Improved glucose metabolism and altered pancreatic structure in transgenic mice overexpressing betacellulin
Maik Dahlhoff1, Nadja Herbach2, Rüdiger Wanke2, Eckhard Wolf1 & Marlon R. Schneider1
Betacellulin, one of several peptides activating the EGFR (ErbB1) and related receptors, is a multipotent growth factor known to posses the unique ability to promote growth and differentiation of pancreatic β-cells.
We investigated the effects of betacellulin overexpression in a recently established transgenic mouse model (Schneider et al., Endocrinology 146, 52375246, 2005). In transgenic animals, overall glucose metabolism was improved as demonstrated by reduced blood glucose levels in fasted animals and a better response after a glucose tolerance test (associated with increased serum insulin levels). Unexpectedly, the absolute and relative (proportional to body weight) pancreas weights were significantly reduced in transgenic mice. Histomorphometrical analyses revealed a reduction in the volume of the exocrine pancreas while the islet and β-cell volume remained unchanged. This resulted in an increase in the relative volume of the latter compartments. Interestingly, the proportion of β-cells within the islets remained unchanged in betacellulin transgenic mice. While betacellulin is normally expressed in the islets, immunohistochemistry revealed that the growth factor is, in addition, strongly expressed in the exocrine pancreas in transgenic mice. This uncovers a hitherto unknown negative effect of betacellulin in the exocrine compartment. Finally, we identified, by immunohistochemistry, an opposite expression pattern of ErbB1 and ErbB4, the primary receptors for betacellulin, in the pancreas. In this organ, ErbB1 is expressed predominantly in the islets, while ErbB4 expression is mostly restricted to the exocrine compartment. Thus, this particular receptor distribution may provide an explanation for the opposing effects exerted by betacellulin in the different pancreatic compartments.
Current experiments involve the study of cell proliferation and apoptosis as well as functional studies on isolated islets including insulin content and release.