Functional changes in beta cells during ageing and senescence
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REVIEW
Functional changes in beta cells during ageing and senescence Cristina Aguayo-Mazzucato 1 Received: 2 March 2020 / Accepted: 21 April 2020 / Published online: 31 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Insulin secretion from beta cells is crucial for maintaining euglycaemia and preventing type 2 diabetes, a disease correlated with ageing. Therefore, understanding the functional changes that beta cell function undergoes with age can reveal new therapeutic targets and strategies to delay or revert the disease. Herein, a systematic review of the literature agrees that, as humans age, their beta cell function declines, independently of peripheral insulin resistance, BMI and waist circumference. Rodent studies reveal that, with age, basal insulin secretion increases with either no change or an increase in stimulated insulin secretion, but the biological significance of this is unclear. The accumulation of senescent beta cells could explain some of these functional changes: transcriptional analysis of senescent and aged beta cells revealed parallel downregulation of several steps along the pathway linking glucose stimulation and insulin secretion. Moreover, specific deletion of senescent cells (senolysis) improved residual beta cell function, gene expression profile and blood glucose levels. In conclusion, cellular senescence could underlie the functional decline of beta cells during ageing and could represent a novel and promising approach for recovering insulin secretion.
Keywords Ageing . Beta cells . Function . Human . Insulin secretion . Review . Rodents . Senescence . Senolysis . Type 2 diabetes Abbreviations GSIS Glucose-stimulated insulin secretion IDR Insulin delivery rate KATP ATP-dependent K+ (channel) RHPA Reverse haemolytic plaque assay RNA-seq RNA sequencing SASP Senescence associated secretory phenotype
Age is one of the main risk factors for type 2 diabetes, a disease where peripheral insulin resistance and insufficient beta cell insulin secretion converge and result in longstanding hyperglycaemia and its complications. The majority of indi-
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-020-05185-6) contains a slideset of the figures for download, which is available to authorised users. * Cristina Aguayo-Mazzucato [email protected] 1
Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA
viduals with type 2 diabetes are over 50 years of age [1], emphasising the importance of understanding the disease from an ageing point of view. Herein, the functional changes in beta cells during ageing are reviewed, with an emphasis on senescence, one of the mechanisms through which beta cells respond to age and stress [2, 3]. In addition, molecular changes induced by age are explored as potential new targets to preserve and enhance beta cell function during ageing and senescence, which represents a new way to understand and treat type 2 diabetes. The lite
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