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

Abstract

Impaired awareness of hypoglycemia (IAH) affects one-quarter of adults with type 1 diabetes and significantly increases the risk of severe hypoglycemia. Differences in regional brain responses to hypoglycemia may contribute to the susceptibility of this group to problematic hypoglycemia. This study investigated brain responses to hypoglycemia in hypoglycemia aware (HA) and IAH adults with type 1 diabetes, using three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) functional MRI to measure changes in regional cerebral blood flow (CBF). RESEARCH DESIGN AND METHODS Fifteen HA and 19 IAH individuals underwent 3D pCASL functional MRI during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global, and regional CBF responses to hypoglycemia (47 mg/dL [2.6 mmol/L]) were measured. RESULTS In response to hypoglycemia, total symptom score did not change in those with IAH (P 5 0.25) but rose in HA participants (P < 0.001). Epinephrine, cortisol, and growth hormone responses to hypoglycemia were lower in the IAH group (P < 0.05). Hypoglycemia induced a rise in global CBF (HA P 5 0.01, IAH P 5 0.04) but was not different between groups (P 5 0.99). IAH participants showed reduced regional CBF responses within the thalamus (P 5 0.002), right lateral orbitofrontal cortex (OFC) (P 5 0.002), and right dorsolateral prefrontal cortex (P 5 0.036) and a lesser decrease of CBF in the left hippocampus (P 5 0.023) compared with the HA group. Thalamic and right lateral OFC differences survived Bonferroni correction. CONCLUSIONS Responses to hypoglycemia of brain regions involved in arousal, decision making, and reward are altered in IAH. Changes in these pathways may disrupt IAH individuals' ability to recognize hypoglycemia, impairing their capacity to manage hypoglycemia effectively and benefit fully from conventional therapeutic pathways to restore awareness.

The impact of postbariatric hypoglycaemia on driving performance: A randomized, single‐blind, two‐period, crossover study in a driving simulator

“…Worryingly, we found no significant difference in reported hypoglycaemic symptoms after GLU compared with ASP, which is in line with previous studies supporting a high prevalence of asymptomatic PBH patients 11 . The paucity of symptoms may indicate worrying hypoglycaemia unawareness as a result of repeated hypoglycaemia 14 . This may impede corrective self‐treatment of hypoglycaemia, which corroborates the need for detection and warning approaches in this population.…”

Increased cerebral FDG‐PET uptake in type 1 diabetes patients with impaired awareness of hypoglycaemia

“…The agreement be- Interestingly, alterations in the frontal cortex have been previously linked to T1D-IAH using other imaging modalities. 9,14,36 Moreover, even though the presence of a neuropsychological compromise in this population is not well-established, some studies reporting cognitive alterations in T1D-IAH were suggestive of frontal dysfunction. 7,8 For its part, the precuneus region is one of the most metabolically active brain area, and is considered to be the core node of the default mode network (DMN).…”

“…Interestingly, alterations in the frontal cortex have been previously linked to T1D‐IAH using other imaging modalities 9,14,36 . Moreover, even though the presence of a neuropsychological compromise in this population is not well‐established, some studies reporting cognitive alterations in T1D‐IAH were suggestive of frontal dysfunction 7,8 .…”

Dynamic response of cerebral blood flow to insulin-induced hypoglycemia

“…As such, it is an important contribution to the understanding of the effects of acute hypoglycemia on human cerebral perfusion. Since abnormal changes in CBF are involved in the pathogenesis of hypoglycemia unawareness 11,41,42 , the ability to monitor the dynamics of CBF during acute hypoglycemia could provide new insights into the pathogenesis of this serious condition. Further, it is important to state that although we refer to the changes in the diffusion coefficient, computed using Eq.…”