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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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Partial pancreatectomy (PP)–induced β-cell replication in mice at 2, 8, 12, 14, and 19 months of age. BrdU was administered for 2 weeks after the procedure before the mice were killed. 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. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: Partial pancreatectomy (PP)–induced β-cell replication in mice at 2, 8, 12, 14, and 19 months of age. BrdU was administered for 2 weeks after the procedure before the mice were killed. 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. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: We then tested whether partial pancreatectomy stimulates β-cell regeneration. To detect all proliferation events during acute β-cell regeneration, mice continuously received BrdU in the drinking water for 2 weeks after pancreatectomy and were then killed immediately. Partial pancreatectomy stimulated β-cell proliferation in mice aged 2 months (from 0.18 ± 0.05 to 1.80 ± 0.36% per day after partial pancreatectomy; P = 0.003) (Figs. 1 and 3). Partial pancreatectomy also stimulated β-cell proliferation in mice aged 8 months compared with control mice (from 0.08 ± 0.02 to 1.06 ± 0.39% per day after partial pancreatectomy; P = 0.04) (Figs. 1 and 3). Notably, the change in total number of BrdU-positive β-cells (the absolute increase in β-cell proliferation) was less in mice aged 8 months than in mice aged 2 months. Still, our results indicate that β-cell regeneration capacity is retained well into maturity, even in mice aged 8 months.


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

Rankin MM, Kushner JA - Diabetes (2009)

Partial pancreatectomy (PP)–induced β-cell replication in mice at 2, 8, 12, 14, and 19 months of age. BrdU was administered for 2 weeks after the procedure before the mice were killed. 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. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682671&req=5

Figure 1: Partial pancreatectomy (PP)–induced β-cell replication in mice at 2, 8, 12, 14, and 19 months of age. BrdU was administered for 2 weeks after the procedure before the mice were killed. 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. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: We then tested whether partial pancreatectomy stimulates β-cell regeneration. To detect all proliferation events during acute β-cell regeneration, mice continuously received BrdU in the drinking water for 2 weeks after pancreatectomy and were then killed immediately. Partial pancreatectomy stimulated β-cell proliferation in mice aged 2 months (from 0.18 ± 0.05 to 1.80 ± 0.36% per day after partial pancreatectomy; P = 0.003) (Figs. 1 and 3). Partial pancreatectomy also stimulated β-cell proliferation in mice aged 8 months compared with control mice (from 0.08 ± 0.02 to 1.06 ± 0.39% per day after partial pancreatectomy; P = 0.04) (Figs. 1 and 3). Notably, the change in total number of BrdU-positive β-cells (the absolute increase in β-cell proliferation) was less in mice aged 8 months than in mice aged 2 months. Still, our results indicate that β-cell regeneration capacity is retained well into maturity, even in mice aged 8 months.

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