Effects of betacellulin overexpression on glucose metabolism and pancreatic structure in transgenic mice

Objectives: BTC, a member of the epidermal growth factor (EGF) family, has been frequently associated with pancreatic endocrine function. BTC is expressed in the pancreas and several pancreatic cell lines, can convert non-β cells into insulin-producing cells and, when injected into rodent models of diabetes, improves glucose tolerance and β-cell volume. In this study we employed functional and stereological methods to evaluate the consequences of BTC excess in transgenic mice.

Methods: Transgenic mice overexpressing BTC under the control of the chicken β-actin promoter were generated by the pronuclear DNA microinjection technique. Western blot analyses and immunohistochemistry were used to detect sites of transgene expression. Glucose metabolism was evaluated by intraperitonial glucose tolerance test and insulin levels were determined with a commercial RIA kit. The volumes of the exocrine and endocrine pancreas were determined by histomorphometry.

Results: Strong BTC expression was detected throughout the pancreatic tissue of transgenic animals. Transgenic mice displayed significantly improved glucose tolerance. Interestingly, 20min after glucose administration to fasted animals serum insulin levels were higher in transgenic mice than in nontransgenic littermates (0.92 ng/ml vs. 0.69 ng/ml; P<0.01). The relative volume of the endocrine pancreas was significantly increased in BTC transgenic mice (1.16% vs. 0.81%; P<0.05). Islet architecture was normal. Surprisingly, we observed a reduction in the relative pancreas weight (0.66% vs. 0.87%; P<0.001) of transgenic mice as a consequence of selective reduction of the exocrine compartment. However, no pathological alterations were observed.

Conclusion: Our results provide further evidence for a role of BTC in improving glucose metabolism by directly acting on the proliferation and/or function of pancreatic islet cells. The effect on the exocrine compartment is particularly remarkable and differs considerably from the alterations observed in transgenic mice overexpressing other EGF receptor ligands.