Longevity of human islet α‐ and β‐cells

Abstract

Pancreatic islet cell regeneration is considered to be important in the onset and progression of diabetes and as a potential cell therapy. Current hypotheses, largely based on rodent studies, indicate continuous turnover and plasticity of α-and β-cells in adults; cell populations in rodents respond to increased secretory demand in obesity (30-fold β-cell increase) and pregnancy. Turnover and plasticity of islet cells decrease in mice within >1 year. In man, morphometric observations on postmortem pancreas have indicated that the cellular expansion is much smaller than the increased insulin secretion that accompanies obesity. Longevity of β-cells in humans >20-30 years has been shown by 14 C measurements and bromo-deoxyuridine (BrdU) incorporation and there is an age-related decline in the expression of proteins associated with cell division and regeneration including cyclin D3 and PDX-1. Quantitative estimation and mathematical modelling of the longevity marker, cellular lipofuscin body content, in islets of subjects aged 1-84 years indicated an age-related increase and that 97% of the human β-cell population was established by the age of 20. New data show that human α-cell lipofuscin content is less than that seen in β-cells, but the age-related accumulation is similar; lipofuscin-positive (aged) cells form ≥95% of the population after 20 years. Increased turnover of cellular organelles such as mitochondria and endoplasmic reticulum could contribute to lipofuscin accumulation with age in long-lived cells. Induction of regeneration of human islet cells will require understanding of the mechanisms associated with age-related senescence. Keywords: α-cells, β-cells, ageing, diabetes, islets, lifespan, longevity, neogenesis, proliferation, replication Date submitted 1 April 2011; date of final acceptance 4 May 2011 IntroductionThe ageing or lifespan of cells has important implications for many different aspects of cellular function including decreased secretory function [1], mitochondrial activity [2,3], increased mutations [4] and increased fragility [5]. Because of the central role of β-cell function/mass in diabetes, the lifespan of islet cells has implications for the onset and progression of type 2 diabetes. A current renewed interest in defects in glucagon secretion in both type 1 and type 2 diabetes [6,7] has expanded research into understanding the regulation of α-cell mass and function [8,9].The search for β-cell replacement therapies for diabetes encompasses both expansion of a potentially reduced functional β-cell mass in vivo in type 1 and type 2 diabetes and expansion of human β-cells in vitro for transplantation [10]. Regeneration/neogenesis or expansion of existing β-cells in vivo has been explored extensively in rodents [11][12][13]. However, it is becoming increasingly obvious that many of the mechanisms identified in these models cannot be transferred directly to human islet cells: adult human islet cells are resistant to procedures inducing proliferation in vitro [5,14] and show gene expression pa...

Young capillary vessels rejuvenate aged pancreatic islets

“…To answer this question, we used both mouse and human islets, as these differ in several aspects, such as cytoarchitecture, cellular plasticity, and turnover (18)(19)(20). Mouse islets were isolated from young mature (2 mo) and old (18 mo) virgin male C57BL/6 mice Significance The regulation of blood glucose is a homeostatic process that declines with age, but it is unknown whether this disturbance is a consequence of intrinsic dysfunction of the regulatory organ, the pancreatic islet.…”

“…To answer this question, we used both mouse and human islets, as these differ in several aspects, such as cytoarchitecture, cellular plasticity, and turnover (18)(19)(20). Mouse islets were isolated from young mature (2 mo) and old (18 mo) virgin male C57BL/6 mice…”

The Role of Reg Proteins in Pancreatic Regeneration

“…Intermediate cells expressing both β-and α-cell markers were observed in the regenerative areas supported the evidence for α-to β-cell transdifferentiation [26]. While β-cell replication is the best supported mechanism to account for islet regeneration in rodents, human β-cells only possess a limited capacity to replicate, and in both human and rodents the capacity declines with age [28]. This could suggest that neogenesis might be the most common mechanism to drive endogenous formation of β-cells in the human pancreas, and observations of single cells and small insulin positive clusters found near the ducts in human pancreas is suggestive for progenitor cells residing in 2 Alloxan treatment selectively destroys insulin-producing cells in the pancreas when administered to rodents and thereby induce pancreatic regeneration [29][30][31][32][33][34].…”

Telomere attrition in beta and alpha cells with age

“…Cnop et al measured the lipofuscin content of islet cells and reported that the number of islet cells in humans is largely established by age 20 years and then remains constant with a low turnover rate (Cnop et al 2010(Cnop et al , 2011. More recently, Mizukami et al reported that Ki67-a marker for cell proliferation-positive rate of β and non-β islet cells is prominent in childhood but significantly decreased over 20 years of age (Mizukami et al, 2014).…”