MK2 enzyme inhibitor for the prevention and treatment of diabetes
Researchers at Columbia University Medical Center (CUMC), working under the guidance of Professor Ira Tabas, have found that excessive activity of the MK2 enzyme in liver cells exacerbates two major metabolic defects underlying diabetes: decreased insulin sensitivity and increased blood glucose levels. They believe that the use of a drug inhibiting this enzyme in combination with methomine – a first–line drug in the treatment of type 2 diabetes mellitus - will significantly increase the possibility of improving the condition of patients with this disease.
Obesity is often accompanied by the development of selective insulin resistance of tissues, which leads to the development of metabolic syndrome or prediabetes, progressing into type 2 diabetes mellitus. The experiments conducted by the authors on a mouse model of obesity revealed one of the previously unknown molecular mechanisms underlying this phenomenon. It turned out that blocking the MK2 enzyme in liver cells, by acting on the p38 protein, suppresses the activity of the liver enzyme CaMKII – Ca-dependent kinase, the hyperactivity of which is characteristic of obesity. The result is a decrease in blood glucose levels and normalization of metabolism.
The most effective drug for the treatment of diabetes today is metformin. However, in many cases it provides only a partial improvement. The authors believe that combining metformin with an MK2 inhibitor would achieve much better results, since these compounds affect different biochemical mechanisms. Moreover, the MK2 inhibitor could serve patients with methomine intolerance well.
The authors have already received, but have not yet published data according to which the MK2 enzyme is hyperactive in the liver of obese people, including those with prediabetes, but not in the liver of people with normal body weight. Moreover, according to the results of a large study of human genetics DIAGRAM, a key component of this mechanism, activating MK2, is associated with diabetes mellitus.
As type 2 diabetes progresses, insulin-producing beta cells are forced to synthesize more and more insulin in order to neutralize the gradually increasing concentration of glucose in the blood. Eventually, they wear out and die, which forces the patient to resort to insulin injections. Tabas believes that the MK2 inhibitor could provide protection for pancreatic beta cells and prevent or delay the progression of prediabetic conditions into a full-fledged disease. The authors plan to test this hypothesis on a mouse model of prediabetes.
Unpublished data by researchers also indicate that inhibition of the MK2 enzyme is not associated with the risk of developing diseases of the cardiovascular system, which is a side effect of some modern antidiabetic drugs.
The authors also demonstrated that the suppression of MK2 activity reduces cholesterol levels in the blood, while other researchers have found that the deficiency of this enzyme protects mice from the development of atherosclerosis. Thus, a theoretical drug that inhibits MK2 is not only safe for the heart, but is also a means of preventing its diseases.
The MK2 inhibitor is seen as an ideal tool for the treatment and prevention of type 2 diabetes and researchers are already working on its creation, however, they note that, like everything related to drug development, it will take a lot of time.
Article by Lale Ozcan et al. Activation of Calcium/Calmodulin-Dependent Protein Kinase II in Obesity Mediates Suppression of Hepatic Insulin Signaling is published in the journal Cell Metabolism.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on CUMC materials:
New Link Between Obesity and Diabetes Found.
26.11.2013