Long-term c-Kit overexpression in beta cells compromises their function in ageing mice

Area of Science:

• Endocrinology
• Cell Biology
• Metabolic Research

Background:

• c-Kit signaling promotes beta cell proliferation and insulin secretion in young mice.
• The effects of long-term c-Kit activation on aging beta cells remain unexplored.

Purpose of the Study:

• To investigate the impact of sustained c-Kit overexpression in aging beta cells on their function and insulin secretion.
• To elucidate the role of insulin receptor signaling in c-Kit-mediated effects on aging beta cells.

Main Methods:

• Metabolic tests (glucose tolerance, insulin secretion) in aging wild-type and c-Kit overexpressing (c-KitβTg) mice.
• Pancreatic histology and islet protein analysis to assess beta cell markers, proliferation, and signaling pathways.
• Generation and analysis of beta cell-specific insulin receptor knockout in aging c-KitβTg mice (c-KitβTg;βIRKO).

Main Results:

• Aging c-KitβTg mice exhibited glucose intolerance and impaired insulin secretion compared to controls.
• Increased beta cell mass, proliferation, FOXO1 expression, and reduced exocytotic proteins were observed in aging c-KitβTg islets.
• Prolonged c-Kit activation led to insulin insensitivity in beta cells, evidenced by reduced Akt phosphorylation upon insulin stimulation.
• Disruption of insulin receptor signaling in aging c-KitβTg;βIRKO mice improved glucose tolerance and beta cell function.

Conclusions:

• Long-term c-Kit overexpression negatively affects insulin exocytosis in aging beta cells.
• Temporal regulation of c-Kit and insulin receptor signaling is critical for maintaining optimal beta cell function.
• Sustained c-Kit activation contributes to beta cell dysfunction through insulin insensitivity.