Glycemic extremes in youth with T1DM: the structural and functional integrity of the developing brain

Abstract

The adult brain accounts for a disproportionally large percentage of the body’s total energy consumption (1). However, during brain development,energy demand is even higher, reaching the adult rate by age 2 and increasing to nearly twice the adult rate by age 10, followed by gradual reduction toward adult levels in the next decade (1,2). The dramatic changes in brain metabolism occurring over the first two decades of life coincide with the initial proliferation and then pruning of synapses to adult levels.The brain derives its energy almost exclusively from glucose and is largely driven by neuronal signaling, biosynthesis, and neuroprotection (3–6).Glucose homeostasis in the body is tightly regulated by a series of hormones and physiologic responses. As a result, hypoglycemia and hyperglycemia are rare occurrences in normal individuals, but they occur commonly inpatients with type 1 diabetes mellitus (T1DM) due to a dysfunction of peripheral glucose-insulin-glucagon responses and non-physiologic doses of exogenous insulin, which imperfectly mimic normal physiology. These extremes can occur more frequently in children and adolescents with T1DM due to the inadequacies of insulin replacement therapy, events leading to the diagnosis [prolonged untreated hyperglycemia and diabetic ketoacidosis (DKA)], and to behavioral factors interfering with optimal treatment. When faced with fluctuations in glucose supply the metabolism of the body and brain change dramatically, largely to conserve resources and, at a cost to other organs, to preserve brain function (7). However,if the normal physiological mechanisms that prevent these severe glucose fluctuations and maintain homeostasis are impaired, neuronal function and potentially viability can be affected (8–11).

Keywords: brain; children; cognition; neuroimaging; type 1 diabetes mellitus.

Figure 1

Schematic representation of the known normal trajectory of whole brain glucose consumption, and whole brain white and gray matter volume during childhood and adolescence. These trajectories are dynamic during the time frame of exposure to many type 1 diabetes-related glycemic extremes.

Figure 2

A) Schematic representation of brain regions in young individuals with T1DM affected by hypoglycemia (green) (thalamus and hippocampus) and hyperglycemia (red) (cuneus and precuneus). Sagittal midline view. B) Schematic representation of brain regions in young individuals with T1DM affected by hypoglycemia (green) (temporal-occipital-prefrontal cortex) and hyperglycemia (red) (prefrontal cortex) lateral view.