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Diabetes Obes Metab. 2016 Sep;18 Suppl 1:58-62. doi: 10.1111/dom.12719.

Effects of ageing and senescence on pancreatic β-cell function.

Author information

1
Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
2
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
3
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
4
Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. yuvald@ekmd.huji.ac.il.

Abstract

Ageing is generally associated with deterioration of organ function and regenerative potential. In the case of pancreatic β-cells, an age-related decline in proliferative potential is well documented, and was proposed to contribute to the increased prevalence of type 2 diabetes in the elderly. The effects of ageing on β-cell function, namely glucose-stimulated insulin secretion (GSIS), have not been studied as extensively. Recent work revealed that, surprisingly, β-cells of mature mice and humans secrete more insulin than young β-cells in response to high glucose concentrations, potentially serving to counteract age-related peripheral insulin resistance. This functional change appears to be orchestrated by p16(Ink4A) -driven cellular senescence and downstream remodelling of chromatin structure and DNA methylation, enhancing the expression of genes controlling β-cell function. We propose that activation of the cellular senescence program drives life-long functional maturation of β-cells, due to β-cell hypertrophy, enhanced glucose uptake and more efficient mitochondrial metabolism, in parallel to locking these cells in a non-replicative state. We speculate that the beneficial aspects of this process can be harnessed to enhance GSIS. Other age-related mechanisms, which are currently poorly understood, act to increase basal insulin secretion levels also in low glucose conditions. This leads to an overall reduction in the amplitude of insulin secretion between low and high glucose at old age, which may contribute to a deterioration in metabolic control.

KEYWORDS:

DNA methylation; ageing; insulin secretion; maturation; p16/Ink4a; senescence; β-cells

PMID:
27615132
DOI:
10.1111/dom.12719
[Indexed for MEDLINE]

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