Recurrent hypoglycemia exacerbates cerebral infarct volume and is associated with disrupted cerebral vascular properties in vivo
Description
Objective. Diabetes mellitus (DM) is a major modern epidemic in which patients become incapable of self-regulating their own blood glucose levels due to deficits in the insulin signaling system. To correct for the lack of regulation, which produces chronic hyperglycemia, pharmacological interventions such as exogenous insulin are used to control blood glucose levels. However, every agent used for this purpose, especially insulin, carries with it the risk of sending a patient’s blood glucose below healthy levels. In humans a blood glucose level of < 70 mg/dL is considered hypoglycemic and is a dangerous side effect of DM treatment. Recent evidence suggests that patients exposed to hypoglycemia have worsened health outcomes than DM patients who do not experience hypoglycemia. We therefore set out to study what the vascular consequences of hypoglycemia are in a rodent model to gain a greater understanding of the risks to DM patients. Methods. We utilized wild type (WT) C57Bl/6J male mice and exposed them to either acute or recurrent episodes of hypoglycemia induced with injections of exogenous insulin. To study the effects of hypoglycemia we utilized two-photon microscopy in animals with surgically implanted glass windows over their somatosensory cortices to allow for imaging of the cerebral vasculature in a living brain. To understand if hypoglycemia causes increased vulnerability to ischemic injury, we then induced experimental strokes in animals exposed to hypoglycemia using the transient middle cerebral artery occlusion method. Results. We found that animals exposed to repeated instances of hypoglycemia do exhibit increased damage after ischemic injury when compared to animals given saline injections alone. We also found that animals experiencing hypoglycemia acutely also lost cerebral capillary tone. However, this loss of tone does not appear to last more than a few hours after the reestablishment of normoglycemia. We further found that animals exposed to hypoglycemia also exhibit a persistent decrease in hematocrit compared to control animals. Conclusions. We show that hypoglycemia is a potential driver of increased ischemic vulnerability in our rodent experiments. While we did not establish any vascular tone or hemodynamic changes driven by hypoglycemia, we believe that the acute loss of tone may accompany underlying changes to the vasculature which condition it towards ischemic vulnerability. Combined with the lower hematocrit levels seen in these animals, we believe that vascular changes underly the increased damage we see, and that hypoglycemia represents a major health challenge for DM patient treatment which should be avoided.