Glucagon-containing α-cells are important for regulating glucose homeostasis along with insulin-secreting β-cells. Glucagon receptor antagonists (GRAs) hold potential as antidiabetic therapies, but there is a concern that GRAs may cause α-cells to proliferate. While studies evaluating this have been carried out in rodents, these have been limited to young mice, raising questions surrounding the effect of GRAs in adult mice and adult animals in general. In this controlled study, investigators gave a highly selective GRA (JNJ-46207382) to both young and adult mice in order to examine the effect of GRAs on measured α-cell turnover and proliferation. Investigators found that in young mice, the GRA caused a 2.5 fold greater α-cell proliferation. In adult mice, administration of the GRA also resulted in α-cell proliferation, but this proliferation was 60% less than what was observed in young mice. In both young and adult mice, pancreas mass was unaltered by the GRA studied, and islet histology was also normal. Taken together, the results from this study suggest that administration of GRA causes a greater degree of expansion of α-cells in young mice as compared to older mice. This has implications for potential GRA use in middle-aged or elderly patients who may have minimal α-cell proliferation. This study was limited, however, in that it used a single GRA molecule in a rodent model that may or may not be generalizable to humans. The mice used in this study were also non-diabetic, therefore, the effect of GRAs on diabetic α-cells requires further study.
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