Impaired islet turnover in human donor pancreata with aging

Reers, Christina; Erbel, Saskia; Espósito, Irene; Schmied, Bruno M.; Büchler, Markus W.; Nawroth, Peter P.; Ritzel, Robert

doi:10.1530/eje-08-0596

Cited by 98 publications

(82 citation statements)

References 35 publications

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“…Evidence for an age-related decrease in an adaptive proliferative response in islets of mice >2 months old has been described [39]. Similarly, in human organ donors, an age-related decrease of replicating cells has been interpreted as evidence of decreased adaptability [48]. These data taken together suggest that, whereas the population of islet cells is established and not plastic in man after about age 20 years, this point is reached in mice at approximately 1 year; adaptability of young mice to obesity, pregnancy and pancreatic damage may model the potential plasticity of human islets in individuals <20 years of age and not the relatively stable condition in adults.…”

Section: Discussionmentioning

confidence: 99%

The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation

et al. 2009

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Aims/hypothesis Defects in pancreatic beta cell turnover are implicated in the pathogenesis of type 2 diabetes by genetic markers for diabetes. Decreased beta cell neogenesis could contribute to diabetes. The longevity and turnover of human beta cells is unknown; in rodents <1 year old, a half-life of 30 days is estimated. Intracellular lipofuscin body (LB) accumulation is a hallmark of ageing in neurons. To estimate the lifespan of human beta cells, we measured beta cell LB accumulation in individuals aged 1-81 years. Methods LB content was determined by electron microscopical morphometry in sections of beta cells from human (nondiabetic, n=45; type 2 diabetic, n=10) and non-human primates (n=10; 5-30 years) and from 15 mice aged 10-99 weeks. Total cellular LB content was estimated by threedimensional (3D) mathematical modelling. Results LB area proportion was significantly correlated with age in human and non-human primates. The proportion of human LB-positive beta cells was significantly related to age, with no apparent differences in type 2 diabetes or obesity. LB content was low in human insulinomas (n=5) and alpha cells and in mouse beta cells (LB content in mouse <10% human). Using 3D electron microscopy and 3D mathematical modelling, the LB-positive human beta cells (representing aged cells) increased from ≥90% (<10 years) to ≥97% (>20 years) and remained constant thereafter. Conclusions/interpretation Human beta cells, unlike those of young rodents, are long-lived. LB proportions in type 2 diabetes and obesity suggest that little adaptive change occurs in the adult human beta cell population, which is largely established by age 20 years.

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Section: Discussionmentioning

confidence: 99%

The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation

et al. 2009

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“…However, the apoptotic rate has been reported to be increased in obese and diabetic individuals compared with the rate in lean and non-diabetic groups [123]. In contrast, a study by Reers et al showed that a decline in beta cell replication with age was not associated with a change in the frequency of apoptosis [124]. The increase in the apoptotic rate has been explained, in part, by the accumulation of amyloid plaques [125], aggregates of islet amyloid polypeptide (IAPP, a hormone co-secreted with insulin), which are increased in islets of diabetic and obese non-diabetic individuals.…”

Section: Old Agementioning

confidence: 91%

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Mezza

Kulkarni

2014

Diabetologia

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Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and agedependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.

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“…In adults, the frequencies reported are in the range of 0.4-0.6% insulin-positive duct cells whether in organ donors or autopsied pancreas, although in some pancreata no insulin-positive cells were detectable [58,69,71,72]. The dynamic nature of these insulin-positive cells is suggested by their increase seen in pancreas organs from obese patients [71,72], in patients with chronic pancreatitis [73] during pregnancy [74], and in patients receiving partial pancreatectomy due to recurrent hypoglycemia 1-2 years after gastric bypass [75].…”

Section: Evidence Of Compensatory Expansion In the Adult Human Pancreasmentioning

confidence: 98%

“…However, this low level of detection may result from the tissue being only retrieved after death. In a recent study on human organ donor pancreata, all pancreata had Ki67 + β-cells, with a stable, albeit low, percentage in donors from 40 to 65 years of age [69]. In another study, donor pancreata had little or no Ki67 + insulin-positive cells, but grafts of isolated islets from such donors had 0.22 ± 0.03% Ki67 + insulinpositive cells after 4 week transplantation in immunocompromised normoglycemic mice; this level was also found in frozen human pancreas obtained at surgery [70].…”

Section: Evidence Of Compensatory Expansion In the Adult Human Pancreasmentioning

confidence: 99%

Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

Bonner-Weir

Guo

Li³

et al. 2012

Rev Diabet Stud

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■ AbstractDiabetes, particularly type 1 diabetes, results from the lack of pancreatic β-cells. β-cell replenishment can functionally reverse diabetes, but two critical challenges face the field: 1. protection of the new β-cells from autoimmunity and allorejection, and 2. development of β-cells that are readily available and reliably functional. This chapter will examine the potential of endogenous replenishment of pancreatic β-cells as a possible therapeutic tool if autoimmunity could be blunted. Two pathways for endogenous replenishment exist in the pancreas: replication and neogenesis, defined as the formation of new islet cells from pancreatic progenitor/stem cells. These pathways of β-cell expansion are not mutually exclusive and both occur in embryonic development, in postnatal growth, and in response to some injuries. Since the β-cell population is dramatically reduced in the pancreas of type 1 diabetes patients, with only a small fraction of the β-cells surviving years after onset, replication of preexisting β-cells would not be a reasonable start for replenishment. However, induction of neogenesis could provide a starting population that could be further expanded by replication. It is widely accepted that neogenesis occurs in the initial embryonic formation of the endocrine pancreas, but its occurrence anytime after birth has become controversial because of discordant data from lineage tracing experiments. However, the concept was built upon many observations from different models and species over many years. Herein, we discuss the role of neogenesis in normal growth and regeneration, as learned from rodent models, followed by an analysis of what has been found in humans.

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Impaired islet turnover in human donor pancreata with aging

Cited by 98 publications

References 35 publications

The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation

The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

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