People with a severe form of diabetes, where the beta cells in the pancreas do not produce or no longer produce enough insulin, have no choice but to regularly inject themselves with artificial insulin to survive. But insulin therapy is not without dangers: it is difficult to dose and, in the long run, can also cause serious metabolic and cardiovascular problems. Scientists at the University of Geneva (UNIGE) have been working for several years on an alternative therapy based on the S100A9 protein. They have now provided proof of principle that this protein can significantly improve metabolism in insulin deficiency. In addition, by deciphering the biological mechanisms at work, they have discovered a previously unknown anti-inflammatory effect that could be key far beyond diabetes. These results are published in the journal Nature Communications.
Insulin therapy, which celebrated its 100th anniversary in 2021, has probably saved the lives of hundreds of millions of people with type 1 diabetes or severe forms of type 2 diabetes. However, it has some risks, if the doses are too high or too low, and is even directly responsible for some life-threatening conditions. As a result, the life expectancy of insulin-dependent diabetics is reduced by 10 to 15 years compared to the norm. “Life-threatening hypoglycemia, negative impact on fat metabolism and increased cholesterol: these are some serious side effects of insulin. That’s why we seek to develop complementary or alternative treatments that are more effective and less dangerous,” summarizes Roberto Coppari. a Professor of the Department of Cell Physiology and Metabolism and Coordinator of the Diabetes Center of the Faculty of Medicine of UNIGE, who directed this work.
The S100A9 protein demonstrates its value
In 2019, Professor Coppari’s team identified a protein called S100A9 that regulates blood glucose, lipids and ketones (a product of the oxidation of fatty acids in the liver when the body no longer has enough glucose to function), without the side effects of insulin.
To develop a drug, however, we had to understand how this protein works accurately and demonstrate its effectiveness in animal models. “
Girorgio Ramadori, associate researcher in the laboratory of Professor Coppari and lead author of the study
The team first set out to decipher the mode of action of S100A9 in diabetic mice. “It turns out that this protein acts on the liver,” says Gloria Ursino, the study’s first author and postdoctoral fellow on the research team. “It activates the TLR4 receptor, which is found in the membrane of certain cells, but not in the hepatocytes, which are the main functional cells of the liver.” This is excellent news from a pharmacological point of view: it means that S100A9 does not need to enter the liver cells to act and allows for a simple mode of administration of injection.
In people with diabetes, 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 each year. “Activation of TLR4 in the liver controls the production of ketones,” explains Gloria Ursino. “But this activation process does not trigger inflammation, whereas TLR4 is usually proinflammatory. Therefore, the S100A9-TLR4 dialogue appears to act as a totally unexpected anti-inflammatory drug.”
A strategy in several steps
The scientists completed their findings by examining the blood of diabetics arriving at the emergency room with severe insulin deficiency. “A slight but insufficient natural increase in S100A9 is detected,” explains Giorgio Ramadori. “Therefore, additional administration of S100A9 is expected to improve this compensatory mechanism.”
Although the idea of a combination of drugs has already been explored, previous research has focused on drugs that increase insulin sensitivity. “But this only leads to the same results with lower doses. The side effects of insulin therapy remain the same,” explains Roberto Coppari. “Here we propose a radically different strategy with a drug that works independently of insulin and cannot cause hypoglycemia or disrupt fat metabolism.”
Scientists will initially test their drug along with low doses of insulin, but do not rule out the possibility of administering the S100A9 protein alone in the future, under specific conditions. To further develop this highly innovative therapy, Roberto Coppari and Giorgio Ramadori have created a new company, Diatheris, with the support of UNITEC, the UNIGE technology transfer office, and FONGIT, the main foundation to support technological entrepreneurship in the canton of Geneva.
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Magazine reference:
Ursino, G., et al. (2022) The non-parenchymal hepatic S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis. Communications of nature. doi.org/10.1038/s41467-022-31803-5.