inflammation

Scientists discover key mechanism linking obesity induced inflammation with type 2 diabetes

by Barbara Hewitt on October 31, 2017

Scientists have discovered the mechanism by which chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance in type 2 diabetes.

A team from the University of California San Diego School of Medicine in the United States have identified exosomes, extremely small vesicles or sacs secreted from most cell types, as the missing link.

(A and N photography/Bigstock.com)

The research report explains that during chronic inflammation, the primary tissue to become inflamed is adipose and 40% of adipose tissue in obesity is comprised of macrophages, specialised immune cells that promote tissue inflammation. Macrophages in turn create and secrete exosomes.

The scientists took macrophages found in adipose tissue of obese mice and harvested their exosomes. Lean, healthy mouse models were treated with these ‘obese’ exosomes and these once normal mice began exhibiting obesity induced insulin resistance despite not being overweight.

When reversing the process, the team found that they could restore insulin sensitivity to obese mice by treating them with exosomes from lean mice. The obese mice remained overweight, but were metabolically healthy.

Similarly, during an in vitro study, when 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. 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,’ said Jerrold Olefsky, professor of medicine in the division of endocrinology and metabolism at the medical school.

‘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 labelling cells, we could see exosomes and the microRNA they carry moving from adipose (fat) tissue through the blood and infiltrating muscle and liver tissues,’ he added.

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. But Olefsky said that there are a number of microRNAs that they hope will lead to new treatment, including drugs.

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. Olefsky 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. We would be able to tell you what is going on in your liver without ever doing a tissue biopsy,’ he added.

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