Hypoglycemia is the major obstacle preventing the benefits associated with intensive insulin therapy in individuals with diabetes. Low glucose levels can lead to cognitive impairment and even brain damage. Therefore, mechanisms to reduce these deleterious effects are important to elucidate. Brain glycogen, the only significant energy store in the brain, has been proposed to play a role in these processes. The overall objective of this proposal is to determine the importance of brain glycogen in memory formation and neuroprotection under hypoglycemic conditions. Genetically engineered mice with deficient brain glycogen stores will be used to address the following aims:
Aim 1. Does reduced brain glycogen impair cognitive function during hypoglycemia? Hypoglycemic mice will be subjected to various learning paradigms to monitor both performance and proteins involved in memory consolidation.
Aim 2. Does brain glycogen provide protection against hypoglycemia-induced neuronal cell death? Mice will be subjected to insulin- induced hypoglycemia to monitor susceptibility to, and mechanism of, neuronal cell death. These studies are expected to improve our understanding of the role of brain glycogen in mammals for cognitive function and neuroprotection during hypoglycemia. Should manipulation of brain glycogen levels prove beneficial, a small molecule regulator of glycogen metabolism in the brain could perhaps be a useful therapeutic for subjects with insulin-treated diabetes and subjects with mutations in glycogen synthase.

Public Health Relevance

Low blood sugar is an all too common occurrence in individuals who treat their diabetes with insulin. This insulin-induced drop in blood sugar can result in drowsiness, lack of coordination, confusion, memory difficulties, and in severe cases, even coma and brain damage. The goal of this study is to investigate the importance of sugar stored in the brain for minimizing the negative consequence of low blood sugar.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15DK078370-02A1
Application #
8626258
Study Section
Special Emphasis Panel (ZRG1-EMNR-P (90))
Program Officer
Teff, Karen L
Project Start
2007-04-01
Project End
2016-08-31
Budget Start
2013-09-20
Budget End
2016-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$420,000
Indirect Cost
$120,000
Name
Ball State University
Department
None
Type
Organized Research Units
DUNS #
065540726
City
Muncie
State
IN
Country
United States
Zip Code
47306
Canada, Sarah E; Weaver, Staci A; Sharpe, Shannon N et al. (2011) Brain glycogen supercompensation in the mouse after recovery from insulin-induced hypoglycemia. J Neurosci Res 89:585-91