Glucagon Receptor Antagonist-Stimulated α-Cell Proliferation Is Severely Restricted With Advanced Age

Area of Science:

• Endocrinology
• Developmental Biology
• Metabolic Regulation

Background:

• Alpha (α)-cells are crucial for glucose homeostasis, but their adult development is under-researched.
• Glucagon receptor antagonists (GRAs) show antidiabetic potential but raise concerns about α-cell growth.
• Previous studies on GRAs used only young rodents, leaving the impact on adult α-cells unclear.

Purpose of the Study:

• To investigate the effect of a novel glucagon receptor antagonist (GRA) on α-cell proliferation and turnover in young and aged mice.
• To determine if GRAs induce uncontrolled α-cell expansion in adult mice.
• To elucidate the lineage and proliferative capacity of GRA-stimulated α-cells.

Main Methods:

• Administration of a novel GRA (JNJ-46207382) to young and aged mice.
• Assessment of basal and GRA-induced α-cell proliferation rates.
• Sequential administration of thymidine analogs to track α-cell lineage and division.

Main Results:

• Basal α-cell proliferation significantly decreases with age.
• GRAs increased α-cell proliferation 2.4-fold in young mice.
• In aged mice, GRA-induced proliferation was reduced but still elevated (3.2-fold) compared to aged controls.
• α-cells divided only once under basal and stimulated conditions, indicating expansion via self-renewal, not progenitor cells.

Conclusions:

• GRA-induced α-cell proliferation is age-dependent, being significantly reduced in aged mice.
• Adult α-cell expansion occurs primarily through self-renewal, similar to β-cells.
• These findings suggest a potentially lower risk of uncontrolled α-cell growth with GRA therapy in adult patients compared to concerns raised by young-rodent studies.