A new type of diabetes that’s not associated with insulin deficiency or obesity has been discovered -- in mice.

In a study published Wednesday, researchers led by Salk Institute scientists found that in a mouse model of the disease regarded as predictive of human diabetes, some develop an unusual type that affects old, lean mice.

This disease is caused by overactivity of a certain kind of immune system cell. The researchers call this new form Type 4 diabetes.

The study was published in the journal Nature. Go to j.mp/type4diabetes for the study.


If the study is confirmed in people — a big if — the public health implications would be profound. Diabetes can lead to blindness, kidney and heart disease, and poor blood circulation that can lead to amputation. Diabetes is usually associated with obesity, and a form that is not may escape detection because doctors aren’t looking for it.

The study was led by the Salk’s Ronald Evans and Ye Zheng. Evans said it’s possible that millions of Americans have this type of diabetes.

“Oftentimes people think that if they’re lean, they’re protected from diabetes, and most physicians would think that,” Evans said.

The researchers envision a potential treatment by developing an antibody drug to reduce levels of these overactive immune cells. That will take at least a few years, Evans said.


Evans estimates that about 20 percent of diabetics over 65 have this newly identified version, and may not be getting the proper care. More than 9.4 million diabetic Americans are over 65 as of 2012, according to the Kaiser Family Foundation. And that number doesn’t count those who haven’t been diagnosed.

So the total number of Americans with this new type of diabetes could reach about 2 million, if Evans’ estimate is accurate.

Evans said treatment of lean, elderly diabetics is less effective, because it’s largely focused on reducing consumption of fat or losing weight, which isn’t a factor for these people. Some of the regular diabetes drugs, such as the standby metformin, show some effectiveness, Evans said. Metformin is a good choice because it’s safe.

But even with the many drugs on the market, more are needed.


“Diabetes in general is not a well-managed disease,” Evans said.

Confirmation needed

Announcing a new form of diabetes is a bit premature, said UC San Diego diabetes researcher Alan Saltiel, who was not involved in the study. Confirmation in humans still needs to be done. That means finding evidence in old, lean people of overactivity of these immune cells, called T regulatory cells, Saltiel said. These “Treg” cells suppress inflammation and tamp down the immune response.

Saltiel, who co-authored an accompanying commentary in Nature, said that despite his caution, the study is significant. It indicates that the story of diabetes is much more complicated than previously thought. Suppressing inflammation was supposed to be a good thing, but this study indicates it’s not always the case.


“It’s very surprising,” Saltiel said. “We didn’t expect these Treg cells to play this role. It’s been assumed that diabetes is kind of an inflammatory disease, that obesity begets inflammation, and then inflammation plays a big role in the generation of diabetes.”

While no animal model equals evidence from humans, Saltiel said the mouse model tested in the study is the best one around. But while it’s accurate in imitating many aspects of human diabetes, he cautioned that it’s not perfect in mimicking what diabetes does in people.

Another expert, Scripps Health clinical endocrinologist Athena Philis-Tsimikas, said the findings make sense.

“Clinically we see a wide variety of patient ‘types’ and body habitus that all have similar rises in blood sugar,” she said by email. “The variation is found in individuals that are older, younger, lean, overweight and different racial/ethnic mix. So the findings in this article are definitely interesting and it would seem logical that with so many clinical pictures that there must be different underlying mechanisms such as those described in this article.”


“One exciting outcome of studies like these are that with so many new therapies in diabetes that the discovery of new mechanisms may allow us to tailor a more unique therapeutic regimen for our individual patients,” Philis-Tsimikas said. “I find this kind of work very exciting and look forward to seeing further work in humans.”

Balancing act

All forms of diabetes involve abnormally high levels of blood sugar. This is mainly regulated by two hormones. Insulin lowers blood sugar levels, and glucagon raises them. With this brake and accelerator system, blood sugar levels can be controlled within a narrow range.

Type 1 diabetes is caused by a lack of insulin, and eventually is fatal unless insulin is provided. It’s caused by an autoimmune reaction that destroys the insulin-producing islet cells in the pancreas. Inflammation is believed to be part of the autoimmune response.


Type 2 diabetes, by far the most common, is caused by resistance to insulin. This requires production of larger amounts of insulin to overcome the resistance and drive down blood sugar levels. It’s related to being overweight and obese. Inflammation produced by other immune cells called macrophages drives obesity-associated insulin resistance, which may be a sign of pre-diabetes.

More tentatively, a third type of diabetes has recently been proposed. It’s called Type 3 diabetes and is associated with Alzheimer’s. It’s thought to be caused by the effects of diabetes on the brain.

A fourth type of diabetes, caused by suppressing inflammation, would add another layer of complexity, Saltiel said.

“People have looked at Tregs in obesity, and the idea was that they were protective, that they were lost in the obese state,” Saltiel said. “What this paper is saying that surprisingly, they’re going up in aging, and aging is another condition associated with resistance to insulin.”


More tentatively, a third type of diabetes has recently been proposed. It’s called type 3 diabetes and is associated with Alzheimer’s. It’s thought to be caused by the effects of diabetes on the brain.

A fourth type of diabetes would add another layer of complexity, Saltiel said.

“People have looked at Tregs in obesity, and the idea was that they were protective, that they were lost in the obese state,” Saltiel said. “What this paper is saying that surprisingly, they’re going up in aging, and aging is another condition associated with resistance to insulin.”