Hypoglycemia Unawareness in T1DM Is Associated with Altered Brain Default Mode Network Connectivity

The impact of hypoglycemia awareness (HA) on brain resting state connectivity remains unclear. To examine the impact of HA on the default mode network (DMN), a functional network in the brain that is active during wakeful rest and associated with introspection, 12 T1DM individuals with hypo unawareness (T1DM-UW) (by Clarke score) (7F/5M, age 44±12 years, BMI 26.4±4.2 kg/m², HbA1c 7.1±0.7) and 15 T1DM-Aware (AW) (10F/5M, age 30±7, BMI 24.5±3.1, HbA1C 7.1±0.9) individuals underwent resting state BOLD fMRI scanning to assess the DMN during a two-step euglycemic (Eu)-hypoglycemic (Hypo) clamp (90-60 mg/dl). T1DM-AW individuals exhibited a hypoglycemia-induced decrease in DMN connectivity (P<0.001). In contrast, T1DM-UW individuals showed no difference in connectivity between conditions. Moreover, the degree of DMN inhibition correlated inversely with plasma cortisol (r=-0.432, p=0.031), norepinephrine (r=-0.40, p=0.038) and positively with hypoglycemia symptom scores (r=0.40, p=0.037). These findings suggest that, unlike T1DM-AW individuals, hypoglycemia fails to elicit changes in the DMN amongst T1DM-UA individuals. Furthermore, the change in DMN connectivity is associated with measures of physiological and interoceptive responses to stress. These findings highlight the need for future studies to investigate whether avoidance of hypoglycemia can restore brain connectivity patterns.