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Adaptive beta-cell proliferation is severely restricted with advanced age.

Rankin MM, Kushner JA - Diabetes (2009)

Bottom Line: However, it is unknown whether this adaptive beta-cell regeneration capacity is retained into old age.We assessed adaptive beta-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: partial pancreatectomy, low-dose administration of the beta-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. beta-Cell proliferation was measured by administration of 5-bromo-2'-deoxyuridine (BrdU) in the drinking water.Basal beta-cell proliferation was severely decreased with advanced age.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

ABSTRACT

Objective: Regeneration of the insulin-secreting beta-cells is a fundamental research goal that could benefit patients with either type 1 or type 2 diabetes. beta-Cell proliferation can be acutely stimulated by a variety of stimuli in young rodents. However, it is unknown whether this adaptive beta-cell regeneration capacity is retained into old age.

Research design and methods: We assessed adaptive beta-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: partial pancreatectomy, low-dose administration of the beta-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. beta-Cell proliferation was measured by administration of 5-bromo-2'-deoxyuridine (BrdU) in the drinking water.

Results: Basal beta-cell proliferation was severely decreased with advanced age. Partial pancreatectomy greatly stimulated beta-cell proliferation in young mice but failed to increase beta-cell replication in old mice. Streptozotocin stimulated beta-cell replication in young mice but had little effect in old mice. Moreover, administration of GLP-1 agonist exendin-4 stimulated beta-cell proliferation in young but not in old mice. Surprisingly, adaptive beta-cell proliferation capacity was minimal after 12 months of age, which is early middle age for the adult mouse life span.

Conclusions: Adaptive beta-cell proliferation is severely restricted with advanced age in mice, whether stimulated by partial pancreatectomy, low-dose streptozotocin, or exendin-4. Thus, beta-cells in middle-aged mice appear to be largely postmitotic. Young rodents may not faithfully model the regenerative capacity of beta-cells in mature adult mice.

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Taconic cohort. Partial pancreatectomy (PP) induced β-cell replication in mice at 2 and 19 months of age. BrdU was administered for 2 weeks after the procedure before the mice were killed. A: Representative pancreatic β-cell histology of pancreas sections immunostained with antibodies against insulin (red) and BrdU (green) and counterstained with DAPI (blue) and photographed with a 40× objective. White arrows indicate insulin and BrdU copositive cells; yellow arrows denote BrdU-labeled non–insulin-containing cells within the islet. Scale bars: 100 μm in full image and 20 μm within inset. B: Quantitative analysis of β-cell regeneration following partial pancreatectomy as a function of age in mice. Results are expressed as percent BrdU-positive β-cells per day and represent means ± SEM (n = 4–6 animals per group). **P < 0.01 sham vs. partial pancreatectomy at 2 months. P <0.05 shams at 2 months vs. shams at 19 months. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 4: Taconic cohort. Partial pancreatectomy (PP) induced β-cell replication in mice at 2 and 19 months of age. BrdU was administered for 2 weeks after the procedure before the mice were killed. A: Representative pancreatic β-cell histology of pancreas sections immunostained with antibodies against insulin (red) and BrdU (green) and counterstained with DAPI (blue) and photographed with a 40× objective. White arrows indicate insulin and BrdU copositive cells; yellow arrows denote BrdU-labeled non–insulin-containing cells within the islet. Scale bars: 100 μm in full image and 20 μm within inset. B: Quantitative analysis of β-cell regeneration following partial pancreatectomy as a function of age in mice. Results are expressed as percent BrdU-positive β-cells per day and represent means ± SEM (n = 4–6 animals per group). **P < 0.01 sham vs. partial pancreatectomy at 2 months. P <0.05 shams at 2 months vs. shams at 19 months. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Our studies on aging were initially performed with F1 hybrid B6129SF1/J mice from The Jackson Laboratory. We chose this strain because it closely approximates the mixed genetic background of laboratory knockout mice (commonly derived from SV129-derived embryonic stem cells and crossed into c57B6). However, we could not rule out the possibility that our results are unique to the F1 hybrid B6129SF1/J strain from The Jackson Laboratory. Consequently, we performed additional studies on aging in a similar but separate genetic cohort, Taconic Farms F1 hybrid c57 SV129 mice. Because the Jackson and Taconic Farms lines have significantly diverged over the years (25), the Taconic Farms F1 hybrid c57 SV129 mice represent a similar but genetically distinct lineage compared with Jackson F1 hybrid B6129SF1/J mice. Consequently, the Taconic Farms F1 hybrid c57 SV129 mice should also approximate the mixed genetic background of laboratory knockout mice. As previously indicated, partial pancreatectomy was well tolerated in the Taconic cohort at 2 and 19 months of age. Partial pancreatectomy robustly induced β-cell regeneration in young Taconic mice (from 0.24 ± 0.09 to 1.33 ± 0.26% per day after partial pancreatectomy; P = 0.009) (Fig. 4). In contrast, partial pancreatectomy had no effect on β-cell proliferation in aged Taconic mice (from 0.020 ± 0.003 compared with 0.019 ± 0.003% per day after partial pancreatectomy; P = 0.84) (Fig. 4). These results independently confirm our observations in the Jackson cohort and further illustrate that partial pancreatectomy–induced β-cell regeneration becomes severely restricted in aged mice. Moreover, these additional studies indicate that our findings may be broadly applicable to genetically engineered mice, which frequently have a mixed c57 SV129 genetic background.


Adaptive beta-cell proliferation is severely restricted with advanced age.

Rankin MM, Kushner JA - Diabetes (2009)

Taconic cohort. Partial pancreatectomy (PP) induced β-cell replication in mice at 2 and 19 months of age. BrdU was administered for 2 weeks after the procedure before the mice were killed. A: Representative pancreatic β-cell histology of pancreas sections immunostained with antibodies against insulin (red) and BrdU (green) and counterstained with DAPI (blue) and photographed with a 40× objective. White arrows indicate insulin and BrdU copositive cells; yellow arrows denote BrdU-labeled non–insulin-containing cells within the islet. Scale bars: 100 μm in full image and 20 μm within inset. B: Quantitative analysis of β-cell regeneration following partial pancreatectomy as a function of age in mice. Results are expressed as percent BrdU-positive β-cells per day and represent means ± SEM (n = 4–6 animals per group). **P < 0.01 sham vs. partial pancreatectomy at 2 months. P <0.05 shams at 2 months vs. shams at 19 months. (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 4: Taconic cohort. Partial pancreatectomy (PP) induced β-cell replication in mice at 2 and 19 months of age. BrdU was administered for 2 weeks after the procedure before the mice were killed. A: Representative pancreatic β-cell histology of pancreas sections immunostained with antibodies against insulin (red) and BrdU (green) and counterstained with DAPI (blue) and photographed with a 40× objective. White arrows indicate insulin and BrdU copositive cells; yellow arrows denote BrdU-labeled non–insulin-containing cells within the islet. Scale bars: 100 μm in full image and 20 μm within inset. B: Quantitative analysis of β-cell regeneration following partial pancreatectomy as a function of age in mice. Results are expressed as percent BrdU-positive β-cells per day and represent means ± SEM (n = 4–6 animals per group). **P < 0.01 sham vs. partial pancreatectomy at 2 months. P <0.05 shams at 2 months vs. shams at 19 months. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Our studies on aging were initially performed with F1 hybrid B6129SF1/J mice from The Jackson Laboratory. We chose this strain because it closely approximates the mixed genetic background of laboratory knockout mice (commonly derived from SV129-derived embryonic stem cells and crossed into c57B6). However, we could not rule out the possibility that our results are unique to the F1 hybrid B6129SF1/J strain from The Jackson Laboratory. Consequently, we performed additional studies on aging in a similar but separate genetic cohort, Taconic Farms F1 hybrid c57 SV129 mice. Because the Jackson and Taconic Farms lines have significantly diverged over the years (25), the Taconic Farms F1 hybrid c57 SV129 mice represent a similar but genetically distinct lineage compared with Jackson F1 hybrid B6129SF1/J mice. Consequently, the Taconic Farms F1 hybrid c57 SV129 mice should also approximate the mixed genetic background of laboratory knockout mice. As previously indicated, partial pancreatectomy was well tolerated in the Taconic cohort at 2 and 19 months of age. Partial pancreatectomy robustly induced β-cell regeneration in young Taconic mice (from 0.24 ± 0.09 to 1.33 ± 0.26% per day after partial pancreatectomy; P = 0.009) (Fig. 4). In contrast, partial pancreatectomy had no effect on β-cell proliferation in aged Taconic mice (from 0.020 ± 0.003 compared with 0.019 ± 0.003% per day after partial pancreatectomy; P = 0.84) (Fig. 4). These results independently confirm our observations in the Jackson cohort and further illustrate that partial pancreatectomy–induced β-cell regeneration becomes severely restricted in aged mice. Moreover, these additional studies indicate that our findings may be broadly applicable to genetically engineered mice, which frequently have a mixed c57 SV129 genetic background.

Bottom Line: However, it is unknown whether this adaptive beta-cell regeneration capacity is retained into old age.We assessed adaptive beta-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: partial pancreatectomy, low-dose administration of the beta-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. beta-Cell proliferation was measured by administration of 5-bromo-2'-deoxyuridine (BrdU) in the drinking water.Basal beta-cell proliferation was severely decreased with advanced age.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

ABSTRACT

Objective: Regeneration of the insulin-secreting beta-cells is a fundamental research goal that could benefit patients with either type 1 or type 2 diabetes. beta-Cell proliferation can be acutely stimulated by a variety of stimuli in young rodents. However, it is unknown whether this adaptive beta-cell regeneration capacity is retained into old age.

Research design and methods: We assessed adaptive beta-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: partial pancreatectomy, low-dose administration of the beta-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. beta-Cell proliferation was measured by administration of 5-bromo-2'-deoxyuridine (BrdU) in the drinking water.

Results: Basal beta-cell proliferation was severely decreased with advanced age. Partial pancreatectomy greatly stimulated beta-cell proliferation in young mice but failed to increase beta-cell replication in old mice. Streptozotocin stimulated beta-cell replication in young mice but had little effect in old mice. Moreover, administration of GLP-1 agonist exendin-4 stimulated beta-cell proliferation in young but not in old mice. Surprisingly, adaptive beta-cell proliferation capacity was minimal after 12 months of age, which is early middle age for the adult mouse life span.

Conclusions: Adaptive beta-cell proliferation is severely restricted with advanced age in mice, whether stimulated by partial pancreatectomy, low-dose streptozotocin, or exendin-4. Thus, beta-cells in middle-aged mice appear to be largely postmitotic. Young rodents may not faithfully model the regenerative capacity of beta-cells in mature adult mice.

Show MeSH
Related in: MedlinePlus