Type 2 diabetes affects millions of people worldwide, and scientists are still working to find its root causes. Researchers have now identified disruptions to the life cycle of the fat storage cells of people with type 2 diabetes by comparing the cells with those of people without type 2 diabetes. This finding points to new potential treatments, and research targeting cellular senescence has produced encouraging results.
Type 2 diabetes – a condition in which the body struggles to regulate blood glucose – affects an estimated 446 million people worldwide. Unlike type 1 diabetes, which is genetic and manifests early in life, type 2 diabetes develops over time. It is a multifaceted disease that disrupts multiple organ systems, and scientists are striving to unravel its root causes.
New research, published in Diabetes, provides clues to the cellular changes underlying type 2 diabetes. A team of researchers from the University of Gothenburg and the University of Naples Federico II compared the fat storage cells of people of similar weight – some with type 2 diabetes and some without – and identified disruptions to the cell life cycle of those with diabetes.
Co-author Ulf Smith, a professor of internal medicine, says that the findings came as a surprise – and could become a “target of future treatment”.
The body’s batteries
Fat storage cells, or adipose cells, are the epicentre of diabetes. They are the body’s energy storage mechanism, converting excess glucose in the blood to fat molecules that can be broken back down into usable glucose later.
An adipose cell’s “basic function is to store fat when in excess and to release it when we need it – for exercise, night-time, starvation, whatever,” Smith explains. “But they are much more complex since they are involved in regulating insulin sensitivity, energy and many other mechanisms and pathways.”
Adipose cells dole out energy based on signals from organs in the form of hormones – including insulin. As you digest a meal, the energy from the food is converted to glucose and distributed throughout the body via the bloodstream. The pancreas needs to secrete insulin, which signals adipose cells to remove glucose from the bloodstream, thus preventing blood glucose from getting too high.
In type 2 diabetes, adipose cells develop insulin resistance – meaning they are no longer as responsive to insulin’s signal to collect rather than release energy.
“Having functional adipose cells that can store and release lipids as needed is really important,” Smith says.
Cellular “retirement” gone awry
To better understand what goes wrong with adipose cells in type 2 diabetes, Smith and his team examined cells from volunteers. The researchers classified the volunteers based on their body mass index (BMI), a ratio of weight to height. Some were designated as lean, others with obesity and the third group with obesity and type 2 diabetes.
The researchers assessed each tissue sample for the number and size of the adipose cells and checked for the presence of certain chemicals associated with senescence – “retirement” associated with ageing and obesity in which cells exit the cell cycle.
Adipose cells are created by cloning cells called preadipocytes. These preadipocytes sometimes enter senescence, meaning that they stop producing new cells but do not die – almost like cellular retirement. Senescent cells also release a flurry of chemicals that prompt neighbouring cells to opt out of the cell cycle too.
Generally, senescence is a protective process, triggered in defective cells to shut down the runaway reproduction of cancer cells. “The negative side is when it targets non-cancer cells and functional cells” such as adipose cells, Smith says.
This is a chain reaction, and if insufficient preadipocytes are available to create new adipose cells, “the existing adipose cells become expanded” in an attempt to compensate, Smith says. “And this leads to inflammation and several changes in the tissue, including whole-body insulin resistance.”
Although senescence by definition happens to cells that can divide, Smith and the team began to suspect that adipose cells might undergo something like senescence too – affecting their ability to store fat.
A new kind of senescence
The researchers isolated mature adipose cells from people with obesity and type 2 diabetes to look for evidence of senescence. There are several telltale senescence markers – including proteins the cells produce and alterations in gene expression – and the team found elevated levels of these in the cells of the people with type 2 diabetes versus the cells from lean people without diabetes. (The authors acknowledge that these baseline cells were taken from volunteers who were younger than the cohort with diabetes, and this is significant since senescence also increases with age.)
The researchers identified key differences in the adipose cells of people with type 2 diabetes, according to co-author Rosa Spinelli, a postdoctoral fellow at the University of Gothenburg’s Department of Molecular and Clinical Medicine.
Among donors of similar BMI and age, people with type 2 diabetes had larger adipose cells and exhibited a greater proportion of senescent adipose cells. Further, people with more senescent adipose cells had higher whole-body insulin resistance.
Future avenues for treatment
The finding that mature adipose cells undergo something like senescence in type 2 diabetes points to new potential treatments, Smith says – and preliminary work targeting cellular senescence in mouse models has produced encouraging results.
The researchers tested two senolytic agents – a class of drugs that selectively attack senescent cells developed in the early 2000s by scientists at the Mayo Clinic – on senescent adipose cells. One of the drugs, dasatinib, is a chemotherapy drug for leukaemia. The other, quercetin, is the naturally occurring chemical responsible for an apple peel’s bitter taste. It is a plant pigment also found in red onions, kale and many berries.
The team used a different chemotherapy drug to simulate senescence in mature adipose cells and applied the senolytic agents to determine whether they could counter its effects.
The senolytics reduced several markers of senescence and inflammation and counteracted the artificial senescence. “We have also shown that this happens when the senescent preadipocytes are treated with the same agents,” Spinelli explains. “These are really important data, because by using these agents, we can improve function in all tissues by targeting different types of senescent cells.”
But how would these results be translated from cells in a petri dish to people? Although a senolytic drug for type 2 diabetes is many, many clinical trials away, such a medication “could be potentially oral, or it could be an intravenous subcutaneous injection,” Smith says.
Previous work with senolytic agents in mouse models shows that “if you use senolytic agents, the body takes about 7–10 days to have more senescent cells accumulate,” Smith says. “Treatment with senolytic agents about four times a month could be possible, or something like that.”
