The fear of hypoglycemia and hypoglycemia unawareness limits the ability of patients with diabetes from achieving the level of glucose control known to reduce the risk of developing microvascular complications. The long term goal of this project is to define the pathogenesis of hypoglycemia-associated autonomic failure (HAAF) with the aim of helping patients better manage their diabetes. The working hypotheses for this project are: 1) recurrent hypoglycemia, like that seen in subjects with type 1 diabetes and iatrogenic hypoglycemia, will lead to an upregulation of glucose availability for the brain (by increased transport and/or increased glycogen storage), thereby facilitating maintenance of cerebral metabolism during subsequent episodes of hypoglycemia, and 2) recurrent hypoglycemia will lead to an increased GABA tone in hypothalamus, thereby suppressing glucose counter regulation during subsequent episodes of hypoglycemia. To address these hypotheses we will examine cerebral metabolism in subjects with type 1 diabetes and hypoglycemia unawareness and in healthy volunteers preconditioned with euglycemia vs. recurrent hypoglycemia to induce HAAF, thereby permitting us to understand the clinical syndrome as well as isolate the effects of recurrent hypoglycemia from those induced by diabetes. We will use magnetic resonance spectroscopy at high and ultra-high fields to examine hypothalamic glucose and GABA metabolism, as well as cerebral glycogen metabolism.
Aim 1 : To determine the contribution of increased glucose availability in the brain to HAAF Specific Aim 1a: To measure kinetic parameters for glucose transport and metabolism in the hypothalamus of subjects with type 1 diabetes and hypoglycemia unawareness and in healthy volunteers preconditioned with euglycemia vs. recurrent hypoglycemia to induce HAAF.
Specific Aim 1 b: To measure brain glycogen turnover and content by 13C MRS in healthy volunteers preconditioned with euglycemia vs. recurrent hypoglycemia to induce HAAF.
Aim 2 : To determine the contribution of increased GABA tone in the hypothalamus to HAAF Specific Aim 2: To measure euglycemic and hypoglycemic GABA levels in the hypothalamus of subjects with type 1 diabetes and HAAF and in healthy volunteers preconditioned with euglycemia vs. recurrent hypoglycemia to induce HAAF.

Public Health Relevance

The fear of hypoglycemia limits the ability of patients with diabetes from achieving the level of glucose control known to reduce the risk of developing the eye, kidney, and nerve problems associated with the disease. Hypoglycemia unawareness, the situation where the first sign of a low blood sugar is unconsciousness, is a particular concern to patients and their families. The long term goal of this project is to determine why some people become unable to detect hypoglycemia before they become unconscious, with the aim of helping patients better manage their diabetes.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS035192-15
Application #
8686965
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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; Kumar, A; Eberly, L E et al. (2014) Hypoglycemia-associated autonomic failure in healthy humans: comparison of two vs three periods of hypoglycemia on hypoglycemia-induced counterregulatory and symptom response 5 days later. J Clin Endocrinol Metab 99:664-70
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
Mangia, Silvia; Kumar, Anjali F; Moheet, Amir A et al. (2013) Neurochemical profile of patients with type 1 diabetes measured by ýýH-MRS at 4 T. J Cereb Blood Flow Metab 33:754-9
Oz, Gulin; Tesfaye, Nolawit; Kumar, Anjali et al. (2012) Brain glycogen content and metabolism in subjects with type 1 diabetes and hypoglycemia unawareness. J Cereb Blood Flow Metab 32:256-63
Shestov, Alexander A; Emir, Uzay E; Kumar, Anjali et al. (2011) Simultaneous measurement of glucose transport and utilization in the human brain. Am J Physiol Endocrinol Metab 301:E1040-9
Henry, Pierre-Gilles; Criego, Amy B; Kumar, Anjali et al. (2010) Measurement of cerebral oxidative glucose consumption in patients with type 1 diabetes mellitus and hypoglycemia unawareness using (13)C nuclear magnetic resonance spectroscopy. Metabolism 59:100-6
Oz, Gulin; Hutter, Diane; Tkac, Ivan et al. (2010) Neurochemical alterations in spinocerebellar ataxia type 1 and their correlations with clinical status. Mov Disord 25:1253-61
Oz, Gulin; Kumar, Anjali; Rao, Jyothi P et al. (2009) Human brain glycogen metabolism during and after hypoglycemia. Diabetes 58:1978-85
Kodl, Christopher T; Seaquist, Elizabeth R (2008) Cognitive dysfunction and diabetes mellitus. Endocr Rev 29:494-511

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