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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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Low-dose streptozotocin (Stz) and exendin-4 induced β-cell replication in mice at 2 and 14–15 months of age. BrdU was administered for 2 weeks before the mice were killed. A: Low-dose streptozotocin. B: Exendin-4. 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 2: Low-dose streptozotocin (Stz) and exendin-4 induced β-cell replication in mice at 2 and 14–15 months of age. BrdU was administered for 2 weeks before the mice were killed. A: Low-dose streptozotocin. B: Exendin-4. 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 used the β-cell toxin streptozotocin to further test the hypothesis that β-cell regeneration capacity is restricted with advanced age. Streptozotocin is a robust stimulus of β-cell regeneration when administered in multiple low doses to adult mice (24). Low-dose streptozotocin was well tolerated and did not cause hyperglycemia or extensive weight loss. As expected, streptozotocin administration stimulated β-cell proliferation in mice aged 2 months by 0.36% per day compared with controls (from 0.18 ± 0.05 to 0.55 ± 0.07% per day after streptozotocin; P = 0.003) (Figs. 2 and 3). However, streptozotocin had little effect in aged mice: β-cell proliferation was only slightly increased in mice aged 15 months compared with controls (from 0.02 ± 0.01 to 0.04 ± 0.01% per day after streptozotocin; P = 0.17) (Figs. 2 and 3).


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

Rankin MM, Kushner JA - Diabetes (2009)

Low-dose streptozotocin (Stz) and exendin-4 induced β-cell replication in mice at 2 and 14–15 months of age. BrdU was administered for 2 weeks before the mice were killed. A: Low-dose streptozotocin. B: Exendin-4. 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 2: Low-dose streptozotocin (Stz) and exendin-4 induced β-cell replication in mice at 2 and 14–15 months of age. BrdU was administered for 2 weeks before the mice were killed. A: Low-dose streptozotocin. B: Exendin-4. 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 used the β-cell toxin streptozotocin to further test the hypothesis that β-cell regeneration capacity is restricted with advanced age. Streptozotocin is a robust stimulus of β-cell regeneration when administered in multiple low doses to adult mice (24). Low-dose streptozotocin was well tolerated and did not cause hyperglycemia or extensive weight loss. As expected, streptozotocin administration stimulated β-cell proliferation in mice aged 2 months by 0.36% per day compared with controls (from 0.18 ± 0.05 to 0.55 ± 0.07% per day after streptozotocin; P = 0.003) (Figs. 2 and 3). However, streptozotocin had little effect in aged mice: β-cell proliferation was only slightly increased in mice aged 15 months compared with controls (from 0.02 ± 0.01 to 0.04 ± 0.01% per day after streptozotocin; P = 0.17) (Figs. 2 and 3).

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