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

Cnop, Miriam; Hughes, Stephen J.; Igoillo-Esteve, Mariana; Hoppa, Michael B.; Sayyed, Farhina; Laar, Lianne van de; Gunter, Jennifer H.; Koning, Eelco J.P. de; Walls, Gerard; Gray, D. W. G.; Johnson, Paul; Hansen, Barbara C.; Morris, John F.; Pipeleers-Marichal, M.; Cnop, I.; Clark, Anne

doi:10.1007/s00125-009-1562-x

Cited by 202 publications

(195 citation statements)

References 50 publications

(77 reference statements)

Supporting

Mentioning

176

Contrasting

Unclassified

Order By: Relevance

“…Highest rate of beta cell proliferation [21,22] Increased insulin secretion, which is, in part, due to transient insulin resistance [44,45] Doubling of beta cell mass by 5 years of age [22] Several-fold increase in beta cell mass from birth to adulthood [50,51] Increase in beta cells per islet and in islet size [51,52] Evidence of beta cell neogenesis and a regenerative response in diabetes [53] Mature beta cells are sensitive to perturbations in cell cycle control [60] Pro-survival effects of lactogen hormones on beta cells [99,100] but not alpha cells [102] Cytoprotective effect of GLP-1 on beta cells [104] GIP stimulates glucagon secretion [113], while GLP-1 inhibits secretion [112] Increase in beta cell mass reported in obesity [119] Reduction in beta cell mass and relative increase in alpha cell mass in diabetes [74] Decline in beta cell function; decline in beta cell replication Beta cell mass remains relatively constant in healthy humans [121] No major alterations in beta cell size [120] Beta cell apoptosis is low and remains constant throughout life [21] In diabetes: Mitochondrial dysfunction, oxidative stress, ER stress and accumulation of intermediate-sized amyloid particles [127] Neonatal age Puberty Adolescence Adulthood Old age diabetes coupled with high expression of IL-6 receptors on alpha cells suggest that this cytokine could contribute to the increased alpha cell mass observed in diabetes [88]. This notion is supported by fasting hypoglucagonaemia and an inability of mice lacking IL-6 to increase their alpha cell mass.…”

Section: Contributors To Maintenance Of Islet Cell Mass In Adult Rodentsmentioning

confidence: 99%

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

Mezza

Kulkarni

2014

Diabetologia

View full text Add to dashboard Cite

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.

show abstract

Section: Contributors To Maintenance Of Islet Cell Mass In Adult Rodentsmentioning

confidence: 99%

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

Mezza

Kulkarni

2014

Diabetologia

View full text Add to dashboard Cite

show abstract

“…1g). Lipofuscin bodies were noted within the alpha cells, suggesting that the islet cells were not neogenic [6]. Confocal Z-stack reconstruction of an islet isolated from a non-diabetic donor and from the type 1 diabetic donor illustrates an islet with low levels of insulin-positive beta cells relative to glucagon-positive alpha cells in the latter (Fig.…”

mentioning

confidence: 97%

“…Membrane capacitance, as a measure of insulin granule exocytosis, was recorded from isolated alpha and beta cells using the patch-clamp technique [5]. Pancreatic tissue samples taken from the body and tail regions of this donor pancreas and from the donor pancreases of three additional type 1 diabetic patients (diabetes duration >10 years, n=2; diabetes duration <48 h, n=1; tissue retrieval at post mortem was approved by the local ethics committee) were prepared for light and electron microscopy [6]; they were then immunolabelled with anti-insulin (in-house antibody), anti-glucagon (Sigma, Poole, UK), anti-somatostatin (DAKO, Glostrup, Denmark) and markers for macrophages (anti-human CD68; DAKO) and lymphocytes (anti-human CD45; DAKO).…”

mentioning

confidence: 99%

Glucose-responsive beta cells in islets isolated from a patient with long-standing type 1 diabetes mellitus

et al. 2010

Self Cite

View full text Add to dashboard Cite

“…However, b-cell proliferation in humans has been reported to rapidly decrease within 5 years after birth, and only minimal b-cell proliferation is observed in adults (6)(7)(8). Estimation of b-cell life span by lipofuscin accumulation or radiocarbon dating has also suggested minimal b-cell turnover in adult humans (9,10). Therefore, clarification of endogenous regenerative capacity in adult humans is critical for interpretation of the results of rodent studies and their application to humans.…”

mentioning

confidence: 99%

Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes

et al. 2015

View full text Add to dashboard Cite

The aim of this study was 1) to clarify b-cell regenerative capacity in the face of glucocorticoid (GC)-induced insulin resistance and 2) to clarify the change in b-and a-cell mass in GC-induced diabetes in humans. We obtained the pancreases from 100 Japanese autopsy case subjects. The case subjects were classified according to whether or not they had received GC therapy before death and the presence or absence of diabetes. Fractional b-cell area (%BCA) and a-cell area (%ACA) were quantified, and the relationship with GC therapy was evaluated. As a result, in case subjects without diabetes, there was no significant difference in %BCA between case subjects with and without GC therapy (1.66 6 1.05% vs. 1.21 6 0.59%, P = 0.13). %ACA was also not significantly different between the two groups. In case subjects with type 2 diabetes, %BCA and %ACA were both significantly reduced compared with control subjects without diabetes; however, neither %BCA nor %ACA was significantly decreased in case subjects with GC-induced diabetes. There was a significant negative correlation between %BCA and HbA 1c measured before death; however, this relationship was attenuated in case subjects with GC therapy. In conclusion, the current study suggests that b-and a-cell mass remain largely unchanged in the face of GC-induced insulin resistance in Japanese individuals, implying limited capacity of b-cell regeneration in adult humans. The absence of apparent b-cell deficit in case subjects with GCinduced diabetes suggests that GC-induced diabetes is mainly caused by insulin resistance and/or b-cell dysfunction, but not necessarily a deficit of b-cell mass.Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are both characterized by a deficit of b-cell mass (BCM) (1,2).Preservation or recovery of BCM is therefore an important therapeutic strategy for both T1DM and T2DM. However, the regenerative capacity of BCM in humans remains largely unknown.In rodents, b-cells have been shown to be able to adaptively increase in response to an increased insulin demand such as obesity or pregnancy (3-5). However, b-cell proliferation in humans has been reported to rapidly decrease within 5 years after birth, and only minimal b-cell proliferation is observed in adults (6-8). Estimation of b-cell life span by lipofuscin accumulation or radiocarbon dating has also suggested minimal b-cell turnover in adult humans (9,10). Therefore, clarification of endogenous regenerative capacity in adult humans is critical for interpretation of the results of rodent studies and their application to humans.It has been reported that BCM is increased by 20 to 50% in obese adult humans without diabetes (8,11), to a smaller degree than in rodents, which usually show a two-to threefold increase (4,5), consistent with lower b-cell turnover in adult humans. Recently, we have also reported that in the Japanese population, no significant increase in BCM was observed in obese adults without diabetes (12). These findings further underscore the limited capacity of BCM expansion in adult...

show abstract

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

Cited by 202 publications

References 50 publications

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

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

Glucose-responsive beta cells in islets isolated from a patient with long-standing type 1 diabetes mellitus

Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes

Contact Info

Product

Resources

About