Only experimental studies could reasonably address these issues. Indeed, post-mortem examination does not yield insight into the proximal processes that precede apoptosis in humans. This may explain that hyperglycaemia tended to be correlated with microglial activation selleck chemicals llc (reflected by CD68 expression), which is prior to apoptosis. Assessment of neuropathological effect of BG control would require brain sampling in patients who had died from septic shock and who had or not been treated with insulin therapy: a task not so easily achievable. Our neuropathological samples were obtained before the widespread implementation of glycemic control with intensive insulin therapy in many critical care units. This is illustrated by the fact that insulin was administered in a small proportion of patients and was not targeted to normoglycaemia.
These observations prevented us from assessing the neuropathological effect of insulin. Moreover, anticipating a neurological benefit from insulin therapy is premature. First of all, even if microglial cells play a major role in host defence of the brain, and are involved in neuroinflammatory and neurodegenerative processes, their implication in sepsis related brain dysfunction is not demonstrated . It is unknown whether microglial apoptosis is an adaptive, negligible or deleterious phenomenon. Unlike the situation in neurons, interpretation of positive ISEL staining in glial and microglial cells is not straightforward. As ISEL is not absolutely specific for double-stranded DNA breaks and can also detect single-stranded breaks as observed in cell multiplication , positive staining may also reflect cell proliferation.
On the other hand, Petito and Roberts  suggested that apoptotic death of reactive astrocytes might be a physiological mechanism whereby the brain removes an excess number of astrocytes that have proliferated after certain types of brain injury. This can also apply for microglia . Second, cerebral glucose metabolism is highly complex and its disturbances in sepsis insufficiently elucidated. Therefore, neuronal sensitivity to hypoglycaemia and hyperglycaemia might be deeply changed in sepsis, making the effect of insulin on neuronal metabolism unpredictable. We have found that neuronal GLUT4 and microglial GLUT5 expression were neither correlated with blood glucose levels or cell apoptosis. This does not rule out that glucose transporters are involved in cell death process. For instance, it has been experimentally shown that GLUT5 is implicated in hyperglycaemia-related microglial cell death . Furthermore, one may have Drug_discovery expected that glucose transporter expression would have been inversely proportionate to blood glucose level [40,42,43].