Differential Resting State Connectivity Responses to Glycemic State in Type 1 Diabetes

Abstract

Context: Individuals with type 1 diabetes mellitus (T1DM) have alterations in brain activity that have been postulated to contribute to the adverse neurocognitive consequences of T1DM; however, the impact of T1DM and hypoglycemic unawareness on the brain's resting state activity remains unclear.

Objective: To determine whether individuals with T1DM and hypoglycemia unawareness (T1DM-Unaware) had changes in the brain resting state functional connectivity compared to healthy controls (HC) and those with T1DM and hypoglycemia awareness (T1DM-Aware).

Design: Observational study.

Setting: Academic medical center.

Participants: 27 individuals with T1DM and 12 HC volunteers participated in the study.

Intervention: All participants underwent blood oxygenation level dependent (BOLD) resting state functional magnetic brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dL)-hypoglycemic (60 mg/dL) clamp.

Outcome: Changes in resting state functional connectivity.

Results: Using 2 separate methods of functional connectivity analysis, we identified distinct differences in the resting state brain responses to mild hypoglycemia between HC, T1DM-Aware, and T1DM-Unaware participants, particularly in the angular gyrus, an integral component of the default mode network (DMN). Furthermore, changes in angular gyrus connectivity also correlated with greater symptoms of hypoglycemia (r = 0.461, P = 0.003) as well as higher scores of perceived stress (r = 0.531, P = 0.016).

Conclusion: These findings provide evidence that individuals with T1DM have changes in the brain's resting state connectivity patterns, which may be further associated with differences in awareness to hypoglycemia. These changes in connectivity may be associated with alterations in functional outcomes among individuals with T1DM.

Trial registration: ClinicalTrials.gov NCT00580710.

© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Study design of 2-step hyperinsulinemic euglycemic-hypoglycemia clamp during rsfMRI BOLD scanning. Plasma glucose levels time courses (mean±standard error of the mean) during the study.

Figure 2.

Hormonal responses to mild hypoglycemia: (A) epinephrine, (B) norepinephrine, (C) glucagon, and (D) cortisol. Open bars denote euglycemia, black bars denote hypoglycemia. Euglycemia values were averaged from time 30 to 45 minutes of clamp. Hypoglycemia values were averaged from time 75 to 90 minutes of clamp. Data presented as mean±standard error of the mean, paired samples t test, *P < 0.05.

Figure 3.

Hypoglycemia symptom scores. (A) Symptoms of hypoglycemia from the Edinburgh Hypoglycemia Symptom score were administered on a Likert scale (1–7) and results were summed. Open bars denote euglycemia, and black bars denote hypoglycemia. (B) Change in Edinburgh symptom scores. Data presented as mean±standard error of the mean, paired samples t test, * P < 0.05.

Figure 4.

Intrinsic connectivity distribution analysis: Group × Glycemia Effects. (A) Brain response to mild hypoglycemia compared to euglycemia across all three groups (covaried for age, body mass index, and plasma glucose levels); initial threshold of P < 0.001, 2-tailed, family-wise error whole brain corrected at P < 0.05). (B) Averaged connectivity values extracted from each participant (region of interest identified from significant cluster in right angular gyrus). Data expressed as mean ± standard error of the mean. (C) Change in connectivity values. Data expressed as mean ± 95% confidence interval.

Figure 5.

Seed based analysis: Group × Glycemia Effects. Brain response to mild hypoglycemia compared to euglycemia across all 3 groups (covaried for age, body mass index, and plasma glucose levels); initial threshold of P < 0.001, 2-tailed, familywise error whole brain corrected at P < 0.05.

Figure 6.

Differences in regional brain responses between mild hypoglycemia and euglycemia conditions. Healthy control, type 1 diabetes mellitus (T1DM)-aware and T1DM-unaware subjects showing differences in brain responses to mild hypoglycemia (Hypo-Eu); covaried by age, body mass index, and plasma glucose levels. Initial threshold of P < 0.001, 2-tailed, familywise error whole brain cluster corrected at α < 0.05).

Figure 7.

Relationship between change in angular gyrus connectivity values and Edinburgh hypoglycemia symptom scores at euglycemia (A), hypoglycemia (B), and euglycemia-hypoglycemia symptom scores (C).