Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose

Abstract

Hypoglycaemia is characterized by decreased blood glucose levels and is associated with different pathologies (e.g. diabetes, inborn errors of metabolism). Depending on its severity, it might affect cognitive functions, including impaired judgment and decreased memory capacity, which have been linked to alterations of brain energy metabolism. Glucose is the major cerebral energy substrate in the adult brain and supports the complex metabolic interactions between neurons and astrocytes, which are essential for synaptic activity. Therefore, hypoglycaemia disturbs cerebral metabolism and, consequently, neuronal function. Despite the high vulnerability of neurons to hypoglycaemia, important neurochemical changes enabling these cells to prolong their resistance to hypoglycaemia have been described. This review aims at providing an overview over the main metabolic effects of hypoglycaemia on neurons, covering in vitro and in vivo findings. Recent studies provided evidence that non-glucose substrates including pyruvate, glycogen, ketone bodies, glutamate, glutamine, and aspartate, are metabolized by neurons in the absence of glucose and contribute to prolong neuronal function and delay ATP depletion during hypoglycaemia. One of the pathways likely implicated in the process is the pyruvate recycling pathway, which allows for the full oxidation of glutamate and glutamine. The operation of this pathway in neurons, particularly after hypoglycaemia, has been re-confirmed recently using metabolic modelling tools (i.e. Metabolic Flux Analysis), which allow for a detailed investigation of cellular metabolism in cultured cells. Overall, the knowledge summarized herein might be used for the development of potential therapies targeting neuronal protection in patients vulnerable to hypoglycaemic episodes.

Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism

“…The high incidence of deficits in motor development in CHI confirms retrospective studies [9, 11]. Glucose is the major cerebral energy substrate, and hypoglycemia impairs neuronal function [12]. In addition, vulnerability of brain regions to insulin-induced hypoglycemia has been shown previously [13].…”

“…The parental-administered instruments CBCL 1.5–5 and CBCL 4–18 showed a statistically significant increase in reported behavioral problems in age group 3 (6–17 years), in particular somatic complaints and attention problems were reported. It is presumed that the reported somatic as well as attention problems are caused by hyperinsulinemic hypoglycemia [12]. Psychoeducation of the patients and their parents could minimize the psychological strain and is, therefore, recommended.…”

Lipoprotein lipase is an important modulator of lipid uptake and storage in hypothalamic neurons

“…At present, it is unknown what role lipid droplets play in hypothalamic neurons. There is evidence that, under conditions of glucose deprivation, neuronal metabolism can be shifted to other substrates including pyruvate, glutamate, lactate, aspartate, ketone bodies, and other fuels [27]. Whether neurons use fatty acids as a fuel source during times of starvation remains to be seen, and we are investigating whether β-oxidation occurs in cultured neurons.…”

Regulation of pyruvate metabolism and human disease

“…Indeed, the brain accounts for 20–25 % of the body’s daily glucose consumption [178]. Ketone bodies may also be used, but only at significant levels during fasting [179].…”