Exosomes from lean individuals can reverse the symptoms of diabetes associated with obesity, a new animal study shows

Inflammatory exosomes are the missing link by which obesity causes type 2 diabetes, researchers from the University of California San Diego have shown. The discovery could lead to earlier diabetes diagnosis and new ways to treat the disease, the researchers say. Overweight or obese individuals have a heightened risk for several health conditions, including type 2 diabetes. In fact, obesity is the most common cause of the disease. Patients with diabetes are insulin resistant, which means their body can no longer keep its blood glucose levels in check. As a result, diabetics are at risk of developing eye disease, kidney disease, heart disease and nerve damage.
Although the link between obesity and type 2 diabetes is well established, exactly how being overweight leads to insulin resistance and diabetes was unknown.

Now, Jerrold Olefsky and his colleagues at UC San Diego have demonstrated that exosomes released by fat tissues play the key role. The study, conducted on mice, was published in the journal Cell on 21 September 2017 [1].
Exosomes are nanoscopic packages of biomolecules that cells use to send and receive messages. In fact, the genetic material exosomes contain can directly reprogram the behaviour of recipient cells.
The new research shows there is a significant difference between the content of exosomes released by the fat tissue of lean individuals and obese individuals – there are “good” exosomes and “bad” exosomes. When Olefsky’s team collected exosomes from the adipose fat of obese mice (“bad” exosomes), and gave them to lean mice, these mice became insulin resistant i.e. diabetic. Even more significantly from a health point of view, the reverse was also true. When obese mice received “good” exosomes from lean mice, their insulin sensitivity and glucose regulation improved. “This is a key mechanism of how diabetes works,” said Olefsky.

Exosomes from adult stem cells to treat diabetes?
Already patients with kidney disease have been treated with exosomes purified from umbilical cord cells – a ready source of “good” exosomes [2]. Patients treated with the extracellular vesicles (exosomes) had a significant improvement over untreated patients and the benefit was seen at 12 months after treatment.
Based on the work by Olefsky’s team, treatment with “good” exosomes collected from the culture of adult stem cells would be an obvious next step to help obese patients with type 2 diabetes.

Understanding exosomes and treating diabetes
Analysing the exosomes released by the obese mice, and comparing them to the content of the lean animals’ exosomes, the researchers identified one snippet of genetic code that could be partly responsible for the diabetes-inducing effects: microRNA-155. Other microRNAs probably also contribute, Olefsky added. “If we can find out which of the microRNAs in those exosomes cause the phenotype of diabetes, we can find drug targets.”
The finding adds to recent research hinting that RNA-laden exosomes are key mediators of diabetes and related disorders. In 2016, researchers at the University of Lyon in France showed exosomes from muscle cells could influence gene expression in the body’s insulin-producing cells [3]. And in 2017, researchers from Harvard studied the exosomes released by adipose tissue, showing it to be a major source of microRNAs. Publishing in the journal Nature, the team showed these exosomes altered glucose sensitivity in mice. The Harvard team identified an alternative microRNA, miR-99b, as a key player in glucose sensitivity.
One option for an “engineered” exosome-based diabetes treatment would be to select cell culture conditions to maximise the good-RNA and minimise the bad-RNA contents of the exosomes the cells release.
Alternatively, healthful fat cells could be collected from lean & fit individuals and cultured to produce large quantities of “good” exosomes as treatments for patients with diabetes. Regenerative exosomes derived from other cell types, including adult stem cells, are already being developed into drugs for other conditions.
A further option is to load-up “good” exosomes from cells with synthetic microRNAs that have been shown to be beneficial – making a super-exosome treatment.

Early diagnosis of diabetes using exosomes
Cataloguing the microRNAs responsible for triggering diabetes would also have implications for disease diagnosis. Doctors could screen patients’ blood for the inflammatory “bad” exosomes that bring on the disease, helping them identify individual patients at risk of developing diabetes before the first symptoms appear.
Type 2 diabetes is also known as the ‘adult onset’ form of the disease. But one implication of the global obesity epidemic is the rise of obesity in children. Type 2 diabetes is now increasingly being diagnosed in young people. Especially among non-European population groups, including Aboriginal and Torres Strait Islander populations, who have a higher risk of developing the disease. Early diagnosis could help these individuals better manage their condition and minimise the lifelong complications of the disease.

Exosomes are important to understand health and sickness
Meanwhile, the full implications of Olefsky’s discovery of the role exosomes play in obesity are still to be established. “This could go beyond insulin resistance,” Olefsky added. “Exosomes could be causing other complications of obesity that may not be related to metabolism.” Even more avenues for exosome research could soon open up.

 

Every month there are more findings supporting the importance of exosomes in health and sickness.

 

 

Written by Dr Ian Dixon, Founder & CEO of Exopharm (www.exopharm.com) November 1, 2017

References
[1] Ying, W., et al. Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity. Cell 171, 1–13 (2017)
[2] Nassar et al. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases Biomaterials Research 20, 21(2016)
[3] Jalabert, A., et al. Exosome-like vesicles released from lipid-induced insulin-resistant muscles modulate gene expression and proliferation of beta recipient cells in mice. Diabetologia 59, 1049–1058 (2016)
[4] Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450-455 (2017)