Platelets, the blood cells that allow coagulation, are highly dependent on their ability to metabolize glucose, according to a new study by researchers at the University of Iowa. The results, published on Cell Reports and in a related paper published on Arteriosclerosis, Thrombosis and Vascular Biology, may have implications for understanding the increased risk of thrombosis – blood clots within blood vessels – in people with diabetes. Platelets are disc-shaped cellular fragments in the blood that, once activated, aggregate to form clots. Increased platelet activation may also contribute to inflammatory conditions such as rheumatoid arthritis and increased mortality due to sepsis. The research team found that mice lacking the proteins that platelets use to import glucose from circulation have a lower platelet count and their platelets live shorter lives. The team found that glucose metabolism is very critical during the entire life cycle of platelets – from production, to what they do in the body, to how they are released from the body.
Two glucose transporters (GLUT1 and GLUT3) are required because glucose enters the platelets. Researchers studied genetically modified mouse models lacking only GLUT1 and GLUT3 or GLUT3 and observed how platelet formation, function and clearance were affected. In the absence of the ability to metabolize glucose, mice produced platelets and the mitochondria of platelets have metabolized other substances instead of glucose to perform their task of generating cell energy. But the mice had a number of platelets lower than normal. The researchers were able to identify two causes for the low number of platelets in mice lacking GLUT1 and GLUT3: less platelets produced and higher platelet clearance. Platelets are created from bone marrow cells called megakaryocytes. The researchers tested the ability of megakaryocytes to generate new platelets by depleting platelet blood and observing subsequent recovery.
They also tested megakaryocytes in culture, stimulating them to create new platelets and found that the generation of new platelets was defective. Clearly there is an obligatory need for glucose to extract platelets from the bone marrow. In addition, the team observed that young platelets were functioning normally, even in the absence of glucose. But as we age, the platelets were eliminated from circulation before normal because they were destroyed. The platelets undergo a new mechanism of necrosis thanks to which the absence of glucose leads to the splitting of a protein called calpain, which marks them by this necrotic route. When the researchers treated the animals with a calpain inhibitor, they saw the increase in platelet clearance decrease. The team also sought to determine if platelets could exist and function when the mitochondria metabolism is stopped. Mice were injected with a mitochondrial poison at a dose that a healthy mouse can tolerate.
In mice with GLUT1 and GLUT3 deficiency, however, the platelet count dropped to zero in about 30 minutes. In the related study in ATVB, the research team showed that GLUT3 played the predominant role in platelet activation and that mice with reduced GLUT3 in platelets survived pulmonary embolism and developed a less severe arthritis in a rheumatoid arthritis model. Dr. Abel states that this study sets the stage for exploring strategies in which modifying platelet glucose utilization could be exploited for therapeutic purposes under conditions where inhibition of platelet activation could be beneficial. The work is part of a larger collaboration funded by the National Institutes of Health with researchers at the University of Utah, which seeks to understand the mechanisms to increase the risk of thrombosis in diabetes. Scientists know that in diabetes, platelets use too much glucose. This increase in glucose metabolism is related to the platelet hyperactivity that characterizes many diabetic vascular complications. Therefore, reducing the ability of platelets to use glucose could be of therapeutic benefit in the context of diabetes.
And now, those affected have one more reason to keep their blood sugar under control.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Fidler TP et al. Arterioscler Thromb Vasc Biol. 2017 Sep; 37(9):1628.
Fidler TP et al., Abel ED. Cell Report 2017 Jul 25; 20(4):881-894.