Impaired awareness of hypoglycemia (IAH), which is a diminished ability to perceive the onset of hypoglycemia (HG) and typically co-exists with a reduction in the counterregulatory hormone responses (CRR) to HG, triples the risk of experiencing potentially fatal severe hypoglycemia for patients with type 1 diabetes (T1D). Our long- term goal remains to identify how recurrent HG leads to the clinical syndrome of IAH in T1D. Here we will study the cerebral mechanisms of IAH in the setting of T1D following exposure to experimental recurrent HG and test the hypothesis that recurrent HG in T1D leads to an upregulation in brain glucose transport and alterations in glutamatergic and GABAergic tone. We will use MRS methodology that permits evaluation of cerebral cortex and hypothalamus in the same session to simultaneously evaluate the cerebral correlates/mediators of impaired awareness and impaired CRR. High MR data quality and reproducibility will be ensured by using high field MR scanners and technical advances we made during the last grant cycle (automated voxel placement, real-time voxel tracking, dynamic frequency and shim updates). Continuous glucose monitoring and actigraphy will be used to chronicle glucose variability and activity/exercise/sleep during the weeks before each experiment to assess the impact of these variables on IAH.
Our specific aims are:
Aim 1 : To measure the neurochemical response to hypoglycemia in T1D (N=50) before and after induction of IAH. Neurochemical profiles including glutamate, GABA and glucose will be measured in the frontal cortex, a region associated with IAH in prior neuroimaging work, and in hypothalamus, which regulates CRR, during euglycemia and HG at 7 tesla, at baseline and after a recurrent HG protocol that robustly induces IAH in patients with T1D and NAH.
Aim 2 : To measure cerebral glucose transport in T1D (N=50) before and after induction of IAH. Kinetic parameters for glucose transport will be measured in the frontal cortex and hypothalamus using hyperglycemic clamps at 3 tesla at baseline and after recurrent HG. These experiments will establish if recurrent HG alters cerebral glucose availability and glutamate and GABA tone in T1D and if these cerebral adaptations are associated with the development of blunted CRR and diminished symptoms in patients with T1D. In addition, we will learn how glycemic excursions and activity/sleep impact the induction of IAH. These observations are expected to lead to new ways to prevent and treat this life-threatening condition in T1D.

Public Health Relevance

We aim to identify how recurrent hypoglycemia in diabetes leads to impaired awareness of hypoglycemia, a devastating problem that prevents patients from achieving optimal glucose control. We plan to use magnetic resonance spectroscopy to learn how hypoglycemia impacts the human brain to cause this syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035192-19
Application #
9838818
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Koenig, James I
Project Start
1997-05-26
Project End
2022-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
19
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Seaquist, Elizabeth R; Moheet, Amir; Kumar, Anjali et al. (2017) Hypothalamic Glucose Transport in Humans During Experimentally Induced Hypoglycemia-Associated Autonomic Failure. J Clin Endocrinol Metab 102:3571-3580
Joers, James M; Deelchand, Dinesh K; Kumar, Anjali et al. (2017) Measurement of Hypothalamic Glucose Under Euglycemia and Hyperglycemia by MRI at 3T. J Magn Reson Imaging 45:681-691
Seaquist, Elizabeth R (2015) The Impact of Diabetes on Cerebral Structure and Function. Psychosom Med 77:616-21
Bedna?ík, Petr; Moheet, Amir; Deelchand, Dinesh K et al. (2015) Feasibility and reproducibility of neurochemical profile quantification in the human hippocampus at 3?T. NMR Biomed 28:685-93
Öz, Gülin (2015) MR Spectroscopy: A Longitudinal Biomarker for Substantia Nigra Pathology in Parkinson's Disease? Mov Disord 30:1304-5
Khowaja, Ameer; Choi, In-Young; Seaquist, Elizabeth R et al. (2015) In vivo Magnetic Resonance Spectroscopy of cerebral glycogen metabolism in animals and humans. Metab Brain Dis 30:255-61
Öz, Gülin; DiNuzzo, Mauro; Kumar, Anjali et al. (2015) Revisiting Glycogen Content in the Human Brain. Neurochem Res 40:2473-81
Adanyeguh, Isaac M; Henry, Pierre-Gilles; Nguyen, Tra M et al. (2015) In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7. Mov Disord 30:662-70
Terpstra, Melissa; Moheet, Amir; Kumar, Anjali et al. (2014) Changes in human brain glutamate concentration during hypoglycemia: insights into cerebral adaptations in hypoglycemia-associated autonomic failure in type 1 diabetes. J Cereb Blood Flow Metab 34:876-82
Moheet, A; Emir, U E; Terpstra, M et al. (2014) Initial experience with seven tesla magnetic resonance spectroscopy of hypothalamic GABA during hyperinsulinemic euglycemia and hypoglycemia in healthy humans. Magn Reson Med 71:12-8

Showing the most recent 10 out of 29 publications