Betacellulin (BTC), an epidermal growth factor family, is known to promote β-cell regeneration. Recently, pancreatic α-cells have been highlighted as a source of new β-cells. We investigated the effect of BTC on α-cells. Insulin+glucagon+ double stained bihormonal cell levels and pancreatic and duodenal homeobox-1 expression were increased in mice treated with recombinant adenovirus-expressing BTC (rAd-BTC) and β-cell-ablated islet cells treated with BTC. In the islets of rAd-BTC-treated mice, both BrdU+glucagon+ and BrdU+insulin+ cell levels were significantly increased, with BrdU+glucagon+ cells showing the greater increase. Treatment of αTC1-9 cells with BTC significantly increased proliferation and cyclin D2 expression. BTC induced phosphorylation of ErbB receptors in αTC1-9 cells. The proliferative effect of BTC was mediated by ErbB-3 or ErbB-4 receptor kinase. BTC increased phosphorylation of ERK1/2, AKT, and mTOR and PC1/3 expression and GLP-1 production in α-cells, but BTC-induced proliferation was not changed by the GLP-1 receptor antagonist, exendin-9. We suggest that BTC has a direct role in α-cell proliferation via interaction with ErbB-3 and ErbB-4 receptors, and these increased α-cells might be a source of new β-cells.

Betacellulin（BTC）是一种表皮生长因子家族，可促进β细胞再生。近来，胰腺α-细胞已被强调为新的β-细胞的来源。我们研究了BTC对α细胞的影响。在表达重组腺病毒的BTC（rAd-BTC）和用BTC治疗的β细胞消融的胰岛细胞治疗的小鼠中，胰岛素+胰高血糖素+双重染色的双激素细胞水平以及胰腺和十二指肠同源盒1的表达增加。在rAd-BTC处理的小鼠的胰岛中，BrdU +胰高血糖素+和BrdU +胰岛素+细胞水平均显着增加，而BrdU +胰高血糖素+细胞则显示出更大的增加。用BTC处理αTC1-9细胞可显着增加增殖和细胞周期蛋白D2表达。BTC诱导αTC1-9细胞中ErbB受体的磷酸化。BTC的增殖作用是由ErbB-3或ErbB-4受体激酶介导的。BTC增加了α细胞中ERK1 / 2，AKT和mTOR的磷酸化以及PC1 / 3的表达和GLP-1的产生，但是BTC诱导的增殖并未被GLP-1受体拮抗剂exendin-9改变。我们认为BTC通过与ErbB-3和ErbB-4受体的相互作用在α细胞增殖中具有直接作用，而这些增加的α细胞可能是新β细胞的来源。