Biological complexity: platelet glucose metabolism (Introduction)

by David Turell , Sunday, August 06, 2017, 19:02 (2454 days ago) @ David Turell

Without glucose platelets can be produced but in smaller quantities. The pathways are outlined for glucose use. As usual very complex:

https://www.sciencedaily.com/releases/2017/08/170804123941.htm

"We found that glucose metabolism is very critical across the entire life cycle of platelets -- from production, to what they do in the body, to how they get cleared from the body," says E. Dale Abel, MD, PhD, professor and DEO of internal medicine at the UI Carver College of Medicine and director of the Fraternal Order of Eagles Diabetes Research Center at the UI.

"Two proteins -- glucose transporter (GLUT) 1 and GLUT3 -- are required for glucose to enter platelets. Abel and his colleagues studied genetically engineered mouse models that were missing GLUT1 and GLUT3 or GLUT3 alone and observed how platelet formation, function, and clearance were affected. (my bold)

In the absence of the ability to metabolize glucose, the mice did produce platelets, and the platelets' mitochondria metabolized other substances in place of glucose to do their job of generating the cells' energy. But the mice had platelet counts that were lower than normal.

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"The researchers were able to pinpoint two causes for the low platelet count in mice lacking GLUT1 and GLUT3: fewer platelets being produced, and increased clearance of platelets.
Platelets are created by cells in the bone marrow called megakaryocytes. The researchers tested the megakaryocytes' ability to generate new platelets by depleting the blood of platelets and observing the subsequent recovery, which was lower than normal. They also tested the megakaryocytes in culture, stimulating them to create new platelets, and found that the generation of new platelets was defective.

"'Clearly, we show that there's an obligate need for glucose to bud platelets off from the bone marrow," Abel says.

"In addition, the team observed that young platelets functioned normally, even in the absence of glucose. But as they aged, the platelets were cleared from the circulation earlier than normal because they were being destroyed.

"We identified a new mechanism of necrosis by which the absence of glucose leads to the cleavage of a protein called calpain, which marks them for this necrotic pathway," Abel says. "If we treated the animals with a calpain inhibitor, we could reduce the increased platelet clearance."

"The team also sought to determine whether platelets could exist and function when mitochondria metabolism is halted. The mice were injected with a mitochondrial poison at a dose that a healthy mouse can tolerate. In the mice deficient in GLUT1 and GLUT3, however, platelet counts dropped to zero within about 30 minutes.

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"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 less severe arthritis in a model of rheumatoid arthritis.

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"'We know that in diabetes, platelets are using too much glucose," Abel says. "This increase in glucose metabolism does correlate with the platelet hyperactivity that characterizes many diabetic vascular complications. Reducing the ability of platelets to use glucose could be of therapeutic benefit in the context of diabetes.'"

Comment: Platelets are vital particles. They set off clotting at wounds. Their lifetime is about 10 days, so a constant supply is vital. Note their production and actions depend upon two distinct specialized proteins (note my bold) allowing glucose to enter them. Once again this complexity requires design for initial development.