p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

Abstract

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16Ink4a in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16Ink4a in beta cells induces hallmarks of senescence—including cell enlargement, and greater glucose uptake and mitochondrial activity—which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

Pancreas regeneration

“…Broad molecular and epigenetic changes occur as β-cells mature and age, with well-documented loss of EZH2 and BMI1, an increase in cell-cycle inhibitors such as P16 INK4a and p18 INK4c , and epigenetic changes 15,88,89 . Some of these changes seem to improve β-cell function 90 , but they may broadly suppress the ability of β-cells to respond to proliferative stimuli. There is longstanding evidence that insulin and glucose, both of which are elevated in obesity or insulin resistance, may directly stimulate β-cell proliferation 91–93 .…”

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

“…In humans, the accumulation of senescent markers has been demonstrated in the skin, T lymphocytes, atherosclerotic lesions, insulin-producing β cells, kidney, endothelium, visceral fat, joint cartilage, cardiac muscle, liver, and many others tissues 98,101–107 . Some tissues are likely to have a greater propensity to developing cellular senescence than others, but research in this area is scarce.…”

Differential influence of tacrolimus and sirolimus on mitochondrial-dependent signaling for apoptosis in pancreatic cells

“…A major impediment for such layout is the harmless impact of SIR on insulin despite its senescence triggering effect. Although recent observations shown that b-cells undergoing senescence in absence of external stress have an enhanced insulin production compared to their regular counterparts [40], the issue of stress-induced premature senescence remains challenging.…”