Tuesday January 25 2011
Brain bleeds may be affected by blood sugar levels
“One reason why people with diabetes can suffer more damage during strokes has been discovered,” reported BBC News. It said a study has found a “protein which increased bleeding when blood sugar levels are high”.
This study involved an experimental model of a hemorrhagic stroke (a brain bleed) in which the brains of rodents were injected with a small amount of blood. The researchers then measured how far the blood spread through the brain over time. The model was tested in rodents with diabetes and controls with normal blood sugar levels.
The model showed that injecting a protein called plasma kallikrein (PK) into rats’ brains increased the rate that blood spread, and this was even faster in diabetic rats or control rats with high blood sugar. Further study found that a different chemical, which activates a protein called glycoprotein VI, reversed this effect.
This is good quality research, providing more evidence to the importance of glucose control for diabetics. This is early research and much further study is needed. The researchers point out that their model is limited because it does not fully mimic the events that lead to a brain bleed. Studies in humans would help to see whether PK plays a role in brain bleeds and whether this is affected by blood sugar levels.
Where did the story come from?
The study was carried out by researchers from Harvard University in the USA. It was funded by the US Institute of Health and the American Heart Association. The study was published in the peer-reviewed journal Nature Medicine.
The BBC covered this research accurately.
What kind of research was this?
The aim of this study was to investigate the role of a protein called plasma kallikrein (PK) in haemorrhagic strokes and how this might be affected by high blood sugar levels. This type of stroke accounts for around 20% of all strokes, occurring when a weakened blood vessel supplying the brain bursts and causes brain damage.
The researchers were interested in this particular protein as their previous work had found that it may affect the function of the blood brain barrier (a group of cells that regulate which chemicals from the blood enter the brain and the waste products of the brain that are cleared into the bloodstream).
The researchers say that recovery after a haemorrhagic stroke is dependent on the volume of blood that has been released into the brain. This volume of blood (hematoma) can expand over time, like a bruise. They say that high blood sugar levels (hyperglycemia), which occurs in diabetes, are thought to be associated with a greater hematoma expansion, but this is not fully understood.
To examine how PK is involved, the researchers modelled haemorrhagic strokes in diabetic and non-diabetic rats and mice. The model is of type 1 diabetes where there is a lack of insulin, as opposed to type 2 diabetes where a person is insensitive to their own insulin and cannot maintain appropriate blood glucose levels.
What did the research involve?
The model involved diabetic and non-diabetic rats and mice. The rodents had been made diabetic by an injection of a toxic chemical that destroyed their insulin-producing cells.
The rats were anaesthetised and their own blood was injected into their brain to simulate a stroke. The researchers then measured the volume of the blood as it increased over time.
To investigate whether PK was involved in hematoma expansion, the researchers injected a chemical that inhibits PK into the rodent’s blood stream and an “anti-PK antibody” that would neutralise the effect of PK into their brains. They also looked at hematoma expansion in mice that were genetically modified so that they did not produce PK.
What were the basic results?
The diabetic mice tended to have greater hematoma expansion than non-diabetic mice, which was as expected from this model of type 1 diabetes.
Injecting the PK inhibitor into diabetic rats resulted in a smaller hematoma spread. In diabetic mice that were engineered to not make the PK protein, hematoma expansion was lower than in diabetic mice that did make this protein.
To see whether the effects on hematoma expansion were dependent on high blood glucose levels (as found in diabetics), diabetic mice were injected with insulin to lower their blood glucose, before they were injected with PK. The large hematoma expansion that would have normally happened in these mice did not occur. In case the process of making the rats diabetic had affected their PK activity rather than the high glucose, the researchers injected non-diabetic rats with glucose to produce a spike of glucose in their blood stream. The hematoma expansion in these hyperglycaemic rats was found to be greater than in the control rats.
The researchers found that the effect of PK on hematoma expansion could be prevented by also injecting the animals with convulxin, a chemical that activates a protein called glycoprotein VI (GPVI). The researchers did this because GPVI binds to collagen, leading to the activation of platelets in the blood. Humans with GPVI defects usually have a mild bleeding disorder.
The researchers examined how PK’s inhibitory effect on collagen-induced platelet aggregation was altered when solutions with different concentrations of salt, mannitol (a type of sugar alcohol) or glucose were injected into the brain. The concentration (osmolarity) of these compounds in the solution was greater than that normally found in blood. High salt, mannitol or sugar solutions injected into the brain increased the inhibitory effect of PK on collagen-induced platelet aggregation. Injecting rats with mannitol to increase the osmolarity of their blood resulted in increased hematoma expansion, similar to PK or blood injection. This made the researchers think that the inhibition of GPVI by PK may be a response mechanism in the brain to changes in concentration (or osmolarity) of the blood.
How did the researchers interpret the results?
The researchers suggest that PK binds to collagen and inhibits the collagen-induced platelet aggregation that is necessary for clotting. They say that a high glucose concentration increases PK binding to collagen, thereby increasing the inhibition of clotting.
They say that in this experimental model of a brain bleed, inhibition of GPVI by PK may be a response mechanism of the brain to changes in concentration (or osmolarity) of the blood.
This early research conducted in animals highlights a potential mechanism for explaining the expansion of a brain bleed after the initial event and why this may be enhanced in diabetics.
This is well-conducted, complex research. As the researchers point out, their model is limited because injecting blood into the brain of a rat does not exactly model the events that cause a spontaneous brain bleed in humans. Using otherwise healthy animals also cannot mimic the changes in blood or blood vessels leading to bleeds occurring in humans. They suggest that more studies are needed to determine the role of PK during a brain bleed and how blood sugar affects this in a clinical setting.