| Autor: |
Wang, Melinda C., Lam, Carol J., Kushner, Jake A., King, Kourtney B., Rankin, Matthew M., Shook, Brian C. |
| Předmět: |
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| Zdroj: |
Diabetes; May2019, Vol. 68 Issue 5, p963-974, 12p, 7 Graphs |
| Abstrakt: |
Glucagon-containing α-cells potently regulate glucose homeostasis, but the developmental biology of α-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 α-cell growth. Surprisingly, previous rodent GRA studies were only performed in young mice, implying that the potential impact of GRAs to drive α-cell expansion in adult patients is unclear. We assessed adaptive α-cell turnover and adaptive proliferation, administering a novel GRA (JNJ-46207382) to both young and aged mice. Basal α-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 α-cell proliferation in young mice. In contrast, GRA-induced α-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 α-cells, we sequentially administered thymidine analogs and quantified their incorporation into α-cells. Similar to previous studies of β-cells, α-cells only divided once in both basal and stimulated conditions. Lack of contribution from highly proliferative "transit-amplifying" cells supports a model whereby α-cells expand by self-renewal and not via specialized progenitors. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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