Pancreatic Beta Cells in Very Old Mice Retain Capacity for Compensatory Proliferation

Stolovich-Rain, Miri; Hija, Ayat; Grimsby, Joseph; Gläser, Benjamin; Dor, Yuval

doi:10.1074/jbc.m112.350736

Cited by 62 publications

(52 citation statements)

References 29 publications

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“…These results are remarkable because a diminished proliferative response is considered a hallmark of islet aging (7). However, our study concurs with recent studies (32,33) showing that beta cells in old mice can increase their proliferative rate under particular circumstances.…”

Section: Discussionsupporting

confidence: 93%

Young capillary vessels rejuvenate aged pancreatic islets

Almaça

Molina

Drigo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

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Pancreatic islets secrete hormones that play a key role in regulating blood glucose levels (glycemia). Age-dependent impairment of islet function and concomitant dysregulation of glycemia are major health threats in aged populations. However, the major causes of the age-dependent decline of islet function are still disputed. Here we demonstrate that aging of pancreatic islets in mice and humans is notably associated with inflammation and fibrosis of islet blood vessels but does not affect glucose sensing and the insulin secretory capacity of islet beta cells. Accordingly, when transplanted into the anterior chamber of the eye of young mice with diabetes, islets from old mice are revascularized with healthy blood vessels, show strong islet cell proliferation, and fully restore control of glycemia. Our results indicate that beta cell function does not decline with age and suggest that islet function is threatened by an age-dependent impairment of islet vascular function. Strategies to mitigate age-dependent dysregulation in glycemia should therefore target systemic and/or local inflammation and fibrosis of the aged islet vasculature.A ging leads to progressive decline of various homeostatic processes in mammals, including a deteriorating regulation of blood glucose levels. Pancreatic islets are small organs composed of endocrine cells that secrete the major hormones insulin, glucagon, and somatostatin, which play a key role in regulating blood glucose levels. Age-dependent dysfunction of islets and the concomitant dysregulation of blood glucose levels increase the risk for type 2 diabetes (1), which in turn contributes to other age-related chronic diseases. In general, it has been assumed that aging causes an intrinsic dysfunction of the insulin-secreting beta cells through reduced proliferative capacity and/or defective insulin secretion (1-9). However, there have been numerous reports that age-dependent impairment of glucose homeostasis is not just a result of intrinsic, age-dependent dysfunction of islets but is also caused by systemic factors. For example, islet function may be compromised by age-related increases in adiposity (10, 11) and by bloodborne factors (12), or it could be affected indirectly by agerelated deficiencies in vascular remodeling (13). Thus, the replicative decline of old pancreatic beta cells can be attributed to systemic factors (12). Recent studies identified factors present in young blood that reverse age-related cognitive impairments and induce vascular remodeling and regeneration in the brain and skeletal muscle (14-16), but so far it has not been feasible to discriminate systemic influences from aging factors intrinsic to islet endocrine cells. Here we address the long-standing question of whether the age-dependent impairment of glucose homeostasis is caused by intrinsic, age-dependent dysfunction of islets or by systemic aging factors.Our strategy to discern age-related intrinsic changes in islet function was to study islets from young mature (2 mo) and aged (18 mo) mice and to fol...

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Section: Discussionsupporting

confidence: 93%

Young capillary vessels rejuvenate aged pancreatic islets

Almaça

Molina

Drigo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

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“…In 2-year-old hyperglycemic mice, Bulavin and colleagues observed streptozotocin-induced β cell proliferation (43). Similarly, Dor and colleagues observed small (but statistically significant) increases in β cell proliferation in 21-and 25-month-old mice following diphtheria toxin-driven β cell death, a provocative stimulus (22). Importantly, none of the studies were able to assess whether increases in β cell proliferation translated to increased β cell mass.…”

Section: Figurementioning

confidence: 99%

The role of aging upon β cell turnover

2013

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Preservation and regeneration of β cell endocrine function is a long-sought goal in diabetes research. Defective insulin secretion from β cells underlies both type 1 and type 2 diabetes, thus fueling considerable interest in molecules capable of rebuilding β cell secretion capacity. Though early work in rodents suggested that regeneration might be possible, recent studies have revealed that aging powerfully restricts cell cycle entry of β cells, which may limit regeneration capacity. Consequently, aging has emerged as an enigmatic challenge that might limit β cell regeneration therapies. This Review summarizes recent data regarding the role of aging in β cell regeneration and proposes models explaining these phenomena.

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“…The effect of ageing upon β cell survival and regeneration is contraversial [145][146][147]. Similar studies were conducted in various organs such as Muscle [148], Skin [149] and Neuronal cells [150].…”

Section: The Effect Of Systemic Microenvironment and Ageingmentioning

confidence: 60%

The Making of Pancreatic β Cells: Advances and Apprehensions

Radha¹,

Muniraj

Rasu³

2016

IJPPE

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Abstract. Diabetes is a dreadful disease, which in its acute stages, causes severe multiple organ failure. It is also one of the world's oldest diseases. Type 1 Diabetes is characterized by the absence of insulin and exogenous insulin dependency. Stem cell therapy is one of the promises of this era, as there are numerous studies on Rodents, Frogs, Zebra fish, Dog and Chick, elucidating the wide array of genes, transcription factors, signaling pathways and compounds, which could promote β cell neogenesis, regeneration, differentiation and trans-differentiation. Even though, a recent PubMed search on the keyword 'Pancreatic beta cell proliferation' revealed around 3000 reports, this review focuses on the trends attempted in recent years and infers certain critical aspects in the observations.

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Pancreatic Beta Cells in Very Old Mice Retain Capacity for Compensatory Proliferation

Cited by 62 publications

References 29 publications

Young capillary vessels rejuvenate aged pancreatic islets

Young capillary vessels rejuvenate aged pancreatic islets

The role of aging upon β cell turnover

The Making of Pancreatic β Cells: Advances and Apprehensions

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