Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice

Abstract

OBJECTIVE The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of β-cell mass. RESEARCH DESIGN AND METHODS We analyzed the capacity of β-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration. RESULTS Young mice responded to high-fat diet by increasing β-cell mass and β-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of β-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and β-cell proliferation was analyzed to assess the regeneration of β-cells. We observed a fourfold increase in β-cell proliferation in young mice after STZ administration, whereas no changes in β-cell proliferation were observed in older mice. The capacity to expand β-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of β-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16 Ink4a expression in the β-cells. Young Bmi1 −/− mice that prematurely upregulate p16 Ink4a failed to expand β-cell mass in response to exendin-4, indicating that p16 Ink4a levels are a critical determinant of β-cell mass expansion. CONCLUSIONS β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16 Ink4a pathway.

Elevation of transcription factor Islet-1 levels in vivo increases β-cell function but not β-cell mass

“…1 Similarly, aging can induce a distinct gene expression program in mouse islets, leading to a decrease in the expression of a small number of genes, including Isl-1. [2][3][4][5] Taken together, these findings suggest that a decrease in Isl-1 expression might contribute to the pathophysiology of the disease and an increase in Isl-1 expression might be beneficial for a β-cell to maintain its full functionality.…”

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…These antiapoptotic effects involve the phosphoinositide 3-kinase [PI3K]/Akt, extracellular signal-regulated kinase1/2 (ERK1/2) and cAMP/PKA pathways [109]. Although ageing is characterised by a low level of beta cell proliferation, mice treated with exendin-4 at different ages show low glucose levels, suggesting a potential beneficial effect in ageing [110].…”

“…In addition, the dramatic age-dependent decline of pancreatic beta cell replication in response to diverse insults (high-fat diet, streptozotocin administration or short-term treatment with the GLP-1 analogue exendin-4) has been correlated by Tschen et al [110] with an increase in Bmi1 levels, a polycomb group protein that regulates the Ink4a locus and modulates the ability of the beta cell mass to expand. Interestingly, a systemic factor has been considered responsible for increasing the proliferation rate of old pancreatic beta cells when parabiosed to young mice [147].…”

Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes

“…It has been reported that BCM is increased by 20 to 50% in obese adult humans without diabetes (8,11), to a smaller degree than in rodents, which usually show a two-to threefold increase (4,5), consistent with lower b-cell turnover in adult humans. Recently, we have also reported that in the Japanese population, no significant increase in BCM was observed in obese adults without diabetes (12).…”

“…In rodents, b-cells have been shown to be able to adaptively increase in response to an increased insulin demand such as obesity or pregnancy (3)(4)(5). However, b-cell proliferation in humans has been reported to rapidly decrease within 5 years after birth, and only minimal b-cell proliferation is observed in adults (6)(7)(8).…”