Acute Hypoglycemia and Inhibitory Synaptic Transmission in Brain Neurons
Abstract
Topic Area: Diabetes The control of blood glucose levels is a serious issue for personnel in the U.S. military and their family members. Among military personnel on active duty, their spouses and Veterans, over 50% are overweight or obese, and these conditions can lead to type 2 diabetes mellitus. Also, the prevalence of patients with type 1 diabetes (autoimmune disease) among U.S. military personnel and their children is similar to that among the civilian population. Diabetes has important effects on the brain. This organ is disproportionally dependent on blood glucose for its energy: in spite of accounting for only 2% of body weight, it consumes about 20% of the energy produced through the metabolism. Thus, low blood glucose (hypoglycemia) has a strong impact on brain function. When blood glucose levels fall below the physiological range (70-110 mg/dl), the brain undergoes functional and morphological abnormalities. When hypoglycemia is moderate (40-60 mg/dl), cognitive function deteriorates; when it is severe (<40 mg/dl), the patient quickly falls into a coma, and this is accompanied by irreversible neuronal damage and sometimes even death of the patient. Hypoglycemia is relatively common among patients with diabetes, both those with the type 1 form and those with the advanced type 2 form. The best way to prevent hypoglycemia is to consistently and effectively maintain physiological blood glucose levels; this involves controlling energy intake, energy expenditure, and insulin levels in the blood. Although these methods have improved considerably in recent decades, patients still suffer hypoglycemic episodes. This is due largely to the rapid nature of changes in blood glucose and insulin levels. In the case of severe hypoglycemia, simply elevating the blood glucose to physiological levels is not sufficient; studies have shown that simple restoration of blood glucose can lead to paradoxical, irreversible loss of brain neurons. In the case of moderate hypoglycemia, the mechanism underlying neuronal dysfunction remains poorly understood, because effective ways of monitoring neuronal function are not readily available. These points highlight the need to understand the fundamental features of hypoglycemia, especially those of moderate hypoglycemia and the mechanisms whereby it influences neuronal function. One key component of brain dysfunction is an imbalance between the excitation and inhibition of brain activity. These activities are mediated by excitatory and inhibitory chemical substances transmitted between neurons (neurotransmitters). It has long been known that, during hypoglycemia, both the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are released to similar degrees in the brain. However, most research to date has focused on how glutamate causes brain dysfunctions and brain damage (known as excitotoxicity). How the inhibitory actions of GABA change during moderate hypoglycemia remains largely unexplored, and this is holding back a full understanding of this condition, as well as the development of the more effective treatments. The aim of the research proposed here is to identify the precise behaviors of GABA during acute hypoglycemia. Specifically, we will test the hypothesis that: (1) an excess of GABA is released by the sending (presynaptic) neurons, but (2) GABA interacts with the receiving (postsynaptic) neurons with reduced efficiency and (3) its effect on postsynaptic neurons is converted from inhibitory to excitatory. Such GABA-associated changes would tip the balance toward the excitation of neurons, which could underlie the brain dysfunctions that occur during hypoglycemia. All three questions will be addressed in a common experimental setup. Specifically, we will test: (1) whether these changes are aggravated after repeated episodes of hypo- and hyperglycemia, as often occurs in patients and (2) to what extent the abn
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810136
Entities
People
- Nobutoshi Harata
Organizations
- United States Army
- University of Iowa