Resting state networks are functionally connected neurons that show similar low-frequency blood oxygen-level dependent (BOLD) signal oscillations. The salience network (SN) is crucial for switching between two other networks: the default mode network (DMN) and the central executive network (CEN). The DMN is active when the brain is not cognitively engaged; the CEN is active when the brain is engaged in a specific task. We hypothesized that impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes (T1D) would be associated with disruption of the integrity of the salience network at hypoglycemia.

Methods: Fourteen nondiabetic (ND), 15 T1D with normal awareness of hypoglycemia (NAH) and 22 T1D with IAH participants, matched for age and T1D duration, underwent a two-step hypoglycemic clamp. Resting state BOLD functional magnetic resonance image (fMRI) time series were obtained, one at 90 mg/dL, one at 47 mg/dL. Images were analyzed using the CONN toolbox in SPM12. We used the right anterior insula (AI) as a seed region for the SN in a seed to voxel analysis.

Results: The SN was identified in all three groups at euglycemia. At hypoglycemia ND and NAH had brisk symptom response and altered coupling between SN and regions associated with the DMN: precuneus (ND p <0.01) and pregenual anterior cingulate cortex (ACC, NAH p <0.01), IAH had lower symptoms and no change in SN coupling. Mean symptom increase at hypoglycemia was 15.3 (ND and NAH) and 1.5 (IAH, p<0.00001). A 2x2 mixed ANOVA interaction between aware groups (HC and NAH n=29) and IAH (n=22) showed differences in connectivity reduction between the ACC and AI at hypoglycemia (pFEW-Corr=0.04).

Conclusions: During hypoglycemia, reduced connectivity between SN and DMN, seen in ND and NAH, may be an important switch for hypoglycemia recognition, facilitating protective behavioral responses. Lack of SN connectivity change may underpin impaired awareness and failure of appropriate responses to hypoglycemia seen in IAH.


P. Jacob: None. C.E. Osborne: None. F. Zelaya: None. S.A. Amiel: None. P. Choudhary: Advisory Panel; Self; AstraZeneca, Insulet Corporation, Medtronic, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; Eli Lilly and Company, Novartis AG, Novo Nordisk Inc., WebMD.

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