Exosomes from obese mice induce insulin resistance in healthy animals.
Inflammation is a driving factor of insulin resistance and type 2 diabetes among patients with obesity; however, the link between these factors has been largely unknown.
The authors of a study published by Cell indicate that exosomes—small vesicles secreted from cells—may be involved.
“The actions induced by exosomes as they move between tissues are likely to be an underlying cause of intercellular communication causing metabolic derangements of diabetes,” said senior author Jerrold Olefsky, MD. “By fluorescently labeling cells, we could see exosomes and the microRNA they carry moving from adipose (fat) tissue through the blood and infiltrating muscle and liver tissues.”
The primary tissue affected by inflammation is adipose, which is largely composed of macrophages that secrete exosomes. When exosomes infiltrate other tissues, they use microRNA (miRNA) to induce actions in the recipient cells, according to the study.
When miRNA binds to a target in RNA, it inactivates the messenger RNA and prevents the protein that would have been encoded from being created. The authors report that these actions show that miRNA can inhibit protein production.
In the study, the authors examined macrophages in adipose tissue of obese mice and extracted exosomes. Lean mice received exosomes from obese mice, which caused the animals to exhibit obesity-induced insulin resistance, according to the study.
The investigators discovered that insulin resistance in obese mice could be reversed with treatment with exosomes from lean mice. Although the mice were overweight, they were metabolically healthy, according to the study.
In an in vitro study, human liver and fat cells treated with exosomes from obese patients, the cells exhibited insulin resistance. When treated with exosomes from lean patients, insulin sensitivity was restored.
“This is a key mechanism of how diabetes works,” Dr Olefsky said. “This is important because it pins the pathophysiology of the disease in inflamed adipose tissue macrophages which are making these exosomes. If we can find out which of the microRNAs in those exosomes cause the phenotype of diabetes, we can find drug targets.”
While the authors hypothesize that there are likely hundreds of miRNAs in exosomes, only 20 to 30 are crucial in insulin resistance.
Additional research is needed, but the authors believe that microRNA-155 is likely involved in insulin resistance. There are anti-diabetic drugs that target the protein, but they elicit significant side effects.
“Still, there are a number of microRNAs that we hope will lead to new, highly druggable targets resulting in new insulin-sensitizing therapeutics,” Dr Olefsky said. “We can obtain exosomes from blood — known as a liquid biopsy — to sequence all of these microRNAs.”
Sequencing exosomes may lead to the discovery of biomarkers for the condition, which could predict a patient’s risk for diabetes and guide therapy decisions, according to the study.
“If we sequence your exosomes, we get a signature to determine the metabolic state of your liver cells, fat cells, macrophages and beta cells,” Dr Olefsky said. “We would be able to tell you what is going on in your liver without ever doing a tissue biopsy.”
The authors also plan to explore whether exosomes may also invade tissues and cause other diseases, according to the study.
“This could go beyond insulin resistance,” Dr Olefsky concluded. “Exosomes could be causing other complications of obesity that may not be related to metabolism.”