“Breakthrough Discovery Brings Closer Hope of an Insulin-Free Life for Diabetes Patients”
[Feb. 6, 2023: Marco Cattaneo, Université de Genève]
Scientists at the University of Geneva (UNIGE) have been working on an alternative therapy based on the protein S100A9 for several years. (PHOTO CREDIT: iStock Photo)
People with a severe form of diabetes, in which the beta cells in the pancreas produce little or no insulin, need regular injections of artificial insulin to survive. However, insulin therapy is not harmless: It is difficult to dose and can lead to serious metabolic and cardiovascular problems in the long run.
Scientists at the University of Geneva (UNIGE) have been working on an alternative therapy based on the protein S100A9 for several years. You have now provided the basic proof that this protein can significantly improve the metabolism in insulin deficiency. Additionally, by deciphering the biological mechanisms at work, they have uncovered a previously unknown anti-inflammatory effect that could prove key well beyond diabetes. These results are published in the journal Nature Communications.
Insulin therapy, which celebrated its 100th anniversary in 2021, is believed to have saved the lives of hundreds of millions of people with type 1 diabetes or severe forms of type 2 diabetes. However, it does come with some risks when doses are too high or too low, and is even directly responsible for some potentially deadly conditions. This shortens the life expectancy of insulin-dependent diabetics by 10 to 15 years compared to the norm.
“Life-threatening hypoglycemia, adverse effects on lipid metabolism, and elevated cholesterol levels: these are some serious side effects of insulin. For this reason we are looking for complementary or alternative treatments, more effective and less dangerous,” summarizes Roberto Coppari, Professor in the Department of Cellular Physiology and Metabolism and Coordinator of the Diabetes Center of the UNIGE Faculty of Medicine, who directed this work.
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The protein S100A9 proves itself
In 2019, Professor Coppari’s team identified a protein called S100A9 that regulates blood sugar, lipids and ketones (a product of fatty acid oxidation in the liver when the body no longer has enough glucose to function) without the side effects of insulin.
“However, in order to develop a drug, we had to understand exactly how this protein works and demonstrate its effectiveness in animal models,” emphasizes Girorgio Ramadori, research associate in Professor Coppari’s laboratory and first author of this study.
The team first set about deciphering the mode of action of S100A9 in diabetic mice. “It turns out that this protein works in the liver,” says Gloria Ursino, first author of the study and postdoc in the research team. “It activates the TLR4 receptor, which is found on the membrane of certain cells but not on the hepatocytes, which are the main functional cells of the liver.”
Roberto Coppari, Gloria Ursino and Giorgio Ramadori (left to right) want to develop complementary or alternative treatments that are more effective and less dangerous than insulin therapy. (CREDIT: Université de Geneve)
This is excellent news from a pharmacological point of view: S100A9 does not need to enter the liver cells to work and allows for a simple injection route of administration.
In diabetics, a lack of insulin can lead to a sudden increase in ketones and acidification of the blood, a mechanism known as diabetic ketoacidosis. This is a life-threatening emergency that affects 2-4% of people with type 1 diabetes each year.
RIP-DTR mice were treated with DT on days 0, 2 and 4 and injected via the tail vein on day 8 with either saline (n=5) or 0.6 mg/kg r-hS100A9 (n=8). Metabolic assessments were performed 3 hours after injection and food deprivation. Our model predicts that extracellular S100A9 activates non-parenchymal hepatic TLR4 signaling, consequently leading to multiple downstream events. (CREDIT: University of Geneva (UNIGE))
“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 normally pro-inflammatory. The S100A9-TLR4 dialogue therefore seems to act like a totally unexpected anti-inflammatory drug.”
A multi-step strategy
The scientists completed their findings by examining the blood of diabetics who came to the emergency room with severe insulin deficiency. “A slight but insufficient natural increase in S100A9 is detected,” explains Giorgio Ramadori. “Therefore, the additional administration of S100A9 is expected to enhance this compensatory mechanism.”
Experimental Groups. Homozygous tuberous sclerosis complex 1-floxed (Tsc1fl/fl) mice received 1 × 10^9 PFU of adenovirus serotype 5 expressing Cre and GFP (Cre recombination results in a Tsc1 null allele in the liver of Tsc1fl /fl mice): Tsc1liver-KO. Control mice were treated with 1 x 10^9 PFU of adenovirus serotype 5 expressing only GFP: 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 a drug combination has been explored, previous research has focused on drugs that increase insulin sensitivity. “But this only leads to the same results at 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 acts independently of insulin and cannot induce hypoglycemia or disrupt lipid metabolism.”
The scientists will initially test their drug in conjunction with low doses of insulin, but do not rule out administering the S100A9 protein alone under certain conditions in the future.
To further develop this highly innovative therapy, Roberto Coppari and Giorgio Ramadori created a start-up company, Diatheris, supported by UNITEC, the technology transfer office of UNIGE, and FONGIT, the main foundation supporting technological entrepreneurship in the canton of Geneva.
For more scientific news, visit our New Discoveries section at The lighter side of the news.
Note: Materials provided by the Université de Genève. Content can be edited for style and length.
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