Diabetes mellitus (DM) is one of the most common diseases in the world. Among its effects are an
increase in the risk of cognitive impairment, including Alzheimer’s disease, and blood-brain barrier (BBB) dysfunction.
DM is characterized by high blood glucose levels that are caused by either lack of insulin (Type I) or
resistance to the actions of insulin (Type II). The phenotypes of these two types are dramatically different, with
Type I animals being thin, with low levels of leptin as well as insulin, whereas Type II animals are often obese
with high levels of both leptin and insulin. The best characterized change in BBB dysfunction is that of disruption.
The brain regions that are disrupted, however, vary between Type I vs Type II DM, suggesting that factors
other than hyperglycemia, perhaps hormonal factors such as leptin and insulin, play a regionally diverse role in
BBB vulnerability or protection. Some BBB transporters are also altered in DM, including P-glycoprotein, lowdensity
lipoprotein receptor-related protein 1, and the insulin transporter as other functions of the BBB, such as
brain endothelial cell (BEC) expression of matrix metalloproteinases (MMPs) and immune cell trafficking. Pericyte
loss secondary to the increased oxidative stress of processing excess glucose through the Krebs cycle is one
mechanism that has shown to result in BBB disruption. Vascular endothelial growth factor (VEGF) induced by
advanced glycation endproducts can increase the production of matrix metalloproteinases, which in turn affects
tight junction proteins, providing another mechanism for BBB disruption as well as effects on P-glycoprotein.
Through the enhanced expression of the redox-related mitochondrial transporter ABCB10, redox-sensitive transcription
factor NF-E2 related factor-2 (Nrf2) inhibits BEC-monocyte adhesion. Several potential therapies, in
addition to those of restoring euglycemia, can prevent some aspects of BBB dysfunction. Carbonic anhydrase
inhibition decreases glucose metabolism and so reduces oxidative stress, preserving pericytes and blocking or
reversing BBB disruption. Statins or N-acetylcysteine can reverse the BBB opening in some models of DM, fibroblast
growth factor-21 improves BBB permeability through an Nrf2-dependent pathway, and nifedipine or
VEGF improves memory in DM models. In summary, DM alters various aspects of BBB function through a
number of mechanisms. A variety of treatments based on those mechanisms, as well as restoration of euglycemia,
may be able to restore BBB functions., including reversal of BBB disruption.
Blood-Brain Glucose Transfer In Diabetes Mellitus: Decreased Number of Glucose Transporters at Blood-Brain Barrier