Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice
Open accessAbstract
OBJECTIVE: The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of β-cell mass. RESEARCH DESIGN AND METHODS: We analyzed the capacity of β-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 β-cell mass and β-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of β-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and β-cell proliferation was analyzed to assess the regeneration of β-cells. We observed a fourfold increase in β-cell proliferation in young mice after STZ administration, whereas no changes in β-cell proliferation were observed in older mice. The capacity to expand β-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of β-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 p16Ink4aexpression in the β-cells. Young Bmi1−/− mice that prematurely upregulate p16Ink4afailed to expand β-cell mass in response to exendin-4, indicating that p16Ink4alevels are a critical determinant of β-cell mass expansion. CONCLUSIONS: β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16Ink4apathway.
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Written from the paper’s full text.
TL;DR
In mice, the capacity to expand or regenerate β-cell mass declines with age across high-fat diet, exendin-4, and streptozotocin models. This age-dependent decline is linked to reduced β-cell proliferation and regulation by the Bmi1/p16Ink4a pathway.
Key findings
- Young mice fed a high-fat diet for 8 weeks showed a fivefold increase in β-cell mass and maintained normoglycemia, whereas old mice showed no β-cell mass increase and became diabetic, with fasting blood glucose consistently >200 mg/dl and glucose >400 mg/dl at 120 min during glucose tolerance testing.
- β-Cell proliferation increased in young mice after high-fat diet (7.5-fold Ki67-positive and 2.3-fold PCNA-positive β-cells), exendin-4 (4-fold Ki67 and 5.5-fold PCNA), and streptozotocin (4-fold Ki67 and 5-fold PCNA), but old mice showed no changes in any model.
- Exendin-4 increased β-cell mass twofold in young mice but not old mice; young Bmi1−/− mice with premature p16Ink4a upregulation failed to expand β-cell mass or proliferation after exendin-4, unlike wild-type littermates (twofold mass increase and threefold proliferation increase).
- p16Ink4a levels increased with age in isolated islets, while Bmi1 levels were higher in young islets and increased after high-fat diet or exendin-4; Bmi1 repressed p16Ink4a, and loss of Bmi1 increased H3K9 acetylation at the Ink4a/Arf locus.
Methods
- Male C57BL/6 mice were studied as young (6-week-old) and old (7- to 8-month-old); high-fat diet experiments used 12 young or 12 old mice fed normal or high-fat diet for 8 weeks, exendin-4 experiments used six young and six old mice injected with exendin-4 (10 nmol/kg) or PBS for 7 days, and streptozotocin experiments used six young and six old mice given a single 90 mg/kg dose and killed at 7 days.
- Outcomes included fasting blood glucose, insulin and glucose tolerance tests, β-cell mass, and immunohistochemistry for insulin, Ki67, PCNA, p16Ink4a, Bmi1, cyclin D2, and p27, plus TUNEL; islets were isolated for immunoblotting, and ChIP was used to assess H3K9 acetylation at the Ink4a/Arf locus.
- Min6 cells were transfected with Bmi1 or control constructs; statistical significance was assessed by unpaired Student’s t test and confirmed by one-way ANOVA for repeated measures, with P < 0.05 considered significant.
Limitations
- The paper states caution is needed in extrapolating from short-lived rodents to long-lived humans, where cellular senescence might be regulated by alternative mechanisms.
- The paper notes that the β-cell population is heterogeneous and aging may change its composition, and that other processes in humans—altered stem/progenitor cell function, increased apoptosis, altered growth factor profiles, and immune changes—may contribute to diminished regenerative capacity.
- The paper states it is possible the Bmi1/p16Ink4a pathway acts in putative stem cells rather than β-cells, and that activation of Bmi1 in distinct pancreatic cell types will be needed to identify the compartment regulating β-cell mass; evident from the text, the experiments are limited to male mice, specific ages, short-term models, and small group sizes (often three to six mice per group).
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- Findingown data
Old mice become diabetic on a high-fat diet.
“Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic.”
Quote in the paperSubstantial claim - Findingown data
Old mice do not display increases in β-cell mass in response to a high-fat diet.
“Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic.”
Quote in the paperSubstantial claim - Findingown data
No changes in β-cell proliferation are observed in older mice after streptozotocin administration.
“We observed a fourfold increase in β-cell proliferation in young mice after STZ administration, whereas no changes in β-cell proliferation were observed in older mice.”
Quote in the paperSubstantial claim - Findingown data
Old mice do not display increases in β-cell proliferation in response to a high-fat diet.
“Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic.”
Quote in the paperSubstantial claim - Findingown data
The capacity to expand β-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 declines with age.
“The capacity to expand β-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age.”
Quote in the paperSubstantial claim
- Findingown data
β-cell proliferation increases fourfold in young mice after streptozotocin administration.
“We observed a fourfold increase in β-cell proliferation in young mice after STZ administration, whereas no changes in β-cell proliferation were observed in older mice.”
Quote in the paperSubstantial claim - Findingown data
Young mice respond to a high-fat diet by increasing β-cell mass.
“Young mice responded to high-fat diet by increasing β-cell mass and β-cell proliferation and maintaining normoglycemia.”
Quote in the paperSubstantial claim - Findingown data
The ability of β-cell mass to expand correlates with higher levels of Bmi1 in β-cells.
“The ability of β-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 p16Ink4aexpression in the β-cells.”
Quote in the paperSubstantial claim - Findingown data
The ability of β-cell mass to expand correlates with decreased levels of p16Ink4a in β-cells.
“The ability of β-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 p16Ink4aexpression in the β-cells.”
Quote in the paperSubstantial claim - Findingown data
Young mice respond to a high-fat diet by increasing β-cell proliferation.
“Young mice responded to high-fat diet by increasing β-cell mass and β-cell proliferation and maintaining normoglycemia.”
Quote in the paperSubstantial claim - Findingown data
Young Bmi1−/− mice that prematurely upregulate p16Ink4a fail to expand β-cell mass in response to exendin-4.
“Young Bmi1−/− mice that prematurely upregulate p16Ink4afailed to expand β-cell mass in response to exendin-4, indicating that p16Ink4alevels are a critical determinant of β-cell mass expansion.”
Quote in the paperSubstantial claim - Findingown data
Young mice maintain normoglycemia on a high-fat diet.
“Young mice responded to high-fat diet by increasing β-cell mass and β-cell proliferation and maintaining normoglycemia.”
Quote in the paperSubstantial claim - Findingown data
After 8 weeks of high-fat diet, both young and old mice display decreased insulin sensitivity compared with mice on a normal diet.
“Insulin tolerance testing performed after 8 weeks of high-fat diet showed that both young and old mice displayed decreased insulin sensitivity compared with mice on a normal diet (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data
Blood glucose levels of old mice after 8 weeks of high-fat diet remained >400 mg/dl by the end of the 120-min glucose tolerance test.
“Glucose tolerance tests showed that blood glucose levels of old mice after 8 weeks of high-fat diet remained >400 mg/dl by the end of the 120-min testing period.”
Quote in the paperSubstantial claim - Findingown data
Young mice after STZ administration had proliferating β-cells.
“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).”
Quote in the paperSubstantial claim - Findingown data
In young mice treated with exendin-4 for 7 days, the number of PCNA-positive β-cells increased 5.5-fold compared with the control group.
“A 4-fold increase of Ki67-positive β-cells and a 5.5-fold increase of PCNA-positive β-cells was observed in the young mice treated with exendin-4 compared with the control group.”
Quote in the paperSubstantial claim - Findingown data
In older mice after STZ administration, no difference in PCNA-positive β-cells was observed.
“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.”
Quote in the paperSubstantial claim - Findingown data
In 14-day-old Bmi1−/− mice, p16Ink4a was upregulated in islets compared with wild-type littermates.
“Immunohistochemistry analysis of pancreatic sections from 14-day-old Bmi1−/− mice and wild-type littermates showed p16Ink4a was upregulated in islets of Bmi1−/− mice (Fig. 4).”
Quote in the paperSubstantial claim - Findingown data
β-cells of 6-month-old mice showed high levels of p16Ink4a.
“Immunohistochemistry revealed that β-cells of 1-month-old mice showed little expression of p16Ink4a, in contrast to high levels of p16Ink4a in 6-month-old mice (Fig. 2D).”
Quote in the paperSubstantial claim - Findingown data
Loss of Bmi1 results in premature increase in the expression of p16ink4a.
“We further showed that loss of Bmi1 results in premature increase in the expression of p16ink4a.”
Quote in the paperSubstantial claim - Findingown data
In young mice treated with exendin-4, p16Ink4a expression levels in islets declined markedly.
“A marked decline of p16Ink4a expression levels was observed in islets of young mice (Fig. 3D and E), which is concomitant with increased Bmi1 levels (Fig. 3H and I).”
Quote in the paperSubstantial claim - Findingown data
In old mice, exendin-4 treatment did not change the number of PCNA-positive β-cells compared with untreated old mice.
“In contrast, the number of Ki67- and PCNA-positive β-cells did not change in old mice after treatment with exendin-4 compared with untreated old mice (Fig. 3B and C).”
Quote in the paperSubstantial claim - Findingown data
Pancreas weight did not show any significant increase after 8 weeks of high-fat diet in both young and old mice.
“Moreover, pancreas weight did not show any significant increase after 8 weeks of high-fat diet in both young and old mice (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
Islets isolated from old mice did not show appreciable levels of Bmi1.
“In contrast, islets isolated from old mice did not show appreciable levels of Bmi1.”
Quote in the paperSubstantial claim - Findingown data
Young mice fed a high-fat diet did not show fasting blood glucose levels significantly different from young mice fed a normal diet.
“In contrast, young mice fed a high-fat diet did not show fasting blood glucose levels that were significantly different from young mice fed a normal diet.”
Quote in the paperSubstantial claim - Findingown data
Older mice displayed fasting blood glucose levels consistently >200 mg/dl after 8 weeks of high-fat diet.
“Measurement of fasting blood glucose revealed that older mice displayed fasting blood glucose levels consistently >200 mg/dl after 8 weeks of high-fat diet, indicating that these mice were unable to maintain glucose homeostasis (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
In islets isolated from 4-week-old Bmi1−/− mice, p16Ink4a levels were increased compared with wild-type mice.
“To directly test whether Bmi1 regulates p16Ink4a, we measured the levels of p16Ink4a in islets isolated from 4-week-old wild-type and Bmi1−/− mice. Immunoblots showed increased levels of p16Ink4a in islets isolated from Bmi1−/− mice (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
Old mice fed high-fat diet did not show any changes in β-cell mass compared with control old mice.
“In contrast, old mice fed high-fat diet did not show any changes in β-cell mass compared with control old mice (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
In old mice, exendin-4 treatment did not decrease p16Ink4a levels in β-cells.
“In contrast, exendin-4 treatment did not lead to a decrease of p16Ink4a levels in the β-cells in the old mice (Fig. 3F and G).”
Quote in the paperSubstantial claim - Findingown data
p16Ink4a levels increase with age in isolated islets.
“As shown inFig. 2C, p16Ink4a levels increase with age in isolated islets.”
Quote in the paperSubstantial claim - Findingown data
In old mice, exendin-4 treatment did not change the number of Ki67-positive β-cells compared with untreated old mice.
“In contrast, the number of Ki67- and PCNA-positive β-cells did not change in old mice after treatment with exendin-4 compared with untreated old mice (Fig. 3B and C).”
Quote in the paperSubstantial claim - Findingown data
In old mice, Bmi1 levels did not differ much between exendin-4-treated and PBS control groups.
“Furthermore, levels of Bmi1 (Fig. 3J and K) did not show much difference between the exendin-4–treated mice and the PBS control group.”
Quote in the paperNot a substantial claim - Findingown data
In young mice after STZ administration, Ki67-positive β-cells increased fourfold.
“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.”
Quote in the paperSubstantial claim - Findingown data
A 7.5-fold increase of Ki67-positive β-cells was observed in young mice fed high-fat diet compared with the control group.
“A 7.5-fold increase of Ki67-positive β-cells and a 2.3-fold increase of PCNA-positive β-cells was observed in the young mice fed high-fat diet compared with the control group.”
Quote in the paperSubstantial claim - Findingown data
High Bmi1 levels were apparent in islets isolated from young mice.
“High Bmi1 levels were apparent in islets isolated from young mice, and increased levels of Bmi1 were apparent after high-fat diet.”
Quote in the paperSubstantial claim - Findingown data
In older mice after STZ administration, no difference in Ki67-positive β-cells was observed.
“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.”
Quote in the paperSubstantial claim - Findingown data
The number of Ki67-positive β-cells did not change in old mice after a high-fat diet compared with those fed normal diet.
“In contrast, the number of Ki67- and PCNA-positive β-cells did not change in old mice after a high-fat diet compared with those fed normal diet (Fig. 2A and B).”
Quote in the paperSubstantial claim - Findingown data
Both young and old mice that received single-dose STZ administration displayed hyperglycemia.
“Both young and old mice that had received single-dose STZ administration displayed hyperglycemia (Fig. 6A).”
Quote in the paperNot a substantial claim - Findingown data
Young mice after 8 weeks of high-fat diet reached baseline by the end of the 120-min glucose tolerance test.
“By contrast, young mice after 8 weeks of high-fat diet reached baseline by the end of the 120-min testing period (Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
Young mice after 8 weeks of high-fat diet showed a fivefold increase in β-cell mass compared with the normal-diet group.
“Young mice after 8 weeks of high-fat diet showed a fivefold increase in β-cell mass compared with the normal-diet group.”
Quote in the paperSubstantial claim - Findingown data
A 2.3-fold increase of PCNA-positive β-cells was observed in young mice fed high-fat diet compared with the control group.
“A 7.5-fold increase of Ki67-positive β-cells and a 2.3-fold increase of PCNA-positive β-cells was observed in the young mice fed high-fat diet compared with the control group.”
Quote in the paperSubstantial claim - Findingown data
In Bmi1−/− mice, there was no difference in β-cell mass between exendin-4- and PBS-treated groups.
“In contrast, no difference in β-cell mass was found between exendin-4– and PBS-treated Bmi1−/− mice.”
Quote in the paperSubstantial claim - Findingown data
In islets isolated from 6-week-old Bmi1−/− mice, H3K9 acetylation at the Ink4a/Arf locus was increased compared with wild-type littermates.
“We examined the levels of H3K9 acetylation associated with the Ink4a/Arf locus in islets isolated from 6-week-old Bmi1−/− mice and their wild-type littermates. In the absence of Bmi1, the levels of H3K9 acetylation were increased, suggesting that Bmi1 mediated repression of p16Ink4a via modulation of chromatin structure (Fig. 5C).”
Quote in the paperNot a substantial claim - Findingown data
Expression of myc-tagged Bmi1 in Min6 cells reduced p16Ink4a protein levels.
“The expression of myc-tagged Bmi1 in the Min6 cells resulted in reduced levels of p16Ink4a protein, thus confirming the repressive effect of Bmi1 on p16Ink4a expression (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data
Old mice injected with STZ had limited numbers of Ki67- or PCNA-positive β-cells.
“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).”
Quote in the paperSubstantial claim - Findingown data
High levels of p16Ink4a in islets from old mice did not change with high-fat diet.
“In contrast, high levels of p16Ink4a in islets from old mice did not change with high-fat diet (Fig. 2E).”
Quote in the paperSubstantial claim - Findingown data
In wild-type mice treated with exendin-4, β-cell proliferation increased threefold.
“We observed a threefold increase in β-cell proliferation after exendin-4 treatment in wild-type mice, whereas no increase was observed in Bmi1−/− mice (Fig. 5E).”
Quote in the paperSubstantial claim - Findingown data
In 14-day-old Bmi1−/− mice, cyclin D2 and p27 levels in islets were unaffected by the absence of Bmi1.
“Other cell cycle targets cyclin D2 and p27 were unaffected by the absence of Bmi1 (Fig. 4).”
Quote in the paperNot a substantial claim - Findingown data
The number of PCNA-positive β-cells did not change in old mice after a high-fat diet compared with those fed normal diet.
“In contrast, the number of Ki67- and PCNA-positive β-cells did not change in old mice after a high-fat diet compared with those fed normal diet (Fig. 2A and B).”
Quote in the paperSubstantial claim - Findingown data
In young mice treated with exendin-4 for 7 days, the number of Ki67-positive β-cells increased 4-fold compared with the control group.
“A 4-fold increase of Ki67-positive β-cells and a 5.5-fold increase of PCNA-positive β-cells was observed in the young mice treated with exendin-4 compared with the control group.”
Quote in the paperSubstantial claim - Findingown data
In Bmi1−/− mice treated with exendin-4, no increase in β-cell proliferation was observed.
“We observed a threefold increase in β-cell proliferation after exendin-4 treatment in wild-type mice, whereas no increase was observed in Bmi1−/− mice (Fig. 5E).”
Quote in the paperSubstantial claim - Findingown data
In islets isolated from young mice, low levels of p16ink4a decreased after 8 weeks of high-fat diet feeding.
“In islets isolated from young mice, low levels of p16ink4a were apparent, which decreased after 8 weeks of high-fat diet feeding.”
Quote in the paperSubstantial claim - Findingown data
After exendin-4 treatment, β-cell mass in young mice showed a twofold increment compared with the control group injected with PBS.
“After exendin-4 treatment, β-cell mass in young mice showed a twofold increment compared with control group injected with PBS.”
Quote in the paperSubstantial claim - Findingown data
Old mice treated with exendin-4 did not show any increases in their β-cell mass.
“In contrast, old mice treated with exendin-4 did not show any increases in their β-cell mass (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
No TUNEL staining was observed in all groups.
“No TUNEL staining (as a measure of apoptosis) was observed in all groups (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
In wild-type mice treated with exendin-4 for 7 days, β-cell mass increased twofold compared with PBS-injected controls.
“After exendin-4 treatment, a twofold increase of β-cell mass was observed in the wild-type mice compared with the PBS-injected control group (Fig. 5D).”
Quote in the paperSubstantial claim - Findingown data
In young mice treated with exendin-4, Bmi1 levels in islets increased.
“A marked decline of p16Ink4a expression levels was observed in islets of young mice (Fig. 3D and E), which is concomitant with increased Bmi1 levels (Fig. 3H and I).”
Quote in the paperNot a substantial claim - Findingown data
In young mice after STZ administration, PCNA-positive β-cells increased fivefold.
“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.”
Quote in the paperSubstantial claim - Findingown data
Bmi1 levels increased in islets from young mice after high-fat diet.
“High Bmi1 levels were apparent in islets isolated from young mice, and increased levels of Bmi1 were apparent after high-fat diet.”
Quote in the paperNot a substantial claim - Findingown data
β-cells of 1-month-old mice showed little expression of p16Ink4a.
“Immunohistochemistry revealed that β-cells of 1-month-old mice showed little expression of p16Ink4a, in contrast to high levels of p16Ink4a in 6-month-old mice (Fig. 2D).”
Quote in the paperSubstantial claim - Findingown data
The age-dependent decline in the capacity for β-cell mass expansion coincides with reduced β-cell proliferation.
“We also show that the age-dependent decline in the capacity for β-cell mass expansion coincides with reduced β-cell proliferation.”
Quote in the paperSubstantial claim - Findingown data
β-cell proliferation is correlated with changes in expression of Bmi1 and p16Ink4a in β-cells.
“We have correlated β-cell proliferation with changes in expression of Bmi1 and p16Ink4a in β-cells that serve as both biological markers and effectors of aging.”
Quote in the paperSubstantial claim - Premisecitation
The endocrine pancreas has endogenous renewal capacity in response to metabolic demands such as pregnancy and insulin resistance.
“Several studies have shown that the endocrine pancreas has endogenous renewal capacity in response to metabolic demands such as pregnancy and insulin resistance (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Bouwens, 2005, Regulation of pancreatic beta-cell mass, Physiol Rev source
Not checked in the free run.
- Premisecitation
A comparable increase in insulin content was not observed in 5- or 15-month-old rats after 90% pancreatectomy.
“For example, a threefold increase of insulin content was measured in the residual pancreas after 90% pancreatectomy in 1-month-old rats; however, a comparable increase was not observed in rats that were 5 or 15 months old (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Tanigawa, 1997, Effect of aging on B-cell function and replication in rat pancreas after 90% pancreatectomy, Pancreas source
Not checked in the free run.
- Interpretationown data
p16Ink4a levels are a critical determinant of β-cell mass expansion.
“Young Bmi1−/− mice that prematurely upregulate p16Ink4afailed to expand β-cell mass in response to exendin-4, indicating that p16Ink4alevels are a critical determinant of β-cell mass expansion.”
Quote in the paperSubstantial claim- Rests on an assumption: p16Ink4a inhibits the cyclin-dependent kinase 4 (CDK4)-cyclin D2 complex and can inhibit cell cycle progression and regeneration of islet cells.
- Rests on an assumption: Transgenic mice that overexpressed p16Ink4a showed reduced islet cell proliferation and a reduction in the regenerative capacity of islets after toxin-mediated destruction.
- Rests on an assumption: Bmi1 loss affects β-cell mass expansion primarily through p16Ink4a upregulation, so Bmi1 knockout mice isolate the effect of premature p16Ink4a upregulation.
- Interpretationown data
β-Cell proliferation and regeneration are regulated by the Bmi1/p16Ink4a pathway.
“β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16Ink4apathway.”
Quote in the paperSubstantial claim- Rests on an assumption: p16Ink4a inhibits the cyclin-dependent kinase 4 (CDK4)-cyclin D2 complex and can inhibit cell cycle progression and regeneration of islet cells.
- Rests on an assumption: Transgenic mice that overexpressed p16Ink4a showed reduced islet cell proliferation and a reduction in the regenerative capacity of islets after toxin-mediated destruction.
- Rests on an assumption: Bmi1 loss affects β-cell mass expansion primarily through p16Ink4a upregulation, so Bmi1 knockout mice isolate the effect of premature p16Ink4a upregulation.
- Interpretationown data
β-Cell proliferation declines with age.
“β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16Ink4apathway.”
Quote in the paperSubstantial claim - Premisecitation
Defective insulin secretion in type 1 and type 2 diabetes is caused in part by loss of β-cell mass.
“Defective insulin secretion in both forms of diabetes is caused in part by loss of β-cell mass (1–4).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] Butler, 2003, β-Cell deficit and increased β-cell apoptosis in humans with type 2 diabetes, Diabetes source
Not checked in the free run.
- cites [2] Gepts, 1965, Pathologic anatomy of the pancreas in juvenile diabetes mellitus, Diabetes source
Not checked in the free run.
- cites [3] Gepts, 1978, Islet cell survival determined by morphology: an immunocytochemical study of the islets of Langerhans in juvenile diabetes mellitus, Diabetes source
Not checked in the free run.
- cites [4] Junker, 1977, An autopsy study of the islets of Langerhans in acute-onset juvenile diabetes mellitus, Acta Pathol Microbiol Scand [A]
Not checked in the free run.
- Premisecitation
A threefold increase of insulin content was measured in the residual pancreas after 90% pancreatectomy in 1-month-old rats.
“For example, a threefold increase of insulin content was measured in the residual pancreas after 90% pancreatectomy in 1-month-old rats; however, a comparable increase was not observed in rats that were 5 or 15 months old (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Tanigawa, 1997, Effect of aging on B-cell function and replication in rat pancreas after 90% pancreatectomy, Pancreas source
Not checked in the free run.
- Premisecitation
New β-cells can arise from proliferation of preexisting β-cells.
“Lineage tracing experiments show that new β-cells can arise from proliferation of preexisting β-cells (8).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Dor, 2004, Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation, Nature source
Not checked in the free run.
- Premisecitation
Regeneration of β-cell mass occurs in rodents after injury or genetic ablation of β-cells.
“Regeneration occurs in rodents after injury or genetic ablation of β-cells (7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Bonner-Weir, 2006, Are there pancreatic progenitor cells from which new islets form after birth?, Nat Clin Pract Endocrinol Metab source
Not checked in the free run.
- Interpretationown data
The capacity of β-cells to regenerate declines with age.
“β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16Ink4apathway.”
Quote in the paperSubstantial claim - Interpretationown data
The age-dependent rise of p16Ink4a levels regulates the age-dependent decline in β-cell proliferation and β-cell mass expansion.
“These data further underscore the importance of the age-dependent rise of p16Ink4a levels in regulating age-dependent decline in β-cell proliferation and β-cell mass expansion.”
Quote in the paperSubstantial claim - Premisecitation
Blood glucose values in 1-month-old rats declined 2 weeks after 90% pancreatectomy.
“Moreover, consistent with the adaptive increase in pancreatic insulin content in the 1-month-old but not older animals after a 90% pancreatectomy, blood glucose values in the 1-month-old rats declined 2 weeks after surgery, whereas no such decline was observed in 5- and 15-month-old rats (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Tanigawa, 1997, Effect of aging on B-cell function and replication in rat pancreas after 90% pancreatectomy, Pancreas source
Not checked in the free run.
- Interpretationown data
Older mice were unable to maintain glucose homeostasis after 8 weeks of high-fat diet.
“Measurement of fasting blood glucose revealed that older mice displayed fasting blood glucose levels consistently >200 mg/dl after 8 weeks of high-fat diet, indicating that these mice were unable to maintain glucose homeostasis (Fig. 1C).”
Quote in the paperSubstantial claim - Interpretationown data
Bmi1 mediates repression of p16Ink4a via modulation of chromatin structure.
“In the absence of Bmi1, the levels of H3K9 acetylation were increased, suggesting that Bmi1 mediated repression of p16Ink4a via modulation of chromatin structure (Fig. 5C).”
Quote in the paperSubstantial claim - Premisecitation
A single injection of STZ leads to loss of approximately 50% of β-cells.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Bonner-Weir, 1981, Responses of neonatal rat islets to streptozotocin: limited B-cell regeneration and hyperglycemia, Diabetes source
Not checked in the free run.
- Premisecitation
No decline in blood glucose was observed in 5- and 15-month-old rats after 90% pancreatectomy.
“Moreover, consistent with the adaptive increase in pancreatic insulin content in the 1-month-old but not older animals after a 90% pancreatectomy, blood glucose values in the 1-month-old rats declined 2 weeks after surgery, whereas no such decline was observed in 5- and 15-month-old rats (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Tanigawa, 1997, Effect of aging on B-cell function and replication in rat pancreas after 90% pancreatectomy, Pancreas source
Not checked in the free run.
- Interpretationown data
Bmi1 represses p16Ink4a expression.
“The expression of myc-tagged Bmi1 in the Min6 cells resulted in reduced levels of p16Ink4a protein, thus confirming the repressive effect of Bmi1 on p16Ink4a expression (Fig. 5B).”
Quote in the paperSubstantial claim - Premisecitation
Studies reporting an increase in β-cell mass with GLP-1-based therapies were undertaken in young rodents.
“Studies to date that have reported an increase in β-cell mass with glucagon-like peptide 1 (GLP-1)-1 based therapies were undertaken in young rodents (17–21).”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [17] Farilla, 2002, Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats, Endocrinology source
Not checked in the free run.
- cites [18] Hadjiyanni, 2008, Exendin-4 modulates diabetes onset in nonobese diabetic mice, Endocrinology source
Not checked in the free run.
- cites [19] Li, 2003, Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis, J Biol Chem source
Not checked in the free run.
- cites [20] Sherry, 2007, Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells, Endocrinology source
Not checked in the free run.
- cites [21] Xu, 1999, Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats, Diabetes source
Not checked in the free run.
- Interpretationown data
The capacity of β-cell mass to expand in response to glucoincretin hormone challenge is severely diminished with aging.
“These data suggest that as adaptive expansion associated with insulin resistance, the capacity of β-cell mass to expand in response to glucoincretin hormones challenge is severely diminished with aging.”
Quote in the paperSubstantial claim - Interpretationown data
Levels of p16ink4a are the primary determinant of the capacity to expand β-cell mass.
“This result indicates that levels of p16ink4a are the primary determinant of the capacity to expand β-cell mass.”
Quote in the paperSubstantial claim- Rests on an assumption: p16Ink4a inhibits the cyclin-dependent kinase 4 (CDK4)-cyclin D2 complex and can inhibit cell cycle progression and regeneration of islet cells.
- Rests on an assumption: Transgenic mice that overexpressed p16Ink4a showed reduced islet cell proliferation and a reduction in the regenerative capacity of islets after toxin-mediated destruction.
- Rests on an assumption: Bmi1 loss affects β-cell mass expansion primarily through p16Ink4a upregulation, so Bmi1 knockout mice isolate the effect of premature p16Ink4a upregulation.
- Premisecitation
Long-term bromodeoxyuridine labeling in 1-year-old mice suggests that β-cell replication rates decline with age.
“Furthermore, long-term bromodeoxyuridine labeling in 1-year-old mice also suggests that β-cell replication rates decline with age (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Teta, 2005, Very slow turnover of β-cells in aged adult mice, Diabetes source
Not checked in the free run.
- Interpretationown data
Young mice, unlike old mice, have the capacity to proliferate and regenerate β-cell mass after β-cell destruction.
“These data indicate that young mice, unlike old mice, have the capacity to proliferate and regenerate β-cell mass after β-cell destruction.”
Quote in the paperSubstantial claim - Premisecitation
The decline in β-cell proliferation with age correlates with increased expression of p16Ink4a in islet cells.
“The decline in β-cell proliferation with age correlates with increased expression of the cell cycle regulator p16Ink4a in islet cells (15).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Krishnamurthy, 2006, p16INK4a induces an age-dependent decline in islet regenerative potential, Nature source
Not checked in the free run.
- Interpretationown data
Older mice have a limited capacity to expand β-cell mass because of age-related accumulation of p16Ink4a.
“Our data suggest that the older mice, unlike younger mice, have a limited capacity to expand β-cell mass because of age-related accumulation of p16Ink4a.”
Quote in the paperSubstantial claim- Rests on an assumption: p16Ink4a inhibits the cyclin-dependent kinase 4 (CDK4)-cyclin D2 complex and can inhibit cell cycle progression and regeneration of islet cells.
- Rests on an assumption: Transgenic mice that overexpressed p16Ink4a showed reduced islet cell proliferation and a reduction in the regenerative capacity of islets after toxin-mediated destruction.
- Rests on an assumption: Bmi1 loss affects β-cell mass expansion primarily through p16Ink4a upregulation, so Bmi1 knockout mice isolate the effect of premature p16Ink4a upregulation.
- Premisecitation
The rate of β-cell proliferation gradually declines with aging in rats to a steady state by 7 months of age.
“The rate of β-cell proliferation gradually declines with aging in rats to a steady state by 7 months of age (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Montanya, 2000, Linear correlation between β-cell mass and body weight throughout the lifespan in Lewis rats: role of β-cell hyperplasia and hypertrophy, Diabetes source
Not checked in the free run.
- Premisecitation
A 1-week daily injection of exendin-4 resulted in a twofold increase in β-cell mass.
“A 1-week daily injection of exendin-4 resulted in a twofold increase in β-cell mass (30).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Buteau, 2006, Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic β-cell mass, Diabetes source
Not checked in the free run.
- Interpretationown data
Young mice, unlike old mice, have the capacity to expand β-cell mass to adapt to insulin resistance.
“Thus, young mice, unlike old mice, have the capacity to expand β-cell mass to adapt to insulin resistance.”
Quote in the paperSubstantial claim - Interpretationown data
Age-related changes that lead to β-cell senescence may be a significant contributing factor to reduced tissue homeostasis and regeneration in older mice.
“Our data indicate that age-related changes that lead to β-cell senescence may be a significant contributing factor to reduced tissue homeostasis and regeneration in older mice.”
Quote in the paperSubstantial claim - Interpretationown data
The plasticity of β-cell mass was correlated with β-cell proliferation and the regulation of the Ink4/Arf locus.
“The plasticity of β-cell mass was correlated with β-cell proliferation and the regulation of the Ink4/Arf locus.”
Quote in the paperSubstantial claim - Interpretationown data
Age-dependent decline in β-cell proliferation curtails the ability of the endocrine pancreas to expand or regenerate β-cell mass in response to changes in metabolic demands, growth factors, or injury.
“Our data suggests that age-dependent decline in β-cell proliferation curtails the ability of the endocrine pancreas to expand or regenerate β-cell mass to respond to changes in metabolic demands, growth factors, or injury.”
Quote in the paperSubstantial claim - Premisecitation
Age-induced increase in p16Ink4a limits the regenerative capacity of β-cells with aging.
“Moreover, the age-induced increase in p16Ink4a has been shown to limit the regenerative capacity of β-cells with aging (15).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Krishnamurthy, 2006, p16INK4a induces an age-dependent decline in islet regenerative potential, Nature source
Not checked in the free run.
- Interpretationown data
Age-related changes within the β-cell may be a significant contributing factor to reduced tissue homeostasis and regeneration in older individuals.
“Our data suggests that age-related changes within the β-cell may be a significant contributing factor to reduced tissue homeostasis and regeneration in older individuals.”
Quote in the paperSubstantial claim - Interpretationown data
The age-dependent decline in the regenerative capacity of β-cells is correlated with the Bmi1/Ink4/Arf pathway.
“Furthermore, we have correlated the age-dependent decline in the regenerative capacity of β-cells with the Bmi1/Ink4/Arf pathway.”
Quote in the paperSubstantial claim - Interpretationcitation
GLP-1-induced increased β-cell mass may not be achievable in typical middle-aged patients because their capacity for β-cell expansion is low.
“It has been suggested that incretin hormone therapy might serve to foster β-cell regeneration in humans with either type 1 or type 2 diabetes, but it is likely that GLP-1–induced increased β-cell mass may not be achievable in typical middle-aged patients with the capacity for β-cell expansion so predictably low in these human subjects (34).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Schuit, 1988, Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells, Proc Natl Acad Sci U S A source
Not checked in the free run.
- Interpretationreasoning
Diminished proliferative capacity of β-cells is the primary cause of why β-cells in old mice expand less successfully.
“We suggest diminished proliferative capacity of β-cells is the primary cause of why β-cells in old mice expand less successfully.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 8
- May combine two claims. 7
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe body weight of both young and old mice showed a 50% increase after 8 weeks of high-fat diet.
“The body weight of both young and old mice showed a 50% increase after 8 weeks of high-fat diet (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe ability to expand β-cell mass in mice declines with age and is correlated with reduced β-cell replication.
“In summary, we have shown here that the ability to expand β-cell mass in mice declines with age and is correlated with reduced β-cell replication.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationProliferation of β-cells appears to play an important role in endogenous renewal.
“The cell source and mechanism leading to the endogenous renewal is not clear, although proliferation of β-cells appears to play an important role (11).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Zhong, 2007, Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells, J Clin Invest source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSeveral studies have established a role for Bmi1 in the regulation of p16Ink4a.
“Because several studies have established a role for the polycomb group protein Bmi1 in the regulation of p16Ink4a (26–28), we analyzed the levels of Bmi1.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [26] Bruggeman, 2005, Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice, Genes Dev source
Not checked in the free run.
- cites [27] Jacobs, 1999, The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus, Nature source
Not checked in the free run.
- cites [28] Molofsky, 2006, Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing, Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataNo statistically significant difference in body weight between groups was noted at the beginning of the study.
“No statistically significant difference in body weight between groups was noted at the beginning of the study.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationThe residual β-cell mass after STZ is sufficient to maintain blood glucose levels, minimizing the role of hyperglycemia in β-cell proliferation and apoptosis.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Bonner-Weir, 1981, Responses of neonatal rat islets to streptozotocin: limited B-cell regeneration and hyperglycemia, Diabetes source
Not checked in the free run.
May combine two claims.
Interpretationown dataIn all three models, young mice had the capacity to expand or regenerate β-cells, whereas the β-cell mass of old mice did not show similar plasticity.
“In all three models, young mice had the capacity to expand or regenerate β-cells, whereas the β-cell mass of old mice did not show similar plasticity.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAn increase in β-cell proliferation is observed 7 days after STZ injection and correlates with regeneration of β-cell mass.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Bonner-Weir, 1981, Responses of neonatal rat islets to streptozotocin: limited B-cell regeneration and hyperglycemia, Diabetes source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe β-cell population is heterogeneous, and aging may change the composition of the β-cell population.
“It is also worth pointing out that the β-cell population is heterogeneous, and aging may change the composition of the β-cell population (34).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Schuit, 1988, Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells, Proc Natl Acad Sci U S A source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationPolycomb group proteins play a role in regulation of expression from the Ink4a/Arf locus, and Bmi1 is implicated in this process.
“Several studies suggest a role for polycomb group proteins in the regulation of expression from the Ink4a/Arf locus, and Bmi1, a key component of the polycomb complex, has been widely implicated in this process (37,38).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitationp16Ink4a is involved in aging and has been linked with type 2 diabetes in genome-wide studies.
“The product of the Ink4a/Arf (Cdkn2a) locus, p16Ink4a (a negative regulator of CDK4 D-type cyclins), is thought to be involved in aging, and in genome-wide studies it has linked with type 2 diabetes (35,36).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [35] 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 [36] 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.
The paper relies on this without support.
p16Ink4a inhibits the cyclin-dependent kinase 4 (CDK4)-cyclin D2 complex and can inhibit cell cycle progression and regeneration of islet cells.
“p16Ink4a inhibits the cyclin-dependent kinase 4 (CDK4)-cyclin D2 complex and can inhibit cell cycle progression and regeneration of islet cells.”
The paper relies on this without support.
Transgenic mice that overexpressed p16Ink4a showed reduced islet cell proliferation and a reduction in the regenerative capacity of islets after toxin-mediated destruction.
“Transgenic mice that overexpressed p16Ink4a showed reduced islet cell proliferation and a reduction in the regenerative capacity of islets after toxin-mediated destruction.”
The paper relies on this without support.
Bmi1 loss affects β-cell mass expansion primarily through p16Ink4a upregulation, so Bmi1 knockout mice isolate the effect of premature p16Ink4a upregulation.
“Because aging can lead to many changes in the β-cell other than p16Ink4a upregulation, we used Bmi1 knockout mice as a model to explore the endogenous capacity to renew in young mice in which p16ink4a is prematurely upregulated.”
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 [28]
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.
Normal-diet fat content differs between methods and Figure 1
MajorThe methods specify that the normal diet provided 4.4% of calories from fat, whereas the Figure 1 caption specifies 12.2% for the normal diet.
“normal diet (4.4% of total calories derived from fat, 3.9 kcal/g; Harlan Teklad)”
“normal diet (ND; 12.2% calories from fat)”
Mouse age for Figure 5A differs between text and caption
MinorThe results describe the islet immunoblot as using 4-week-old mice, but the Figure 5A caption says the mice were 6 weeks old.
“we measured the levels of p16Ink4a in islets isolated from 4-week-old wild-type and Bmi1−/− mice.”
“A: Protein levels of Bmi1 and p16 in isolated islets from 6-week-old wild-type and Bmi1−/− mice.”
Mouse age for the ChIP analysis differs between text and caption
MinorThe results say the ChIP analysis used islets from 6-week-old mice, whereas the Figure 5C caption identifies them as 4 weeks old.
“We examined the levels of H3K9 acetylation associated with the Ink4a/Arf locus in islets isolated from 6-week-old Bmi1−/− mice and their wild-type littermates.”
“ChIP analysis for the indicated antibodies at the Ink4a/Arf locus in islets isolated from wild-type (WT) and Bmi1−/− mice (4 weeks old) (bottom panel).”
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Flagged first, then by citations
Research works printed but not linked: 2
- Kjems, 2003, The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects, Diabetes, 52, 380, 10.2337/diabetes.52.2.380 · DOI · Paper page
- Valk-Lingbeek, 2004, Stem cells and cancer; the polycomb connection, Cell, 118, 409, 10.1016/j.cell.2004.08.005 · DOI · Paper page
Cited by
Sorted by citations
Glucagon-like peptide 1 (GLP-1)
Müller, T. D., Finan, B., Bloom, S. R., D'Alessio, D., Drucker, D. J., Flatt, P. R., Fritsche, A., Gribble, F., Grill, H. J., Habener, J. F., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.09.010 · Cited by 1,868 · see citing works
GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art
Nauck, M. A., Quast, D. R., Wefers, J., & Meier, J. J. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101102 · Cited by 1,647 · see citing works
Pharmacology, physiology, and mechanisms of incretin hormone action.
Campbell, J. E., & Drucker, D. J. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.008 · Cited by 1,500 · see citing works
GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus
Meier, J. J. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.140 · Cited by 1,311 · see citing works
In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.
Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.052 · Cited by 988 · see citing works
The Discovery and Development of Liraglutide and Semaglutide
Knudsen, L. B., & Lau, J. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00155 · Cited by 970 · see citing works
Incretin hormones: Their role in health and disease
Nauck, M. A., & Meier, J. J. (2018) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13129 · Cited by 950 · see citing works
Butler, A. E., Campbell-Thompson, M., Gurlo, T., Dawson, D. W., Atkinson, M., & Butler, P. C. (2013) · Diabetes · doi:10.2337/db12-1686 · Cited by 457 · see citing works
Self-citationAdaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy
Butler, A. E., Cao-Minh, L., Galasso, R., Rizza, R. A., Corradin, A., Cobelli, C., & Butler, P. C. (2010) · Diabetologia · doi:10.1007/s00125-010-1809-6 · Cited by 435 · see citing works
Glucolipotoxicity of the pancreatic beta cell
Poitout, V., Amyot, J., Semache, M., Zarrouki, B., Hagman, D., & Fontés, G. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.08.006 · Cited by 382 · see citing works
Expansion of β-cell mass in response to pregnancy
Rieck, S., & Kaestner, K. H. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.11.001 · Cited by 358 · see citing works
Liu, J.-Y., Souroullas, G. P., Diekman, B. O., Krishnamurthy, J., Hall, B. M., Sorrentino, J. A., Parker, J. S., Sessions, G. A., Gudkov, A. V., & Sharpless, N. E. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1818313116 · Cited by 306 · see citing works
Incretin Action in the Pancreas: Potential Promise, Possible Perils, and Pathological Pitfalls
Drucker, D. J. (2013) · Diabetes · doi:10.2337/db13-0822 · Cited by 272 · see citing works
β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance
Aguayo-Mazzucato, C., van Haaren, M., Mruk, M., Lee, T. B., Crawford, C., Hollister-Lock, J., Sullivan, B. A., Johnson, J. W., Ebrahimi, A., Dreyfuss, J. M., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.015 · Cited by 198 · see citing works
The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent
Furman, B. L. (2012) · Toxicon · doi:10.1016/j.toxicon.2010.12.016 · Cited by 166 · see citing works
Hannou, S. A., Wouters, K., Paumelle, R., & Staels, B. (2015) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2015.01.008 · Cited by 159 · see citing works
Glucagon Like Peptide-1 Receptor Expression in the Human Thyroid Gland
Gier, B., Butler, P. C., Lai, C. K., Kirakossian, D., DeNicola, M. M., & Yeh, M. W. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2407 · Cited by 157 · see citing works
Hodes, R. J., Sierra, F., Austad, S. N., Epel, E., Neigh, G. N., Erlandson, K. M., Schafer, M. J., LeBrasseur, N. K., Wiley, C., Campisi, J., et al. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13299 · Cited by 132 · see citing works
Incretins in obesity and diabetes
Chia, C. W., & Egan, J. M. (2020) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14211 · Cited by 93 · see citing works
Smits, M. M., Tonneijck, L., Muskiet, M. H. A., Kramer, M. H. H., Cahen, D. L., & van Raalte, D. H. (2016) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12593 · Cited by 74 · see citing works
Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis
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Forny Germano, L., Koehler, J. A., Baggio, L. L., Cui, F., Wong, C. K., Rittig, N., Cao, X., Matthews, D., & Drucker, D. J. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.102019 · Cited by 50 · see citing works
Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys
Nicol, L. E., O’Brien, T. D., Dumesic, D. A., Grogan, T., Tarantal, A. F., & Abbott, D. H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106527 · Cited by 41 · see citing works
PKA Enhances the Acute Insulin Response Leading to the Restoration of Glucose Control
Kaihara, K. A., Dickson, L. M., Ellenbroek, J. H., Orr, C. M. D., Layden, B. T., & Wicksteed, B. (2015) · Diabetes · doi:10.2337/db14-1051 · Cited by 22 · see citing works
- Authors
- Tschen, S.-I., Dhawan, S., Gurlo, T., & Bhushan, A.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Bhushan, Anil
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2009-02-19
- Volume
- 58
- Issue
- 6
- Pages
- 1312-1320
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2682690
- OpenAlex
- W2163146250
- Cited by
- 331
- References
- 37
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 14 · 2023: 19 · 2022: 20 · 2021: 17 · 2020: 11 · 2019: 19 · 2018: 17 · 2017: 24 · 2016: 24 · 2015: 19 · 2014: 23 · 2013: 21 · 2012: 24
- FWCI
- 29.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK068763, R01DK080996)
- 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, beta cell regeneration, aging, beta-cell mass expansion, high-fat diet, exendin-4, glucagon-like peptide-1, streptozotocin, BMI1, p16INK4a, Polycomb group proteins, type 2 diabetes, age-related diabetes
- MeSH terms
- Exenatide, Aging, Animals, Cell Division, Diabetes Mellitus, Experimental, Dietary Fats, Female, Hypoglycemic Agents, Immunohistochemistry, Male, Mice, Inbred C57BL, Nuclear Proteins, Peptides, Proto-Oncogene Proteins, Regeneration, Repressor Proteins, Venoms, Mice, Knockout, Insulin-Secreting Cells, Mice, Glucagon-Like Peptide 1, Polycomb Repressive Complex 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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