The impact of hypoglycaemia awareness status on regional brain responses to acute hypoglycaemia in men with type 1 diabetes

Abstract

Aims/hypothesis Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes increases the risk of severe hypoglycaemia sixfold and can be resistant to intervention. We explored the impact of IAH on central responses to hypoglycaemia to investigate the mechanisms underlying barriers to therapeutic intervention. Methods We conducted [15 O]water positron emission tomography studies of regional brain perfusion during euglycaemia (target 5 mmol/l), hypoglycaemia (achieved level, 2.4 mmol/l) and recovery (target 5 mmol/l) in 17 men with type 1 diabetes: eight with IAH, and nine with intact hypoglycaemia awareness (HA). Results Hypoglycaemia with HA was associated with increased activation in brain regions including the thalamus, insula, globus pallidus (GP), anterior cingulate cortex (ACC), orbital cortex, dorsolateral frontal (DLF) cortex, angular gyrus and amygdala; deactivation occurred in the temporal and parahippocampal regions. IAH was associated with reduced catecholamine and symptom responses to hypoglycaemia vs HA (incremental AUC: autonomic scores, 26.2 ± 35.5 vs 422.7 ± 237.1; neuroglycopenic scores, 34.8 ± 88.8 vs 478.9 ± 311.1; both p < 0.002). There were subtle differences (p < 0.005, k ≥ 50 voxels) in brain activation at hypoglycaemia, including early differences in the right central operculum, bilateral medial orbital (MO) cortex, and left posterior DLF cortex, with additional differences in the ACC, right GP and post-and pre-central gyri in established hypoglycaemia, and lack of deactivation in temporal regions in established hypoglycaemia. Conclusions/interpretation Differences in activation in the post-and pre-central gyri may be expected in people with reduced subjective responses to hypoglycaemia. Alterations in the activity of regions involved in the drive to eat (operculum), emotional salience (MO cortex), aversion (GP) and recall (temporal) suggest differences in the perceived importance and urgency of responses to hypoglycaemia in IAH compared with HA, which may be key to the persistence of the condition.

Impaired Awareness of Hypoglycemia Disrupts Blood Flow to Brain Regions Involved in Arousal and Decision Making in Type 1 Diabetes

“…Despite similarity of global CBF, regional CBF responses to hypoglycemia were different between HA and IAH groups in our study. Within our HA group, hypoglycemia resulted in an increase in thalamic CBF, a region involved in sensory and motor signal relay (27), and a reduction in hippocampal and temporal cortex CBF on whole-brain analysis, data consistent with previous reports (10,11,17,24,28). Hippocampal and temporal structures are involved in multiple aspects of memory, classically episodic (personal autobiographical events) and semantic (factual information) memory and, more recently, short-term or working memory (29).…”

“…Our ROIs were selected a priori, each representing functional associations that are important factors in hypoglycemia awareness, arousal and sensory transmission (thalamus), autonomic function (ACC), reward and decision making (DLPFC and OFC), and memory (hippocampus). All five regions have been commonly observed in PET and fMRI studies as responding to hypoglycemia (9)(10)(11)17,18,(21)(22)(23)(24)28). Small-volume correction revealed CBF increases within the thalamus, right lateral OFC, and right DLPFC seen in HA were significantly less in IAH, and the fall in hippocampal CBF seen in HA was reduced in IAH.…”

“…The most important difference, however, is likely to be the depth of hypoglycemic challenge. Brain responses evolve as hypoglycemia progresses (11,17), and counterregulatory responses can be triggered at concentrations ,60 mg/dL in diabetes (37). Clinically, the majority of individuals with type 1 diabetes will experience plasma glucose concentrations ,60 mg/dL (3.3 mmol/L) (6).…”

“…Between-group, hypothesisled analyses of a priori-defined regions of interest (ROIs)dthe thalamus, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), OFC, and hippocampusdwere performed. These regions were selected on the basis of a review of published literature establishing key cerebral structures involved in the response to hypoglycemia (9)(10)(11)17,18,(21)(22)(23)(24). ROI masks were created using the Wake Forest University School of Medicine PickAtlas (25).…”

“…Whether this is due to adaptations in brain regions involved in behavior and decision making is unknown. Positron emission tomography (PET) and functional MRI (fMRI) have been used to investigate brain responses to hypoglycemia in individuals without diabetes and with type 1 diabetes; however, the described impacts of hypoglycemia awareness status are not conclusive (9)(10)(11)(12). Data on global blood flow, an important possible mediator for differences in response, have been discrepant between studies (10,13).…”