Glucagon Receptor Antagonist–Stimulated α-Cell Proliferation Is Severely Restricted With Advanced Age
| Autor: | Carol J. Lam, Matthew M. Rankin, Jake A. Kushner, Brian Christopher Shook, Kourtney B King, Melinda C Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Aging medicine.medical_specialty Basal rate Rodent Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism Mice 03 medical and health sciences 0302 clinical medicine Internal medicine biology.animal Receptors Glucagon Internal Medicine medicine Animals Hypoglycemic Agents Glucose homeostasis Progenitor cell Receptor biology Cell growth Antagonist 030104 developmental biology Endocrinology Islet Studies Glucagon-Secreting Cells Glucagon receptor Thymidine |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db18-1293 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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