Patients with type 1 diabetes (T1DM) are exposed to the risk of experiencing severe episodes of hypoglycemia (HG) as they undergo insulin treatment to maintain the glucose control that is necessary to prevent diabetes complications. Recurrent HG can lead to development of the hypoglycemia-associated autonomic failure (HAAF) and to the syndrome of HG unawareness, where patients lose the ability to recognize symptoms of HG until they become unable to treat themselves. Strict avoidance of HG partially restores awareness of HG, however it is very difficult to achieve. Drugs and therapies that directly target the brain mechanisms responsible for HG unawareness have promise as better ways to prevent and/or reverse HAAF, thus crucially advancing care for patients with diabetes. In order to effectively design and monitor such treatments, it is necessary however to first characterize the physiological and pathological brain responses to HG, a research topic that has been only partly covered by current literature and that is at the center of the current proposal. I this project we will utilize state-of-the-art MRI methods to monitor non-invasively the brain responses during controlled experimental HG in a subject population which includes HG-unaware and HG-aware T1DM subjects, and healthy controls with and without a treatment that induces HAAF. Hypoglycemia-induced brain activations will be identified during different phases of HG by changes in cerebral blood flow. Multiple brain functionally- connected networks will also be monitored by using resting-state functional MRI, with an imaging protocol recently developed within the Human Connectome Project. Our central hypothesis is that altered brain responses to HG in HG-unaware T1DM subjects, as indentified by measures of brain activation patterns and functionally-connected brain networks, are a result of antecedent HG episodes, not diabetes. Therefore we expect that the activation patterns and the brain networks of HG-unaware T1DM subjects will be different from healthy and HG-aware T1DM subjects, but will resemble those of healthy controls who undergo HAAF induction. Our research team is uniquely positioned to conduct this research, as it has gained extensive expertise in mastering high magnetic field MR applications, and holds a long track record of MR research in diabetes. Ultimately, the study design of this proposal will allow identifying with unprecedented sensitivity the altered brain responses to HG in those T1DM patients who are unable to recognize the symptoms of HG, thus filling a critical gap of knowledge which will have significant impact in defining strategies that will reduce the complications of management of diabetes. Our study has been designed to be conducted on a clinical 3 Tesla scanner, thus making a transition to future multi-center studies feasible and seamless.

Public Health Relevance

Patients with type 1 diabetes (T1DM) are exposed to the risk of experiencing severe hypoglycemia (HG) while undergoing insulin treatment, and can develop the syndrome of HG unawareness. Currently, there are no effective treatments to prevent or reverse HG unawareness. This research project will identify the altered brain responses to HG in those T1DM patients who are unable to recognize the symptoms of HG. Understanding the physiological and pathological brain responses to HG is essential for designing drugs and therapies that target the brain mechanisms responsible for HG unawareness, thus reducing the complications of management of diabetes and improving the life of patients with this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK099137-05
Application #
9505878
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Teff, Karen L
Project Start
2014-09-07
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Mascali, Daniele; DiNuzzo, Mauro; Serra, Laura et al. (2018) Disruption of Semantic Network in Mild Alzheimer's Disease Revealed by Resting-State fMRI. Neuroscience 371:38-48
Tommasin, Silvia; Mascali, Daniele; Gili, Tommaso et al. (2017) Task-Related Modulations of BOLD Low-Frequency Fluctuations within the Default Mode Network. Front Phys 5:
Bednarik, Petr; Moheet, Amir A; Grohn, Heidi et al. (2017) Type 1 Diabetes and Impaired Awareness of Hypoglycemia Are Associated with Reduced Brain Gray Matter Volumes. Front Neurosci 11:529
DiNuzzo, Mauro; Mascali, Daniele; Moraschi, Marta et al. (2017) Temporal Information Entropy of the Blood-Oxygenation Level-Dependent Signals Increases in the Activated Human Primary Visual Cortex. Front Phys 5:
DiNuzzo, Mauro; Giove, Federico; Maraviglia, Bruno et al. (2015) Monoaminergic Control of Cellular Glucose Utilization by Glycogenolysis in Neocortex and Hippocampus. Neurochem Res 40:2493-504
Moheet, Amir; Mangia, Silvia; Seaquist, Elizabeth R (2015) Impact of diabetes on cognitive function and brain structure. Ann N Y Acad Sci 1353:60-71