Cellular aging process surprisingly enhances insulin secretion

Gene mechanism could have important implications for diabetes treatment.

A scientist looks through a microscope (photo credit: INGIMAGE)
A scientist looks through a microscope
(photo credit: INGIMAGE)
Hebrew University and North American researchers have discovered a program in body cells that unexpectedly enhances the production of insulin in the pancreas’s beta cells of mice and humans.
The discovery, reported in the latest issue of the prestigious journal Nature Medicine, could have an important impact on the treatment of diabetes.
The cellular program, led by HU post-doctoral fellow Dr. Ronny Helman under the guidance of Dr. Ittai Ben-Porath and Prof. Yuval Dor and in collaboration with scientists from Canada and the US, said that the mechanism causes human and mouse pancreatic beta cells to work harder and secrete more insulin.
The researchers examined the activity of a gene named p16, which is known to activate a program called senescence in cells. Senescence prevents cells from dividing, and is therefore important in preventing cancer.
The activity of the p16 gene increases in human and mouse pancreatic beta cells during aging and limits their potential to divide.
This activity is thus seen as having a negative effect – the lack of ability of these cells to divide can contribute to diabetes, since beta cells are the cells responsible for secreting insulin when blood glucose levels are high, and their loss causes diabetes.
However, it was unknown whether senescent beta cells could continue functioning at all.
To their surprise, the researchers discovered that during normal aging, p16 and cellular senescence improve the primary function of beta cells; the secretion of insulin upon glucose stimulation.
Due to the fact that insulin secretion increases during the normal aging of mice and is driven by elevated p16 activity, some of these cells actually start to function better.
The discovery may have broad implications for the understanding and treatment of diabetes, Helman said, by highlighting a new mechanism by which beta cell function and insulin secretion can be enhanced.
It also raises the possibility that drugs that can affect cell division, and senescence may influence beta cell function – for better or worse.
Drugs that can induce senescence are currently given to cancer patients, yet their effects on insulin secretion have not been well studied.
In light of these findings, it is conceivable that tools which can activate senescence could be implemented for better treatment of diabetes.
The researchers also found that activation of p16 and senescence in beta cells of mice that suffer from diabetes enhanced insulin secretion, thereby partially reversing the disease and improving the health of the mice.
Similar experiments conducted on human cells in the lab strongly suggest that senescence-induced enhancement of insulin secretion is conserved between mice and humans, and point to the p16 gene as its main driver in both organisms.
“Cell senescence is generally thought to represent a state in which cells lose their functionality, and contribute to tissue aging and disease. It was therefore very striking to observe that when beta cells enter this state during normal aging, the program allows them to function better, rather than worse,” said Ben-Porath of the Institute for Medical Research Israel-Canada (IMRIC) in the Hebrew University’s Faculty of Medicine.
“The findings suggest that what we call aging is in fact a continuum, starting with a maturation process that actually improves the function of cells and tissue, at the expense of regenerative potential. This has important implications for how we think about beta cell function and dysfunction in diabetes,” said Helman.
These findings are unique in that they indicate for the first time that during healthy aging, the function of beta cells improves, at least in some aspects.
The study also provides a basic understanding about what happens to beta cells during aging, namely a trade-off between their ability to divide and regenerate and their ability to function well.
In fact, p16 and cellular senescence, which until now have been viewed as responses to damage, stress and tumor development, in fact also regulate normal functional tissue maturation with age, in the case of pancreatic beta cells.