Impact of Hypoglycemia on Brain Metabolism During Diabetes

Abstract

Diabetes is a metabolic disease afflicting millions of people worldwide. A substantial fraction of world's total healthcare expenditure is spent on treating diabetes. Hypoglycemia is a serious consequence of anti-diabetic drug therapy, because it induces metabolic alterations in the brain. Metabolic alterations are one of the central mechanisms mediating hypoglycemia-related functional changes in the brain. Acute, chronic, and/or recurrent hypoglycemia modulate multiple metabolic pathways, and exposure to hypoglycemia increases consumption of alternate respiratory substrates such as ketone bodies, glycogen, and monocarboxylates in the brain. The aim of this review is to discuss hypoglycemia-induced metabolic alterations in the brain in glucose counterregulation, uptake, utilization and metabolism, cellular respiration, amino acid and lipid metabolism, and the significance of other sources of energy. The present review summarizes information on hypoglycemia-induced metabolic changes in the brain of diabetic and non-diabetic subjects and the manner in which they may affect brain function.

Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

“…In diabetic subjects, increased levels of ketone bodies can occur despite the high glucose plasma concentrations due to defective insulin release and impaired glucose uptake by the insulin-sensitive tissues. Under these conditions, the liver produces ketone bodies to serve the brain, heart and skeletal muscles which, due to insulin resistance and impaired glucose uptake/internalization, cannot rely on glucose supply [21]. Insulin injection may revert KB levels [19].…”

Starvation-induced regulation of carbohydrate transport at the blood-brain barrier is TGF-β-signaling dependent

“…Interestingly, it has been reported that endothelial GLUT1 expression is increased upon hypoglycemia (Boado and Pardridge, 1993;Kumagai et al, 1995;Simpson et al, 1999, reviewed in Patching, 2016Rehni and Dave, 2018). However, the molecular mechanisms that control this upregulation are not yet understood.…”

Microglial metabolic flexibility supports immune surveillance of the brain parenchyma

“…Glucose is considered to be the main source of metabolic fuel for the brain, with small stores of glycogen in astrocytes to temporarily (<30 min) support neuronal function during metabolic stress [26][27][28][29][30] . The reliance on continuous glucose supply to the brain becomes apparent when glucose levels are compromised, such as in stroke 31,32 , in cases of severe hypoglycemia as seen in diabetic management with insulin 33,34 , and during hypoglycorrhachia (low cerebrospinal fluid (CSF) glucose) in patients with bacterial meningitis 35 or GLUT1 deficiency 36 . As neuronal health deteriorates in the absence of glucose, it is critical that microglia perform immune protection and debris clearance functions in energy-deprived environments.…”