Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia
Janice Jin Hwang, … , Rajita Sinha, Robert Sherwin
Janice Jin Hwang, … , Rajita Sinha, Robert Sherwin
Published January 30, 2018
Citation Information: J Clin Invest. 2018;128(4):1485-1495. https://doi.org/10.1172/JCI97696.
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Clinical Medicine Endocrinology

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

Abstract

BACKGROUND. Among nondiabetic individuals, mild glucose decrements alter brain activity in regions linked to reward, motivation, and executive control. Whether these effects differ in type 1 diabetes mellitus (T1DM) patients with and without hypoglycemia awareness remains unclear. METHODS. Forty-two individuals (13 healthy control [HC] subjects, 16 T1DM individuals with hypoglycemia awareness [T1DM-Aware], and 13 T1DM individuals with hypoglycemia unawareness [T1DM-Unaware]) underwent blood oxygen level–dependent functional MRI brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dl)-hypoglycemic (60 mg/dl) clamp for assessment of neural responses to mild hypoglycemia. RESULTS. Mild hypoglycemia in HC subjects altered activity in the caudate, insula, prefrontal cortex, and angular gyrus, whereas T1DM-Aware subjects showed no caudate and insula changes, but showed altered activation patterns in the prefrontal cortex and angular gyrus. Most strikingly, in direct contrast to HC and T1DM-Aware subjects, T1DM-Unaware subjects failed to show any hypoglycemia-induced changes in brain activity. These findings were also associated with blunted hormonal counterregulatory responses and hypoglycemia symptom scores during mild hypoglycemia. CONCLUSION. In T1DM, and in particular T1DM-Unaware patients, there is a progressive blunting of brain responses in cortico-striatal and fronto-parietal neurocircuits in response to mild-moderate hypoglycemia. These findings have implications for understanding why individuals with impaired hypoglycemia awareness fail to respond appropriately to falling blood glucose levels. FUNDING. This study was supported in part by NIH grants R01DK020495, P30 DK045735, K23DK109284, K08AA023545. The Yale Center for Clinical Investigation is supported by an NIH Clinical Translational Science Award (UL1 RR024139).

Authors

Janice Jin Hwang, Lisa Parikh, Cheryl Lacadie, Dongju Seo, Wai Lam, Muhammad Hamza, Christian Schmidt, Feng Dai, Anne-Sophie Sejling, Renata Belfort-DeAguiar, R. Todd Constable, Rajita Sinha, Robert Sherwin

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Figure 4

Group × glycemia effects.

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Group × glycemia effects. (A) Axial slices showing the differences in br...
(A) Axial slices showing the differences in brain responses to mild hypoglycemia compared with euglycemia across all 3 groups (covaried for age and BMI, threshold of P < 0.001, 2-tailed, FWE whole-brain corrected). (B) Region of interest (ROI) identified from significant cluster in right striatum (caudate). General linear model β-weights extracted from each participant, presented as mean (95% CI). Healthy control n = 13, T1DM-Aware n = 16, T1DM-Unaware n = 13.