[Feb. 6, 2023: Marco Cattaneo, Universit de Genve]
Scientists at the University of Geneva (UNIGE) have been working for several years on an alternative therapy based on the S100A9 protein. (Credit: iStock photo)
People with a severe form of diabetes, where the beta cells of the pancreas do not produce enough insulin or no longer produce enough insulin, have no choice but to be regularly injected with synthetic insulin to survive Is. But insulin therapy is not without its dangers: It’s difficult to dose and, over the long term, it can even lead to 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. Furthermore, by understanding the biological mechanisms at work, they have discovered a previously unknown anti-inflammatory effect that may prove important beyond diabetes. These results have been published in the journal Nature Communications.
Insulin therapy, which celebrates its 100th anniversary in 2021, has potentially saved the lives of millions of people suffering from severe forms of type 1 diabetes or type 2 diabetes. However, it does have some risks if the dose is too high or too low, and has even been directly responsible for some potentially fatal conditions. As a result, the life expectancy of insulin-dependent diabetics is reduced by 10 to 15 years compared to the norm.
“Life-threatening hypoglycaemia, negative effects on fat metabolism and increased cholesterol: these are some of the serious side effects of insulin. This is why we are looking to develop complementary or alternative treatments that are more effective and less dangerous” , summarizes Roberto Copari, a professor in the Department of Cell Physiology and Metabolism and coordinator of the Diabetes Center of the UNIGE Faculty of Medicine, who directed it. Work.
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S100A9 Protein Proves Its Worth
In 2019, Professor Kopari’s team identified a protein called S100A9, which can metabolize blood glucose, lipids and ketones (a product of fatty acid oxidation in the liver when the body doesn’t have enough glucose to function) without the side effects of insulin. is) controls.
“To develop a drug, however, we had to understand exactly how this protein works and demonstrate its effectiveness in animal models,” said Giorgio Ramadori, a research associate in Professor Kopari’s laboratory and lead author of this study. insist on.
The team first set out to understand S100A9’s mode of action in diabetic mice. “It turns out that this protein acts in the liver,” says Gloria Ursino, first author of the study and a postdoctoral fellow on the research team. “It activates the TLR4 receptor, which is located on the membrane of some cells, but not on hepatocytes, which are the main functional cells of the liver.”
Roberto Copari, Gloria Ursino and Giorgio Ramadori (left to right) seek to develop complementary or alternative treatments that are more effective and less dangerous than insulin therapy. (Credit: Universit de Geneve)
This is excellent news from a pharmacological point of view: it means that S100A9 does not need to enter liver cells to act and allows for a simpler injection mode of administration.
In people with diabetes, a lack of insulin can cause a sudden increase in ketones and acidification of the blood, a mechanism known as diabetic ketoacidosis. It is a life-threatening emergency that affects 2-4% of people with type 1 diabetes each year.
RIP-dTR mice were treated with DT at days 0, 2, and 4 and at day 8, either with saline (n = 5) or 0.6 mg/kg R-HS100A9 (n = 8) by tail vein was injected through Metabolic assessment was performed 3 h after injection and removal of food. Our model predicts that extracellular S100A9 activates non-parenchymal hepatic TLR4 signaling resulting in multiple downstream events. (Credit: University of Geneva (UNIGE))
“TLR4 activation in the liver regulates the production of ketones,” explains Gloria Ursino. “But this activation process does not trigger inflammation, whereas TLR4 is normally pro-inflammatory. The S100A9-TLR4 interaction therefore acts as a completely unexpected anti-inflammatory drug.”
A strategy in several steps
The scientists completed their results by examining the blood of diabetics who came to the emergency room with severe insulin deficiency. “A slight but insufficient natural increase has been detected in S100A9,” explains Giorgio Ramadori. “Therefore, additional administration of S100A9 is expected to enhance this compensatory mechanism.”
experimental group. Homozygous tuberous sclerosis complex 1 floxed (Tsc1fl/fl) mice were administered 1 10^9 PFU of adenovirus serotype 5 expressing Cre and GFP (Cre recombination results in the Tsc1 null allele in the livers of Tsc1fl/fl mice ): Tsc1liver-KO. Control mice were injected with 1 10^9 PFU of adenovirus serotype 5 expressing GFP only: Tsc1fl/fl. b Plasma insulin levels of insulin-deficient mice and healthy controls (p = 0.0003 and p = 0.0001). C mRNA content of Tcs1 in liver (p = 0.0584) and skeletal muscle (gastrocnemius) of the indicated groups. (Credit: University of Geneva (UNIGE))
While the idea of combining drugs has already been explored, previous research has focused on drugs that increase insulin sensitivity. “But it gives the same results only with a lower dose. The side effects of insulin therapy remain the same,” explains Roberto Copari. “Here, we propose a fundamentally different strategy with a drug that acts independently of insulin and that can neither trigger hypoglycaemia nor inhibit fat metabolism.”
The scientists will initially test their drug with a low dose of insulin, but do not rule out the possibility of giving the S100A9 protein alone in the future under specific circumstances.
To further develop this highly innovative therapy, Roberto Coppari and Giorgio Ramadori founded a start-up company, Diatheris, supported by UNITEC, UNIGE’s technology transfer office, and FONGIT, the main foundation supporting technological entrepreneurship in the canton of Geneva. has been created.
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Comment: Materials provided by Universit de Geneve. The content can be edited for style and length.
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