UC San Diego scientists say they’ve discovered a cause of insulin resistance — a hallmark of type 2 diabetes — and reversed it in mice.

If the study is confirmed in people, it will answer a longstanding question about how insulin resistance arises. The research also has implications for therapy and diagnosis of type 2 diabetes, a major health problem.

The study found that immune cells in fat tissue emit messaging molecules that control the process. These molecules are encased in nano-sized particles called exosomes. The exosomes are released from the immune cells and travel around the body to carry their messages.


Demonstrating cause and effect, the researchers gave exosomes derived from insulin-resistant mice to insulin-sensitive mice, making them insulin resistant. Giving exosomes derived from insulin-sensitive mice to insulin-resistant ones made them insulin-sensitive.

The study was published Thursday in the journal Cell. Jerrold M. Olefsky, a UCSD professor of medicine, was senior author. Wei Ying, a researcher also at UCSD, was the first author. Go online to j.mp/exoins for the study.

Olefsky likened the exosomes to radio messages, helping cells communicate with each other.

“We weren’t on the frequency to hear it,” Olefsky said.


Olefsky chanced upon exosomes in his ongoing work to uncover the causes of type 2 diabetes, and find drugs to fight it.

Type 2 patients make insulin, but are unable to use it efficiently. Patients tend to put on weight and show other signs of metabolic disruption. Complications of type 2 diabetes include kidney and heart disease, anemia, retinal damage and an increased risk of Alzheimer’s.

About 30 million Americans had diabetes as of 2015, 90 to 95 percent of them with type 2 diabetes, according to the Centers for Disease Control and Prevention.

In some cases, but not all, exercise, diet and losing weight can reverse type 2 diabetes. But how it arises in the first place isn’t clear. Ethnicity may play a role; those of African, Hispanic and Native American ancestry are at higher risk, as are those with a parent or sibling who has the disease.


Type 2 diabetes, insulin resistance and other associated metabolic changes cause widespread effects throughout the body. How those changes are linked hasn’t been clear.

“We know that it involves lots of different organs and we know it involves the liver and the adipose tissue and the pancreas and the muscle,” Olefsky said. “We knew that these tissues must be talking to each other in some way. But no one knew how.”

“And I think the exciting part about this exosome project is that discovery. This is the language. This is how they’re talking.”

Newly discovered language

The process appears to be driven by fragments of RNA called microRNAs, Olefsky said. These molecules help control how genes are activated or suppressed, and are being studied for potential drugs. Exosomes contain not only microRNAs, but many other biological molecules.


One microRNA disproportionately found in the exosomes from obese mouse macrophages, called miR-155, has already been implicated in insulin resistance. Mice without the ability to make this microRNA were found to remain insulin sensitive, compared to controls. Humans also make this microRNA.

Exosomes used to be considered mere debris, a cell’s way of taking out the trash. But evidence has accumulated that exosomes deliver a vast amount of messages between different kinds of cells, influencing them in ways previously undetected.

Olefsky has been studying type 2 diabetes for many years. A 2014 study Olefsky led found that an excess of fatty acids in fat cells resulted in a lack of oxygen. This produced inflammation in the adipose tissue, which in turn led to insulin resistance, obesity and related diseases.

As part of this process, immune cells called macrophages migrate to the fat tissue. Olefsky said they clearly appear to be causing insulin resistance, which in turn is linked to obesity and type 2 diabetes.


“Obesity causes inflammation and that’s kind of where we’ve been wobbling for the past two or three years,” Olefsky said. “Well, obesity causes inflammation. All these macrophages get into fat tissue and then you get insulin resistance. How does that work?”

A potential answer dawned on Olefsky after he read a study about the presence of microRNAs in macrophages.

“I wondered if they could be important because the cancer biology people had already shown that cancer cells can make exosomes that get in the blood and circulate around, and they’re using them as biomarkers of cancer,” he said. “And I thought, could this also work for metabolic disease?”

Sending the message

To test that idea, Olefsky and colleagues isolated macrophages from adipose tissue, and cultured them in the lab. The macrophages indeed secreted exosomes.


Researchers then treated mice with the secreted exosomes, derived from both normal mice and obese, insulin-resistant mice. Transferring them from one kind of mouse to the other converted them to the kind of mouse that they were taken from.

Interestingly, the lean mice didn’t become obese, but they still developed insulin resistance.

“You just take the obese exosomes, you give them to a lean mouse, and the mouse gets the metabolic disease,” Olefsky said. “It doesn’t get obese but it gets the metabolic disease.”

Likewise, the obese mice remained obese, but became insulin-sensitive.


“We take those lean macrophage exosomes and give them to an obese diabetic mouse and the mouse gets better. The glucose metabolism normalizes, the insulin resistance goes away.“

Now, the challenge is to determine which other microRNAs in the adipose exosomes are involved in insulin resistance.

“In aggregate they probably have 500-600 microRNAs inside of them, Olefsky said. “But not all of them are important and some of them are just sort of passengers that get swept up in the tide, and they’re very low levels of them, and they’re not biologically significant.

“And we think that in these macrophage exosomes, there’s about somewhere between 20 and 40 that might be biologically significant. And we have developed a process to identify the most important ones.”


For further reading

Young cardiac cells rejuvenate heart in animal study

UCSD, Janssen, collaborate on metabolic diseases

Removing a protein reverses insulin resistance in diabetic mice

Obesity-related disease trigger found, says UCSD team


Studies identify new diabetes therapies

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