Instead of insulin?
Insulin therapy celebrated its 100th anniversary in 2021. It has saved the lives of hundreds of millions of people suffering from type 1 diabetes or an insulin-dependent form of type 2 diabetes. However, insulin therapy comes with some risks if the doses are too high or too low, and is even directly associated with potentially fatal conditions. Life–threatening hypoglycemia, negative effects on fat metabolism and elevated cholesterol levels are some serious side effects of insulin. Therefore, the life expectancy of insulin-dependent diabetics is reduced by 10-15 years compared to the norm.
Researchers are seeking to develop additional or alternative treatments that would be more effective and less dangerous. A group from the University of Geneva (UNIGE) has been working on an alternative therapy based on the S100A9 protein for several years. In a new paper, they presented fundamental evidence that this protein can significantly improve metabolism in diabetes mellitus.
In people with diabetes, insulin deficiency can cause a sudden increase in ketone levels and acidification of the blood, resulting in diabetic ketoacidosis. This is a life-threatening condition that occurs annually in 2-4% of people with type 1 diabetes.
In 2019, Professor Roberto Coppari's group determined for the first time that S100A9 regulates blood glucose and lipid levels. In a new study, she showed that S100A9 reduces ketone levels – a product of fatty acid oxidation in the liver, which is triggered when the body lacks glucose to function – without the side effects characteristic of insulin therapy.
The group focused on the mechanisms of action of S100A9 in mice with diabetes. It turned out that in the liver it activates the membrane Toll-like receptor 4 (TLR4), located on nonparenchymtose cells, and not on hepatocytes. Activation of TLR4 in the liver controls ketone production, but this process does not cause inflammation, although TLR4 is usually pro-inflammatory. Thus, the S100A9-TLR4 complex seems to act quite unexpectedly as an anti-inflammatory drug.
Accordingly, the action of S100A9, limited to the liver but not associated with hepatocytes (the main functional unit of the liver), corrects hyperketonemia and hyperglycemia caused by insulin deficiency, without causing hypoglycemia in mice with diabetes.
Scientists examined the blood of diabetic patients admitted to the emergency department with severe insulin deficiency, and found a small but insufficient increase in natural S100A9. Therefore, they believe that the additional introduction of S100A9 will strengthen this compensatory mechanism.
Although the idea of a combination of drugs for diabetics has already been studied, previous studies have focused on drugs that increase insulin sensitivity. But this leads to the same results, only at lower doses: the side effects of insulin therapy remain the same. The introduction of S100A9 is a radically different strategy that works independently of insulin and does not cause either hypoglycemia or impaired fat metabolism.
Initially, scientists will test their drug in combination with low doses of insulin, and then study the possibility of introducing only the S100A9 protein under certain conditions.
Article by G.Ursino et al. Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis is published in the journal Nature Communicatoins.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru .