Hyperglycemia, hypoglycemia and dementia: role of mitochondria and uncoupling proteins

Diabetes mellitus is one of the most prevalent chronic diseases. Since glucose is the main fuel of the brain, its levels should be maintained within a narrow range to ensure normal brain function. Indeed, the literature shows that uncontrolled blood glucose levels, whether too high or too low, impact brain structure and function potentiating cognitive impairment. Uncoupling proteins (UCPs) are a family of mitochondrial anion carrier proteins located on the inner mitochondrial membrane, and their primary function is to leak protons from the intermembrane space into the mitochondrial matrix. The specific role of neuronal UCPs has been widely discussed and although there is no general agreement, there is a strong conviction that these proteins may be involved in the defense against mitochondrial reactive oxygen species (ROS) production and, consequently, protecting against oxidative damage. The generation of ROS is increasingly recognized as playing an important role in diabetes, neurodegenerative disorders and aging where mitochondria are both sources and targets of these reactive species. This review examines the neurodegenerative events associated with diabetes, highlighting the role of hyperglycemia and/or hypoglycemia on cognitive function. The role of mitochondria, neuronal UCPs and their impact in central nervous system will be elucidated. Finally, we will discuss neuronal UCPs as possible therapeutic targets for the treatment of diabetes-associated central complications and neurodegenerative diseases, namely Alzheimer's and Parkinson's diseases.