Protein improves metabolism of insulin-dependent diabetics

People with a severe form of diabetes, where the beta cells of the pancreas do not produce or no longer produce enough insulin, have no choice but to inject themselves regularly with artificial insulin in order to survive. Scientists at the University of Geneva (UNIGE) have been working on an alternative therapy based on the S100A9 protein, and have now provided proof of principle that this protein can significantly improve metabolism in insulin deficiency. Their results are published in the journal Nature Communications.

Insulin therapy has probably saved the lives of hundreds of millions of people suffering from type 1 diabetes or severe forms of type 2 diabetes, but it is difficult to dose and, in the long term, it can also lead to serious metabolic and cardiovascular problems. Consequently, the life expectancy of insulin-dependent diabetics is reduced by 10 to 15 years compared to the norm.

In 2019, Professor Roberto Coppari’s team at UNIGE identified a protein called S100A9 that regulates blood glucose, lipids and ketones (a product of fatty acidic oxidation in the liver when the body no longer has enough glucose to function), without the side effects of insulin. Seeking to understand how this protein works, they set out to decipher the mode of action in diabetic mice.

“It turns out that this protein acts in the liver,” said Gloria Ursino, a first author of the study. “It activates the TLR4 receptor, which is located on the membrane of certain cells, but not on the hepatocytes, which are the main functional cells of the liver.” This means that S100A9 does not need to enter the liver cells to act and allows for a simple injection mode of administration.

In diabetic people, insulin deficiency can cause a sudden increase in ketones and acidification of the blood, a mechanism called diabetic ketoacidosis. This is a life-threatening emergency that affects 2–4% of people with type 1 diabetes every year.

“TLR4 activation in the liver controls the production of ketones,” Ursino said. “But this activation process does not trigger inflammation, whereas TLR4 is usually pro-inflammatory. The S100A9-TLR4 dialogue therefore seems to act as a totally unexpected anti-inflammatory drug.”

The scientists completed their results by examining the blood of diabetic people arriving at the emergency room with severe insulin deficiency. Girorgio Ramadori, lead author of the study, noted, “A slight but insufficient natural increase in S100A9 is detected. Therefore, additional administration of S100A9 is expected to enhance this compensatory mechanism.”

While the idea of a combination of drugs has already been explored, previous research has focused on drugs that increase insulin sensitivity. According to Coppari, “This only leads to the same results with lower doses — the side effects of insulin therapy remain the same. Here, we propose a radically different strategy with a drug that works independently of insulin and that can neither trigger hypoglycaemia nor disrupt fat metabolism.”

The scientists will initially test their drug in conjunction with low doses of insulin, but do not rule out the possibility of administering the S100A9 protein alone in the future, in specific conditions. To further develop their therapy, Coppari and Ramadori have created a startup company, Diatheris.

Image credit: ©stock.adobe.com/au/wip-studio

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