The Diabetic Brain During Hypoglycemia

Abstract

Many factors impact the fluctuating rates of glucose flux and clearance in one’s daily life (meal size and composition, gastric emptying rate, physical activity, etc.). With this constantly changing need for circulating insulin abundance, it is challenging for the treatment strategy to be entirely successful in individuals with type 1 diabetes (T1D), and transient periods of hypoglycemia occur. Humans have evolved metabolic strategies to cope with hypoglycemia, and these include counter-regulatory endocrine responses to increase hepatic glucose production as well as selection of alternative fuels for mitochondrial respiration. The central nervous system can use glycolytic end products that were produced by other tissues (circulating lactate) as well as ketones to some extent. The ability to take up and oxidize these alternative fuels is likely critical for tolerance of and survival through hypoglycemia. The traditional view was that glycolysis makes pyruvate and that only under anaerobic conditions would lactate be generated. It is now recognized that glycolysis makes lactate even under fully aerobic conditions because of the intrinsic kinetic properties of lactate dehydrogenase, which rapidly interconverts pyruvate and lactate and favors lactate on a mass basis. Thus, lactate can be considered the major product of glycolysis even when the fate of glycolytic carbon is primarily mitochondrial oxidation. The basal lactate concentration in tissues and arterial circulation is at least 10 times greater than pyruvate and even higher under stresses that increase the glycolytic rate (1,2), so lactate is the primary shuttling form of glycolytic end products through the cytoplasm and through the circulation from one organ to another. The liver releases glucose to share its carbohydrate fuel depot with other tissues. …