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The missing link in diabetes
Chronic tissue inflammation results from obesity. It is an underlying cause of insulin resistance and type 2 diabetes. But the exact way this occurs had remained hidden until now. In a paper, published in the journal Cell on September 21, University of California San Diego School of Medicine researchers identified exosomes - extremely small vesicles or sacs secreted from most cells - as the missing link.
"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. 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."
During chronic inflammation, the primary tissue to become inflamed is adipose, which stores fat. Forty percent of adipose tissue in obesity is made up of macrophages - specialized immune cells that promote tissue inflammation. Macrophages in turn create and secrete exosomes.
Ectosomes bud directly from the plasma membrane, whereas exosomes are released indirectly
When exosomes get into other tissues, they use the microRNA (miRNA) they carry to initiate reaction in those recipient cells. The macrophage-secreted miRNAs are looking for messenger RNAs. When the miRNA finds its target RNA, it binds to it, rendering the messenger RNA inactive. The protein that would have been encoded by the messenger RNA is no longer made. In this way, miRNAs are a way to inhibit the production of key proteins.
A team led by Olefsky took macrophages found in adipose tissue of obese mice and harvested their exosomes. Lean, healthy mouse models were treated with these "obese" exosomes and once-normal mice began exhibiting obesity-induced insulin resistance despite not being overweight.
Similarly, in an in-vitro study, where human liver and fat cells were treated with "obese" exosomes, these cells became insulin resistant. Conversely, when they were treated with "lean" macrophage exosomes, they became highly sensitive to insulin.
"This is a key mechanism of how diabetes works," says Olefsky. "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."
Olefsky estimates there are probably several hundred miRNAs in exosomes, but only 20 to 30 are key. Determining which miRNAs to target will require more research, but the team has already found one likely suspect: microRNA-155, which inhibits a well-known metabolic protein called PPAR?. The researchers note that there are existing clinically effective anti-diabetic drugs that target this protein, but they trigger side effects deemed not acceptable in clinical practice.
Olefsky: "Still, there are a number of microRNAs that we hope will lead to new, highly druggable targets resulting in new insulin-sensitizing therapeutics. We can obtain exosomes from blood - known as a liquid biopsy - to sequence all of these microRNAs."
By sequencing exosomes, researchers can obtain genetic signatures that could lead to biomarkers for this disease, similar to how liquid biopsies are used to find drugs that will be effective in cancer treatment. Olfesky hopes that biomarkers for diabetes will one day be used to determine if a person is at high risk of diabetes in the next year or never. Biomarkers may also predict which patients will respond to specific therapies.
"If we sequence your exosomes, we get a signature to determine the metabolic state of your liver cells, fat cells, macrophages and beta cells," Olefsky explains. "We would be able to tell you what is going on in your liver without ever doing a tissue biopsy."
While the team was focused on exosomes from adipose tissue, there are also exosomes created in the liver and other cells. Olefsky wants to study these exosomes and determine if they also move between tissues causing metabolic reactions.
Olefsky: "This could go beyond insulin resistance. Exosomes could be causing other complications of obesity that may not be related to metabolism."
From the paper:
We have known for a long time that cells communicate with their neighbors by secreting a wide array of small molecules and macromolecules. However, in the past three decades, it has become increasingly apparent that cells also release membrane-bounded vesicles not merely to discard selected cellular contents but as an extension of the intercellular communication network. Indeed, there is now vigorous and widespread interest in the roles of these extracellular vesicles (ECVs) as purveyors between cells of growth factors, selected receptors, cytoplasmic signaling proteins, transcription factors, a range of nucleic acid transcripts, DNA, and selected lipids (1). Although generation of ECVs may be a ubiquitous cellular activity, interest in this process has been especially intense with regard to communication within embryonic tissues during development, between cancer cells and their surrounding stroma, between stem cells and their more differentiated neighbors, and as part of modulatory interactions in the immune system (1, 2). Evidently, deciphering where and how ECVs are formed and how cargoes are selected are key goals in ongoing efforts to understand this multi-molecular mode of export. A new article by Jackson et al appearing in this special issue of the Biophysical Journal has not only clarified a key step in the export mechanism but more importantly has reported facile strategies for resolving and analyzing ECVs having distinct origins within the cell (3).
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An electron microscope image showing the bright, round shaped vesicles known as exosomes.
Image Credit: UC San Diego Health