Age-dependent Decline in Beta Cell Proliferation Restricts the Capacity of Beta Cell Regeneration in Mice

Abstract

Objective: To elucidate whether age plays a role in the expansion or regeneration of beta cell mass.

Research Design and Methods: We analyzed the capacity of beta cell expansion in 1.5-month and 8-month-old mice in response to a high fat diet, short-term treatment with GLP-1 analog Exendin-4 or after streptozotocin (STZ) treatment.

Results: Young mice responded to high-fat diet by increasing beta cell mass, beta cell proliferation and maintained normoglygemia. Old mice by contrast, did not display any increases in beta cell mass or beta cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of beta cell mass with respect to age, young and old mice were injected with a single does of STZ and beta cell proliferation analyzed to assess the regeneration of beta cells. We observed a 4-fold increase in beta cell proliferation in young mice after STZ treatment while no changes in beta cell proliferation were observed in older mice. The capacity to expand beta cell mass in response to short-term treatment with GLP-1 analog Exendin-4 also declined with age. The ability of beta cell mass to expand was correlated with higher levels of Bmi1 and decreased levels of p16^Ink4a expression in the beta cells. Young Bmi1^−/− mice that prematurely upregulate p16^Ink4a failed to expand beta cell mass in response to Exendin-4 indicating that p16^Ink4a levels are critical determinant of beta cell mass expansion.

Conclusions: Beta cell proliferation and the capacity of beta cells to regenerate declines with age and is regulated by the Bmi1/p16^Ink4a pathway.