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Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice.

Tschen SI, Dhawan S, Gurlo T, Bhushan A - Diabetes (2009)

Bottom Line: The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of beta-cell mass.The capacity to expand beta-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age.The ability of beta-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 beta-cells.

View Article: PubMed Central - PubMed

Affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

ABSTRACT

Objective: The aim of this study was 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- 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 beta-cell mass and beta-cell proliferation and maintaining normoglycemia. 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 dose of STZ, and beta-cell proliferation was analyzed to assess the regeneration of beta-cells. We observed a fourfold increase in beta-cell proliferation in young mice after STZ administration, whereas 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 the GLP-1 analog exendin-4 also declined with age. The ability of beta-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 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 a 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.

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β-Cell regeneration capacity is severely diminished in old mice. A: Blood glucose of young and old mice after STZ or sham injection of vehicle alone. B: Percentage Ki67-positive cells of young and old mice after STZ or sham injection. Values are averaged from four slides for each mouse and three mice in each group. C: Percentage PCNA-positive cells of young and old mice after STZ or sham injection. Values are averaged from two slides for each mouse and three mice in each group. D– G: Pancreatic sections from control (D and F) or STZ-administered (E and G) young (D and E) and old (F and G) mice were immunostained with antibodies to PCNA (red) and to insulin (green). 4′6-diamidino-2-phenylindole–stained nuclei appear blue. * P < 0.05; ** P < 0.01. (A high-quality digital representation of this figure is available in the online issue).
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Figure 6: β-Cell regeneration capacity is severely diminished in old mice. A: Blood glucose of young and old mice after STZ or sham injection of vehicle alone. B: Percentage Ki67-positive cells of young and old mice after STZ or sham injection. Values are averaged from four slides for each mouse and three mice in each group. C: Percentage PCNA-positive cells of young and old mice after STZ or sham injection. Values are averaged from two slides for each mouse and three mice in each group. D– G: Pancreatic sections from control (D and F) or STZ-administered (E and G) young (D and E) and old (F and G) mice were immunostained with antibodies to PCNA (red) and to insulin (green). 4′6-diamidino-2-phenylindole–stained nuclei appear blue. * P < 0.05; ** P < 0.01. (A high-quality digital representation of this figure is available in the online issue).

Mentions: To assess the effect of aging on β-cell regeneration capacity, we adapted a standard regeneration model that uses a single injection of STZ to lead to a loss of ∼50% of the β-cells (31). We used this model for two reasons:1) an increase in β-cell proliferation is observed 7 days after STZ injection that correlates with regeneration of β-cell mass, and 2) the residual β-cell mass is sufficient to maintain blood glucose levels, thus potentially minimizing the role of hyperglycemia in β-cell proliferation and apoptosis. Young and old mice were subject to a single dose of 90 mg/kg STZ to induce partial loss of β-cells, and Ki67- and PCNA-positive β-cells were evaluated 7 days later. Both young and old mice that had received single-dose STZ administration displayed hyperglycemia (Fig. 6A). A number of proliferating β-cells were observed in young mice after STZ administration. In contrast, old mice injected with STZ had limited numbers of Ki67- or PCNA-positive β-cells (Fig. 6B, C, and E). Quantification of Ki67-positive β-cells in young mice after STZ administration revealed a fourfold increase in proliferating β-cells, whereas no difference was observed in older mice after STZ administration. Quantification of PCNA-positive β-cells showed a fivefold increase in proliferating β-cells in young mice after STZ administration, whereas no difference was observed in older mice. These data indicate that young mice, unlike old mice, have the capacity to proliferate and regenerate β-cell mass after β-cell destruction.


Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice.

Tschen SI, Dhawan S, Gurlo T, Bhushan A - Diabetes (2009)

β-Cell regeneration capacity is severely diminished in old mice. A: Blood glucose of young and old mice after STZ or sham injection of vehicle alone. B: Percentage Ki67-positive cells of young and old mice after STZ or sham injection. Values are averaged from four slides for each mouse and three mice in each group. C: Percentage PCNA-positive cells of young and old mice after STZ or sham injection. Values are averaged from two slides for each mouse and three mice in each group. D– G: Pancreatic sections from control (D and F) or STZ-administered (E and G) young (D and E) and old (F and G) mice were immunostained with antibodies to PCNA (red) and to insulin (green). 4′6-diamidino-2-phenylindole–stained nuclei appear blue. * P < 0.05; ** P < 0.01. (A high-quality digital representation of this figure is available in the online issue).
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Related In: Results  -  Collection

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Figure 6: β-Cell regeneration capacity is severely diminished in old mice. A: Blood glucose of young and old mice after STZ or sham injection of vehicle alone. B: Percentage Ki67-positive cells of young and old mice after STZ or sham injection. Values are averaged from four slides for each mouse and three mice in each group. C: Percentage PCNA-positive cells of young and old mice after STZ or sham injection. Values are averaged from two slides for each mouse and three mice in each group. D– G: Pancreatic sections from control (D and F) or STZ-administered (E and G) young (D and E) and old (F and G) mice were immunostained with antibodies to PCNA (red) and to insulin (green). 4′6-diamidino-2-phenylindole–stained nuclei appear blue. * P < 0.05; ** P < 0.01. (A high-quality digital representation of this figure is available in the online issue).
Mentions: To assess the effect of aging on β-cell regeneration capacity, we adapted a standard regeneration model that uses a single injection of STZ to lead to a loss of ∼50% of the β-cells (31). We used this model for two reasons:1) an increase in β-cell proliferation is observed 7 days after STZ injection that correlates with regeneration of β-cell mass, and 2) the residual β-cell mass is sufficient to maintain blood glucose levels, thus potentially minimizing the role of hyperglycemia in β-cell proliferation and apoptosis. Young and old mice were subject to a single dose of 90 mg/kg STZ to induce partial loss of β-cells, and Ki67- and PCNA-positive β-cells were evaluated 7 days later. Both young and old mice that had received single-dose STZ administration displayed hyperglycemia (Fig. 6A). A number of proliferating β-cells were observed in young mice after STZ administration. In contrast, old mice injected with STZ had limited numbers of Ki67- or PCNA-positive β-cells (Fig. 6B, C, and E). Quantification of Ki67-positive β-cells in young mice after STZ administration revealed a fourfold increase in proliferating β-cells, whereas no difference was observed in older mice after STZ administration. Quantification of PCNA-positive β-cells showed a fivefold increase in proliferating β-cells in young mice after STZ administration, whereas no difference was observed in older mice. These data indicate that young mice, unlike old mice, have the capacity to proliferate and regenerate β-cell mass after β-cell destruction.

Bottom Line: The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of beta-cell mass.The capacity to expand beta-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age.The ability of beta-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 beta-cells.

View Article: PubMed Central - PubMed

Affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

ABSTRACT

Objective: The aim of this study was 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- 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 beta-cell mass and beta-cell proliferation and maintaining normoglycemia. 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 dose of STZ, and beta-cell proliferation was analyzed to assess the regeneration of beta-cells. We observed a fourfold increase in beta-cell proliferation in young mice after STZ administration, whereas 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 the GLP-1 analog exendin-4 also declined with age. The ability of beta-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 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 a 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.

Show MeSH