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Cited by 327Pancreatic function and diabetesDiabetes Treatment and ManagementDiabetes and associated disorders

Adaptive β-Cell Proliferation Is Severely Restricted With Advanced Age

Open access
Rankin, Matthew M., Kushner, Jake A.·2009·Diabetes
DOI 10.2337/db08-1198PMC PMC2682671
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Abstract

OBJECTIVE: Regeneration of the insulin-secreting β-cells is a fundamental research goal that could benefit patients with either type 1 or type 2 diabetes. β-Cell proliferation can be acutely stimulated by a variety of stimuli in young rodents. However, it is unknown whether this adaptive β-cell regeneration capacity is retained into old age. RESEARCH DESIGN AND METHODS: We assessed adaptive β-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: partial pancreatectomy, low-dose administration of the β-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. β-Cell proliferation was measured by administration of 5-bromo-2′-deoxyuridine (BrdU) in the drinking water. RESULTS: Basal β-cell proliferation was severely decreased with advanced age. Partial pancreatectomy greatly stimulated β-cell proliferation in young mice but failed to increase β-cell replication in old mice. Streptozotocin stimulated β-cell replication in young mice but had little effect in old mice. Moreover, administration of GLP-1 agonist exendin-4 stimulated β-cell proliferation in young but not in old mice. Surprisingly, adaptive β-cell proliferation capacity was minimal after 12 months of age, which is early middle age for the adult mouse life span. CONCLUSIONS: Adaptive β-cell proliferation is severely restricted with advanced age in mice, whether stimulated by partial pancreatectomy, low-dose streptozotocin, or exendin-4. Thus, β-cells in middle-aged mice appear to be largely postmitotic. Young rodents may not faithfully model the regenerative capacity of β-cells in mature adult mice.

AI snapshot

Written from the paper’s full text.

TL;DR

In mice, adaptive β-cell proliferation stimulated by partial pancreatectomy, low-dose streptozotocin, or exendin-4 is robust in young adulthood but severely restricted by early middle age (12 months). Basal β-cell proliferation also declines with age, while acinar regeneration remains in old mice.

Key findings

  • Basal β-cell proliferation decreased from 0.18 ± 0.05 to 0.08 ± 0.02% per day between 2 and 8 months (P = 0.008), fell further to 0.03 ± 0.01% per day by 12 months (P = 0.03), and remained low at 14 and 19 months.
  • Partial pancreatectomy stimulated β-cell proliferation at 2 months (0.18 ± 0.05 to 1.80 ± 0.36% per day; P = 0.003) and 8 months (0.08 ± 0.02 to 1.06 ± 0.39% per day; P = 0.04), but failed at 19 months (0.03 ± 0.01 to 0.03 ± 0.00% per day; P = 0.84); 12 months showed an intermediate response (0.03 ± 0.01 to 0.25 ± 0.09% per day; P = 0.03), and 14 months showed no substantial increase (0.02 ± 0.01 to 0.05 ± 0.02% per day; P = 0.31).
  • Low-dose streptozotocin stimulated β-cell proliferation at 2 months (0.18 ± 0.05 to 0.55 ± 0.07% per day; P = 0.003) but had little effect at 15 months (0.02 ± 0.01 to 0.04 ± 0.01% per day; P = 0.17); exendin-4 stimulated proliferation at 2 months (0.76 ± 0.07% per day; P = 0.00001 vs sham) but not at 14 months (0.08 ± 0.03% per day; P = 0.13).
  • Acinar cell regeneration was preserved in aged mice: at 19 months, partial pancreatectomy increased acinar proliferation from 0.53 ± 0.11 to 1.07 ± 0.10% per day (P = 0.02).

Methods

  • Experimental mouse study across ages using male F1 hybrid B6129SF1/J mice from The Jackson Laboratory and a separate Taconic Farms F1 hybrid c57 SV129 cohort; stimuli were ~50% partial pancreatectomy, low-dose streptozotocin (30 mg/kg daily for 5 days), or exendin-4 (24 nmol/kg daily for 21 days).
  • β-Cell proliferation was measured by continuous BrdU in drinking water (1 mg/ml) for 14 or 21 days, with DAPI/insulin/BrdU or DAPI/insulin/BrdU/Ki67 staining; islet morphometry, RT-PCR, and immunoblotting were also performed.
  • Results are reported as means ± SE/SEM and compared with unpaired, two-tailed Student’s t tests.

Limitations

  • The paper states that the 19-month partial pancreatectomy cohort included only three mice, whereas other groups had four to seven animals.
  • The paper states that RT-PCR results are from a single experiment with technical repeats averaged, although representative data were confirmed in an independent experiment.
  • Evident from the text: all experiments used male mice of two F1 hybrid backgrounds, no human data are presented, and the mechanism linking age to proliferation restriction is not directly tested; aged streptozotocin and exendin-4 groups were 14–15 months, not 19 months.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2337/db08-1198

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 38 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Partial pancreatectomy reduced β-cell mass by approximately one-half.

    “partial pancreatectomy reduced β-cell mass by approximately one-half”
    Quote in the paperSubstantial claim
  • Findingcitation

    Basal β-cell proliferation decreased from 2 to 8 months (from 0.18 ± 0.05 to 0.08 ± 0.02% per day; P = 0.008).

    “Confirming our previous observations (17), basal β-cell proliferation decreased from 2 to 8 months (from 0.18 ± 0.05 to 0.08 ± 0.02% per day; P = 0.008) (Figs. 1 and 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Teta, 2005, Very slow turnover of β-cells in aged adult mice, Diabetes source

      Not checked in the free run.

  • Findingown data

    Partial pancreatectomy was well tolerated across a wide range of ages.

    “As expected, partial pancreatectomy was well tolerated across a wide range of ages.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Basal β-cell proliferation remained low in 14- and 19-month-old mice (P = 0.01 at 14 months compared with 2 months; P = 0.03 at 19 months compared with 2 months).

    “Basal β-cell proliferation further decreased by 12 months (to 0.03 ± 0.01% per day; P = 0.03) and remained low in 14- and 19-month-old mice (P = 0.01 at 14 months compared with 2 months; P = 0.03 at 19 months compared with 2 months).”
    Quote in the paperSubstantial claim
  • Findingown data

    β-Cell area and mass continuously increased with age in resected pancreata.

    “β-Cell area and mass also continuously increased with age in resected pancreata.”
    Quote in the paperSubstantial claim
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    Streptozotocin had little effect in aged mice: β-cell proliferation was only slightly increased in mice aged 15 months compared with controls.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Partial pancreatectomy modestly reduces β-cell mass while leaving sufficient β-cell function for normal control of glucose homeostasis.

    “Partial pancreatectomy modestly reduces β-cell mass while leaving sufficient β-cell function for normal control of glucose homeostasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Blood glucose values and postoperative weight loss were equivalent in pancreatectomized and sham-operated mice.

    “Blood glucose values and postoperative weight loss were equivalent in pancreatectomized and sham-operated mice (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Total β-cell area and β-cell mass continuously increased with age in control mice.

    “The total β-cell area and β-cell area mass continuously increased with age in control mice (Table 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    Low-dose streptozotocin was well tolerated and did not cause hyperglycemia or extensive weight loss.

    “Low-dose streptozotocin was well tolerated and did not cause hyperglycemia or extensive weight loss.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    β-Cell mass can slowly expand in adult rodents in response to increased insulin requirements or during pregnancy.

    “β-Cell mass can slowly expand in adult rodents in response to increased insulin requirements (3) or during pregnancy (4).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Bonner-Weir, 2001, β-Cell turnover: its assessment and implications, Diabetes source

      Not checked in the free run.

    • cites [4] Parsons, 1992, Adaptation of islets to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion, Endocrinology

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Splenic partial pancreatectomy is a reliable and well-tolerated procedure in adult mice of all ages.

    “Thus, splenic partial pancreactomy is a reliable and well-tolerated procedure in adult mice of all ages.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    p16Ink4a is differentially expressed in aging tissues and has been shown to restrict islet growth.

    “p16Ink4a is differentially expressed in aging tissues and has been shown to restrict islet growth (27,28).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Krishnamurthy, 2004, Ink4a/Arf expression is a biomarker of aging, J Clin Invest source

      Not checked in the free run.

    • cites [28] Krishnamurthy, 2006, p16INK4a induces an age-dependent decline in islet regenerative potential, Nature source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Age is a major factor limiting human β-cell regeneration.

    “In this study, we advance the hypothesis that age is a major factor limiting human β-cell regeneration.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Several recently discovered risk loci for type 2 diabetes have been implicated in cell cycle control of β-cells and could theoretically influence adult β-cell mass or alter the timing of cell cycle exit of adult β-cells.

    “Interestingly, several of the recently discovered risk loci for type 2 diabetes have been implicated in cell cycle control of β-cells and could theoretically influence adult β-cell mass or alter the timing of cell cycle exit of adult β-cells (36–39).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [36] Steinthorsdottir, 2007, A variant in CDKAL1 influences insulin response and risk of type 2 diabetes, Nat Genet source

      Not checked in the free run.

    • cites [37] Zeggini, 2007, Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes, Science source

      Not checked in the free run.

    • cites [38] Scott, 2007, A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants, Science source

      Not checked in the free run.

    • cites [39] Saxena, 2007, Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels, Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Continuous BrdU administration reduces proliferation of islet components by ∼25%, as measured by heavy water incorporation into DNA.

    “However, Hellerstein and colleagues (26) recently reported that continuous BrdU administration reduces proliferation of islet components by ∼25%, as measured by heavy water incorporation into DNA.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Chen, 2007, Measurement of pancreatic islet cell proliferation by heavy water labeling, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    Young rodents may not faithfully model the regenerative capacity of mature adult human β-cells.

    “Because our results in rodents indicate that β-cell regeneration capacity declines with age, we hypothesize that young rodents may not faithfully model the regenerative capacity of mature adult human β-cells.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Differential expression of negative regulators of cell cycle such as p16Ink4a or p15Ink4b could potentially explain the age-dependent decline in adaptive β-cell proliferation capacity.

    “Thus, differential expression of negative regulators of cell cycle such as p16Ink4a or p15Ink4b could potentially explain the age-dependent decline in adaptive β-cell proliferation capacity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Gestational diabetes mellitus is much more frequent with advanced maternal age.

    “Similarly, gestational diabetes mellitus is much more frequent with advanced maternal age (33,34).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Mestman, 1980, Outcome of diabetes screening in pregnancy and perinatal morbidity in infants of mothers with mild impairment in glucose tolerance, Diabetes Care source

      Not checked in the free run.

    • cites [34] Paulson, 2002, Pregnancy in the sixth decade of life: obstetric outcomes in women of advanced reproductive age, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regeneration of β-cell function in experimental animal models has been widely observed in rodents but remains elusive and controversial in humans.

    “Regeneration of β-cell function in experimental animal models has been widely observed in rodents but remains elusive and controversial in humans (13,14).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Scharfmann, 2008, Expanding human beta cells, Diabetologia source

      Not checked in the free run.

    • cites [14] Meier, 2008, Beta cell mass in diabetes: a realistic therapeutic target?, Diabetologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    β-cells could have a developmental program that allows them to replicate early in adulthood to match insulin secretion capacity to peripheral insulin requirements.

    “Under this schema, β-cells could have a developmental program that allows them to replicate early in adulthood to match insulin secretion capacity to peripheral insulin requirements.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The Jackson and Taconic Farms lines have significantly diverged over the years, so Taconic Farms F1 hybrid c57 SV129 mice represent a similar but genetically distinct lineage compared with Jackson F1 hybrid B6129SF1/J 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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Bothe, 2004, Genetic and behavioral differences among five inbred mouse strains commonly used in the production of transgenic and knockout mice, Genes Brain Behav source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Restricted β-cell mass expansion could have severe consequences in elderly patients with type 2 diabetes, limiting compensatory β-cell mass expansion to cope with increased insulin requirements.

    “Restricted β-cell mass expansion could have severe consequences in elderly patients with type 2 diabetes, limiting compensatory β-cell mass expansion to cope with increased insulin requirements.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Type 2 diabetes is typically a disease of the elderly, most commonly diagnosed during middle age or beyond.

  • May combine two claims.

    Premisecitation

    Continuous low-dose BrdU administration in the drinking water is generally well tolerated and does not severely reduce β-cell proliferation compared with short-term infusions of high-dose BrdU.

    “Continuous low-dose BrdU administration in the drinking water is generally well tolerated and does not severely reduce β-cell proliferation compared with short-term infusions of high-dose BrdU (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Teta, 2005, Very slow turnover of β-cells in aged adult mice, Diabetes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    β-Cell replication might then become fully restricted when adult insulin requirements are established in middle age.

    “β-Cell replication might then become fully restricted when adult insulin requirements are established in middle age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Islets from human cadaveric donors are typically in the 4th-6th decade of life and are therefore much more mature.

    “Notably, islets from human cadaveric donors are typically in the 4th–6th decade of life and are therefore much more mature (32).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Ihm, 2006, Effect of donor age on function of isolated human islets, Diabetes source

      Not checked in the free run.

21 of 21

  • The paper relies on this without support.

    Type 2 diabetes is typically a disease of the elderly, most commonly diagnosed during middle age or beyond.

    “Notably, type 2 diabetes is typically a disease of the elderly, most commonly diagnosed during middle age or beyond.”

  • The paper relies on this without support.

    The F1 hybrid B6129SF1/J strain closely approximates the mixed genetic background of laboratory knockout mice.

    “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).”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The ability of β-cells to expand after injury or a high-fat diet declines with age in both humans and mice.

    “The capacity of the β-cell to expand in response to injury or a high-fat diet decreases with age in both humans and mice [28,29].”

    From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [29]

  • Age-related declines of pancreatic islet function and of islet proliferative capacity have been described.

    “However, age-related declines of pancreatic islet function4, 14 and of islet proliferative capacity15, 16; have been described.”

    From Diabetes in Older Adults: A Consensus Report (2012) · cites this paper as [16]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Incorrect 12-month pancreatectomy weight change

    Minor

    In the Jackson cohort, the reported initial and final weights imply a loss of 8.4 g, not 8.0 g. The gap exceeds rounding to one decimal place.

    Reported 8 · recomputed 8.4

  • Figure 3 sample-size range excludes a reported group

    Minor

    Figure 3 includes the 19-month partial-pancreatectomy results but states that groups contained 4-6 animals; the methods say that cohort contained only three mice.

  • Exendin-4 BrdU-labeling periods conflict

    Minor

    The methods specify 21 days of BrdU labeling during exendin-4 treatment, whereas the caption covering the exendin-4 results says BrdU was administered for 2 weeks.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Maedler, 2006, Aging correlates with decreased β-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1, Diabetes, 55, 2455, 10.2337/db05-1586 · DOI · Paper page

Cited by

Sorted by citations

Authors
Rankin, M. M., & Kushner, J. A.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
Kushner, Jake A.
ORCID
Kushner, Jake A.
Venue
Diabetes
Publisher
American Diabetes Association
Published
2009-03-05
Volume
58
Issue
6
Pages
1365-1372
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db08-1198
PMC
PMC2682671
OpenAlex
W2101990128
Cited by
327
References
39
Citations by year
2026: 4 · 2025: 12 · 2024: 12 · 2023: 10 · 2022: 15 · 2021: 15 · 2020: 12 · 2019: 18 · 2018: 16 · 2017: 18 · 2016: 23 · 2015: 31 · 2014: 27 · 2013: 26 · 2012: 26
FWCI
29.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Juvenile Diabetes Research Foundation International
  • March of Dimes Foundation
  • Charles H. Hood Foundation
  • Children's Hospital of Philadelphia
  • University of Pennsylvania
  • Pediatric Endocrine Society
  • National Institutes of Health (DK 19525)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 19525, R01DK081469, K08DK064101, R03DK078546, P30DK019525)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
beta-cell proliferation, aging, beta cell regeneration, partial pancreatectomy, streptozotocin, exendin-4, GLP-1 receptor agonists, type 1 diabetes, type 2 diabetes
MeSH terms
Acclimatization, Aging, Animals, Cell Division, Female, Kinetics, Male, Mice, Inbred C57BL, Mice, Inbred Strains, Pancreatectomy, Insulin-Secreting Cells, Mice

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