for beta cell proliferation has not been elucidated. Therefore, we investigated which ErbBs are involved and some molecular mechanisms by which BTC regulates beta cell proliferation.

The expression of ErbB-1, ErbB-2, ErbB-3, and ErbB-4 mRNA was detected by RT-PCR in both a beta cell line (MIN-6 cells) and C57BL/6 mouse islets. Immunoprecipitation and western blotting analysis showed that BTC treatment of MIN-6 cells induced phosphorylation of only ErbB-1 and ErbB-2 among the four EGF receptors. BTC treatment resulted in DNA synthetic activity, cell cycle progression, and bromodeoxyuridine (BrdU)-positive staining. The proliferative effect was blocked by treatment with AG1478 or AG825, specific tyrosine kinase inhibitors of ErbB-1 and ErbB-2, respectively. BTC treatment increased mRNA and protein levels of insulin receptor substrate-2 (IRS-2), and this was blocked by the ErbB-1 and ErbB-2 inhibitors. Inhibition of IRS-2 by siRNA blocked cell cycle progression induced by BTC treatment. Streptozotocin-induced diabetic mice injected with a recombinant adenovirus expressing BTC and treated with AG1478 or AG825 showed reduced islet size, reduced numbers of BrdU-positive cells in the islets, and did not attain BTC-mediated remission of diabetes.

These results suggest that BTC exerts proliferative activity on beta cells through the activation of ErbB-1 and ErbB-2 receptors, which may increase IRS-2 expression, contributing to the regeneration of beta cells.

Partial Text: Islet transplantation is currently the most promising treatment for type 1 diabetes, but there are side effects associated with the immunosuppressive agents and limitations resulting from a shortage of pancreas donors [1]. Therefore, generation of new beta cells either in vitro or in vivo is a high priority issue in diabetes treatment, and the identification of factors regulating the expansion of insulin-producing cells has potential importance for the treatment of diabetes.

The pancreatic beta cell mass is dynamic and can increase when exposed to appropriate environmental and physiological changes, such as obesity and pregnancy [27], and growth stimuli such as BTC, glucagon-like peptide-1 [28] and gastrin [29]. As diabetes results from absolute or relative deficiency of the beta cell mass, restoration of the beta cell mass might be one strategy for the treatment of diabetes. For this, various methods have been investigated including differentiation of insulin-producing cells from progenitor/stem cells and regeneration of beta cells.