Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications

Donath, M Y; Halban, Philippe A.

doi:10.1007/s00125-004-1336-4

Cited by 371 publications

(271 citation statements)

References 91 publications

(91 reference statements)

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“…26 Conversely, apoptosis may also be the causal factor in diabetes development, as shown in Perk − / − and Pdx-1 − / − mouse models of diabetes. [27][28][29][30] In E2F1/E2F2-deficient cells, altered expression of proapoptotic mediators and mitochondrial membrane depolarization preceded the onset of diabetes, suggesting that apoptosis is a triggering event for pancreatic degeneration and diabetes in our mouse model. Furthermore, our results demonstrate that apoptosis in mice lacking E2F1/E2F2 is exclusively dependent on p53, since targeted inactivation of p53 hinders apoptosis and restores normal pancreas phenotype.…”

Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 84%

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

et al. 2015

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Tissue homeostasis requires tight regulation of cellular proliferation, differentiation and apoptosis. E2F1 and E2F2 transcription factors share a critical role in tissue homeostasis, since their combined inactivation results in overall organ involution, specially affecting the pancreatic gland, which subsequently triggers diabetes. We have examined the mechanism by which these E2Fs regulate tissue homeostasis. We show that pancreas atrophy in E2F1/E2F2 double-knockout (DKO) mice is associated with mitochondrial apoptosis and activation of the p53 pathway in young animals, before the development of diabetes. A deregulated expression of E2F target genes was detected in pancreatic cells of young DKO animals, along with unscheduled DNA replication and activation of a DNA damage response. Importantly, suppression of DNA replication in vivo with aphidicolin led to a significant inhibition of the p53 pathway in DKO pancreas, implying a causal link between DNA replication stress and p53 activation in this model. We further show that activation of the p53 pathway has a key role in the aberrant phenotype of DKO mice, since targeted inactivation of p53 gene abrogated cellular apoptosis and prevented organ involution and insulin-dependent diabetes in mice lacking E2F1/E2F2. Unexpectedly, p53 inactivation unmasked oncogenic features of E2F1/E2F2-depleted cells, as evidenced by an accelerated tumor development in triple-knockout mice compared with p53 − / − mice. Collectively, our data reveal a role for E2F1 and E2F2 as suppressors of replicative stress in differentiating cells, and uncover the existence of a robust E2F-p53 regulatory axis to enable tissue homeostasis and prevent tumorigenesis. These findings have implications in the design of approaches targeting E2F for cancer therapy.

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Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 84%

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

et al. 2015

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“…In the first place, beta cell replication is notoriously difficult to measure in adult human pancreatic specimens, a shortcoming exacerbated by dependence on histological markers, such as Ki67 (which still remains our best marker for indicating cell replication in sections), that only indicate a portion of the cell cycle and therefore lead to underestimation of the degree of replication [7]. Second, no concrete indicators of adult pancreatic stem cells or beta cell progenitor cells currently exist.…”

mentioning

confidence: 99%

“…The concept of beta cell neogenesis, as based on the appearance of insulin-positive cells within pancreatic ducts, therefore rests upon a certain degree of faith. This issue can be addressed experimentally by lineage tracing studies in animal models, but such studies are obviously impossible to perform in humans [7]. Doubts relating to transdifferentiation are based on similar shortcomings.…”

mentioning

confidence: 99%

Pancreatic regeneration in type 1 diabetes: dreams on a deserted islet?

Atkinson

Rhodes

2005

Diabetologia

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“…Rat primers are not suited for detection of gene expression in gerbil tissues (unpublished observation, A. Jörns, Hanover, Germany). Thus our results do not provide a rationale for prevention studies using IL-1β antibodies [5] in humans with type 2 diabetes mellitus. On the other hand, type 2 diabetes mellitus is a heterogeneous disease and it cannot be ruled out that an inflammatory background represents a component of the disease process in some patients [27,28].…”

Section: Discussionmentioning

confidence: 57%

“…Recently it has been proposed that cytokines may also be involved in the aetiopathology of beta cell death in type 2 diabetes mellitus [4][5][6][7]. Major support for this hypothesis was derived from experiments on the gerbil Psammomys obesus (sand rat) [8,9], an established type 2 diabetes animal model [10,11].…”

Section: Introductionmentioning

confidence: 99%

Beta cell death in hyperglycaemic Psammomys obesus is not cytokine-mediated

2006

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Aims/hypothesis It has recently been proposed that IL-1β may be responsible for beta cell death in type 2 diabetes mellitus. Major support for this assumption was derived from experiments in the gerbil Psammomys obesus (sand rat), a model for nutritionally induced non-insulin-dependent type 2 diabetes. Using gerbil-specific primers for the analysis of gene expression, we investigated the validity of this hypothesis. Methods Gene expression was analysed by real-time RT-PCR of isolated and laser-microdissected islets and by in situ RT-PCR, both in beta cells and in immune cells, as well as in lymph nodes and spleen. Results We were unable to detect Il-1β and the IL-1β-inducible enzyme inducible nitric oxide synthase (iNos) by in situ RT-PCR, either in the pancreatic beta cells, or in the small number of non-activated immune cells of healthy and diabetic Psammomys obesus after 1 and 3 weeks on a highenergy diet. Very low levels of Il-1β and iNos mRNA were detectable in collagenase-isolated and laser-microdissected islets of normoglycaemic gerbils by real-time RT-PCR without any increase of these mRNAs in islets from diabetic animals. These results were confirmed by electron microscopy with immunogold staining for IL-1β and insulin. Conclusions/interpretation The diabetic syndrome induced in Psammomys obesus by high-energy diet is a classical type 2 diabetes model, which does not show any evidence of an involvement of the proinflammatory cytokine IL-1β or of activated immune cells in its pathogenesis. This is clearly at variance with the situation in type 1 diabetes.

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Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications

Cited by 371 publications

References 91 publications

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

Pancreatic regeneration in type 1 diabetes: dreams on a deserted islet?

Beta cell death in hyperglycaemic Psammomys obesus is not cytokine-mediated

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