Current and Future Developments in Physiology

Current and Future Developments in Physiology

Control of Pancreatic Beta Cell Function and Plasticity in Health and Diabetes

Plasticity in insulin-producing cells (β-cells) of the pancreas is a major contributor to metabolic control. Targeted regeneration of pancreatic β-cells for the reversal of diabetes (by optimizing ...
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Aging and β-Cell Proliferation, Molecular and Signaling Changes and What This Means for Targeted Regeneration

Pp. 20-41 (22)

Aaron R. Cox

Abstract

Increased age confers a greater risk for the development of type 2 diabetes (T2D), and also has significant consequences for β-cell growth and regeneration. Pancreatic insulin-producing β-cells are long-lived, and exhibit very little turnover in adult life. The severe decline in β-cell proliferation contributes to a decreased capacity for β-cell regeneration with age. β-cell regeneration is dependent on mitogenic signals, receptor and downstream signal transduction, cell cycle progression, and epigenetic regulation of gene expression, all of which are significantly affected by increasing age. Studies suggest that circulating growth factors and their receptors are decreased with age, along with important intracellular signaling molecules, such as Pdx-1 and FoxM1. Cell cycle progression is inhibited by an increased expression of cell cycle inhibitors and a reduction in cell cycle kinase complexes (Cyclin/Cdks). Moreover, decreased expression of epigenetic silencers, such as polycomb group proteins, results in derepression of the cell cycle inhibitor p16, and a significant reduction in β-cell proliferation. Collectively, these age-induced changes present obstacles for the design of β-cell regenerative therapies for diabetes; however, some reports suggest that even very old β-cells can re-enter cell cycle. Future studies will further define the effects of aging on β-cell proliferation and elucidate new drug targets for diabetes therapy.

Keywords:

Aging, β-cell regeneration, Cell cycle, Diabetes, Epigenetics, Molecular signals, Proliferation.

Affiliation:

McNair Medical Institute, Baylor College of Medicine, Houston, Texas, U.S.A.