Hypoglycemia unawareness is a complication of intensive insulin therapy often encountered after episodes of iatrogenic hypoglycemia. The associated blunting of counterregulation has been reported to occur in healthy humans after a single episode ofhypoglycemia. The mechanisms by which the brain detects low blood sugar concentrations are uncertain. The brain contains approximately 3 mM glycogen that may serve as a fuel during moderate hypoglycemia. In most tissues, glycogen metabolism is insulin- and glucose-sensitive. Brain glycogen thus provides an aspect of cerebral carbohydrate metabolism that is sensitive to alterations in glucose homeostasis such as those seen in diabetic patients. The purpose of this project is to determine the effect of hypoglycemia on brain glycogen and glucose metabolism and a potential involvement of glycogen metabolism in mediating hypoglycemia unawareness. In addition, we will assess the relationship between glucose transport and cerebral blood flow during hypoglycemia. The hypotheses of this project are (a) That brain glycogen concentration and metabolism are modulated by plasma glucose and/or insulin concentrations in vivo. (b) That brain glycogen can serve as a reservoir of glucose equivalents that are used for extended time periods during hypoglycemia in vivo when glucose transport becomes rate limiting for metabolism and cerebral blood flow is increased. (c) That following a hypoglycemic episode, the brain stores more brain glycogen such that longer and deeper subsequent hypoglycemia is necessary to deplete brain glycogen, which may provide a mechanism leading to hypoglycemia unawareness with the following specific aims: (1) To separate the effect of acutely elevated brain glucose concentrations from elevated plasma insulin concentrations on in vivo brain glycogen metabolism. (2) To determine the degree of supercompensation of brain glycogen following graded hypoglycemia and to establish that brain glycogen serves as a significant reservoir of glucosyl units during hypoglycemia. (3) To determine that depletion of brain glycogen as well as the acute increase in CBF is triggered when brain glucose concentrations approach the low Km of hexokinase.
These aims will be achieved in rat brain using localized 1H and 13C NMR spectroscopy and perfusion-based fMRI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS042005-01A2
Application #
6579070
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Jacobs, Tom P
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$265,382
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
van Heeswijk, Ruud B; Morgenthaler, Florence D; Xin, Lijing et al. (2010) Quantification of brain glycogen concentration and turnover through localized 13C NMR of both the C1 and C6 resonances. NMR Biomed 23:270-6
van Heeswijk, Ruud B; Uffmann, Kai; Comment, Arnaud et al. (2009) Hyperpolarized lithium-6 as a sensor of nanomolar contrast agents. Magn Reson Med 61:1489-93
Xin, Lijing; Frenkel, Hanne; Mlynárik, Vladimír et al. (2009) Selective resonance suppression 1H-[13C] NMR spectroscopy with asymmetric adiabatic RF pulses. Magn Reson Med 61:260-6
Poitry-Yamate, Carol; Lei, HongXia; Gruetter, Rolf (2009) The rate-limiting step for glucose transport into the hypothalamus is across the blood-hypothalamus interface. J Neurochem 109 Suppl 1:38-45
Morgenthaler, Florence D; Lanz, Bernard R; Petit, Jean-Marie et al. (2009) Alteration of brain glycogen turnover in the conscious rat after 5h of prolonged wakefulness. Neurochem Int 55:45-51
Comment, A; Rentsch, J; Kurdzesau, F et al. (2008) Producing over 100 ml of highly concentrated hyperpolarized solution by means of dissolution DNP. J Magn Reson 194:152-5
Lei, Hongxia; Mlynarik, Vladimir; Just, Nathalie et al. (2008) Snapshot gradient-recalled echo-planar images of rat brains at long echo time at 9.4 T. Magn Reson Imaging 26:954-60
Morgenthaler, Florence D; van Heeswijk, Ruud B; Xin, Lijing et al. (2008) Non-invasive quantification of brain glycogen absolute concentration. J Neurochem 107:1414-23
Mlynarik, Vladimir; Kohler, Ingrid; Gambarota, Giulio et al. (2008) Quantitative proton spectroscopic imaging of the neurochemical profile in rat brain with microliter resolution at ultra-short echo times. Magn Reson Med 59:52-8
van Heeswijk, Ruud B; Laus, Sabrina; Morgenthaler, Florence D et al. (2007) Relaxivity of Gd-based contrast agents on X nuclei with long intrinsic relaxation times in aqueous solutions. Magn Reson Imaging 25:821-5

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