Targeting a hitherto enigmatic protein could help to treat people with insulin resistance

This story was originally posted on the Science News DK website, written by Eliza Brown. This features Dr. Ed Conway, Professor of Medicine & Dr. Jan Eriksson, Professor of Clinical Diabetes Research & Clinical Endocrinology. 

A new study highlights the CD248 protein as potentially being key in combatting insulin resistance, a core problem in type 2 diabetes. Experiments showed that mice lacking the CD248 gene were shielded from the obesity and insulin resistance normally caused by the high-fat diets fed to mice. The researchers noted similar effects in human fat cells (adipocytes), suggesting that CD248 is involved in insulin responsiveness. Although still far from clinical application, targeting CD248 represents a promising avenue for developing treatments for people with insulin resistance, offering new hope in fighting diabetes.

Photo taken from Science News DK.

Photo taken from Science News DK.

A little-known cellular protein called CD248 could hold the key to treating – and perhaps even reversing – the insulin resistance in type 2 diabetes, scientists say.

New research, published in eBioMedicine, found that mice with the CD248 gene removed were protected from the effects of a high-fat diet, including obesity and insulin resistance. And crucially, evidence indicates that CD248 may play a similar role in humans, since the study found that human fat cells with higher levels of CD248 are more resistant to insulin.

Although there is a long way to go before people could pick up CD248 silencers at their local pharmacy, the researchers say that CD248 is a promising target for drug development.

Insulin resistance and a bad-guy protein

As you digest a meal, cells in your pancreas release insulin – a hormone that instructs tissues all over the body to absorb sugar from the bloodstream and move it into storage in fat cells. But under certain conditions, some cells across the body become insulin resistant – meaning they do not follow insulin’s instructions or are less responsive to them. This can lead to high blood sugar, a marker of type 2 diabetes.

Despite the importance of insulin resistance in diabetes, no drug on the market targets it directly, says study author Ed Conway, a haematologist and Professor of Medicine at the Centre for Blood Research at the University of British Columbia, Vancouver, Canada. And since CD248 sits on the surface of cells, it could be easy for drugs to reach.

The authors say that they happened on the relationship between CD248 and insulin resistance accidentally. About a decade ago, Conway was studying the role of CD248 in blood clotting when he encountered a Wikipedia report that mentioned off-the-charts levels of CD248 in fat cells. Simultaneously, researchers at Karolinska Institutet in Stockholm, Sweden had identified high levels of CD248 in a scan of fat cells from people who were obese and/or had diabetes.

“Nobody had noted that before,” Conway says, and not much was known about CD248’s function. More than 10 years later, it remains somewhat of a mystery.

Dr. Ed Conway

Dr. Ed Conway

Many diseases are caused by an important part of the body that becomes overzealous. For instance, some forms of arthritis are caused by an overactive immune system. But interestingly, that does not seem to be the case for CD248. Although this protein does not have a clear role in healthy cell functioning, high amounts of CD248 have been implicated in several clinical disorders. For example, it seems to be involved in promoting blood clotting and is present in high concentrations in the cells surrounding tumours.

“We do know that it promotes inflammation, scarring and cell growth, and these things are not necessarily always bad,” Conway explains. “But the body must have redundant mechanisms because, at least in mice, a total lack of CD248 causes no apparent harm,” he says. Thus, for example, mice lacking the CD248 gene had normal liver and kidney function. In fact, the mice seemed to fare better overall without CD248 – they had a lower risk of the growth of some tumours, arthritis, blood clots and heart, liver and kidney conditions.

“It would be analogous to an appendix,” he says. “If taken away, it makes no difference, but we do not really know what the function is all by itself.” But just as researchers have discovered potential functions for the appendix over time – including supporting the immune system and as a reservoir of beneficial gut bacteria – Conway says we cannot rule out that CD248 has a role we have not pinned down yet.

Of mice and men

After seeing the elevated levels of CD248 among people with insulin resistance, the researchers set out to determine whether knocking out CD248 could benefit insulin responsiveness and glucose regulation.

First, Conway and his team fed high-fat diets to both knockout mice and mice with an intact CD248 gene. That is how scientists typically provoke insulin resistance in mice and simulate type 2 diabetes.

The researchers found that the knockout mice were protected from the high-fat diet, Conway explains. They did not become obese and did not develop insulin resistance like their siblings with the intact gene did.

Even more striking was a series of experiments in which adult mice had the CD248 gene removed after diabetes onset. “If you make a mouse obese and with diabetes and then remove the CD248 gene, the diabetes reverses and glucose metabolism goes back to normal.”

Dr. Jan Eriksson

Dr. Jan Eriksson

The scientists even found a smoking gun: how CD248 disrupts a cell’s response to insulin. Using fluorescent imaging, they determined that in immature fat cells of mice, CD248 sits very close to the insulin receptor, another membrane protein that is responsible for relaying insulin’s signal to the cell’s interior. Further experiments demonstrated that the close interaction of CD248 with the insulin receptor, makes it harder for insulin to bind to its receptor and to trigger the movement of glucose from the blood into the cell

But as researchers often joke, science has made mice immortal a dozen different ways – what matters for medicine is whether the same holds true for people. Co-author Jan Eriksson, Professor of Clinical Diabetes Research and Clinical Endocrinology at the Uppsala University Hospital in Sweden, and his research colleagues tested whether CD248 plays a similar role in human fat cells.

Eriksson took samples of belly fat from 10 people and exposed them to insulin. Just like in mice, the human fat cells with high levels of CD248 were less responsive.

Far from the market

Conway’s team has already identified one important potential limitation for CD248 as a drug target – CD248 interventions seem to affect male mice much more than females.

“Female mice still respond, but it is not as dramatic,” Conway says. “Another group in the United Kingdom did not find any effects of CD248 in female mice. We do not know the reason for these sex differences.” It is unclear how this sex-dependent difference could translate to people, but initial results from Eriksson’s lab suggest that women have higher rates of CD248 expression than men.

Scientists need to better understand the relationship between insulin resistance and CD248 before it becomes a human drug target, the authors say. “We do not really know why CD248 goes up,” Conway explains. Does CD248 promote fat accumulation, or does fat accumulation increase CD248 levels? “Some thin people have type 2 diabetes, for example. They have elevated levels of CD248 as well.”

In any case, the techniques used to remove or silence the CD248 gene in mice cannot yet be used on humans, Eriksson adds.

CD248 shows promise as a potential drug target – but “it will never be the complete solution” for insulin resistance, Eriksson emphasises. “These conditions are complex.”

“There are many, many genes and many, many molecular factors involved,” he says. “And the interaction with your behaviour and environmental situation is also extremely strong.”