Abstract
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.
Highlights
Diabetes mellitus (DM) is characterized by prolonged high blood glucose levels due to absolute or relative deficiency of insulin
To confirm that recombinant adenovirus-expressing BTC (rAd-BTC) treatment efficiently regulates blood glucose levels, we injected Recombinant adenovirus (rAd)-BTC or rAd-βgal (4 × 109 pfu) into STZ-induced diabetic C57BL/6 male mice and blood glucose levels were monitored for 4 weeks
Intraperitoneal glucose tolerance tests at 2 weeks after rAdBTC treatment showed that blood glucose levels in rAd-BTCtreated mice were significantly lower at the 60, 90, and 120 min points following glucose injection compared with the rAdβgal-treated mice (Supplementary Figure 1B), indicating that rAd-BTC treatment showed the glucose-lowering effects, as we previously found (Shin et al, 2008)
Summary
Diabetes mellitus (DM) is characterized by prolonged high blood glucose levels due to absolute or relative deficiency of insulin. Recent reports indicated that the possible conversion of non-β-cells in the islets to β-cells to replenish the reduced β-cell mass is possible (Thorel et al, 2010; Aguayo-Mazzucato and BonnerWeir, 2018; Gromada et al, 2018). In this regard, α-cells have been highlighted in the islets as a source of new β-cells and a direct progenitor of β-cells under conditions of extreme destruction of β-cells (Thorel et al, 2010)
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