Scientists of the Harvard School of Public Health discovered a novel mechanism, partly responsible for a disrupted metabolism in obesity. In their article, recently published in Nature Medicine, the authors present a process that takes place in liver cells, which can eventually lead to insulin resistance and type 2 diabetes.
Until now, the mechanism behind the development of type 2 diabetes through obesity remained elusive. According to Gökhan Hotamisligil, senior author of the article, one of the involved processes takes place in the liver: “the metabolic stress induced in obesity causes structural changes in liver cells, affecting their function.” Eventually, this causes insulin resistance and diabetes.
The researchers came to this conclusion after studying thousands of liver cells from obese and healthy mice with an electron microscope and other imaging techniques. They counted the contact points between two organelles - the endoplasmic reticulum (ER) and mitochondria. In obese mice, they found a significant higher number of these connections compared to healthy mice.
In liver cells, connections between ER and mitochondria are necessary for the function of both organelles – they take care of the calcium ion supply to the mitochondria. However, according to the authors, an increased amount of these connections causes an increased concentration of calcium. In turn, this causes mitochondrial stress and a disrupted metabolism.
Hotamisligil and his colleagues provided evidence for their theory by introducing a synthetic molecule in healthy mice, reducing the space between ER and mitochondria in liver cells and evoking calcium influx in mitochondria. This led to a disrupted metabolism, making the mice more sensitive to high-fat diet induced insulin resistance and diabetes.
In the future, the authors hope to be able to reverse this process. Theoretically, by normalising the number of contact points between ER and mitochondria in obese mice, the mitochondrial stress could be diminished. This could eventually lead to development of a therapy to treat insulin resistance and type 2 diabetes in humans.
Source: Nature Medicine.
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