Glucagon receptor antagonist–stimulated A-cell proliferation is severely restricted with advanced age

Abstract

Glucagon-containing a-cells potently regulate glucose homeostasis, but the developmental biology of a-cells in adults remains poorly understood. Although glucagon receptor antagonists (GRAs) have great potential as antidiabetic therapies, murine and human studies have raised concerns that GRAs might cause uncontrolled a-cell growth. Surprisingly, previous rodent GRA studies were only performed in young mice, implying that the potential impact of GRAs to drive a-cell expansion in adult patients is unclear. We assessed adaptive a-cell turnover and adaptive proliferation, administering a novel GRA (JNJ-46207382) to both young and aged mice. Basal a-cell proliferation rapidly declined soon after birth and continued to drop to very low levels in aged mice. GRA drove a 2.4-fold increase in a-cell proliferation in young mice. In contrast, GRA-induced a-cell proliferation was severely reduced in aged mice, although still present at 3.2-fold the very low basal rate of aged controls. To interrogate the lineage of GRA-induced a-cells, we sequentially administered thymidine analogs and quantified their incorporation into a-cells. Similar to previous studies of b-cells, a-cells only divided once in both basal and stimulated conditions. Lack of contribution from highly proliferative “transit-amplifying” cells supports a model whereby a-cells expand by self-renewal and not via specialized progenitors.