Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia.
Myocardial regions perfused through a coronary stenosis may cease contracting, but remain viable. Clinical observations suggest that increased glucose utilization may be an adaptive mechanism in such "hibernating" regions. In this study, we used a combination of 13C-NMR spectroscopy, GC-MS analysis, and tissue biochemical measurements to track glucose through intracellular metabolism in intact dogs infused with [1-13C]glucose during a 3-4-h period of acute ischemic hibernation. During low-flow ischemia [3-13C]alanine enrichment was higher, relative to plasma [1-13C]glucose enrichment, in ischemic than in nonischemic regions of the heart, suggesting a greater contribution of exogenous glucose to glycolytic flux in the ischemic region (approximately 72 vs. approximately 28%, P < 0.01). Both the fraction of glycogen synthase present in the physiologically active glucose-6-phosphate-independent form (46 +/- 10 vs. 9 +/- 6%, P < 0.01) and the rate of incorporation of circulating glucose into glycogen (94 +/- 25 vs. 20 +/- 15 nmol/gram/min, P < 0.01) were also greater in ischemic regions. Measurement of steady state [4-13C)glutamate/[3-13C]alanine enrichment ratios demonstrated that glucose-derived pyruvate supported 26-36% of total tricarboxylic acid cycle flux in all regions, however, indicating no preference for glucose over fat as an oxidative substrate in the ischemic myocardium. Thus during sustained regional low-flow ischemia in vivo, the ischemic myocardium increases its utilization of exogenous glucose as a substrate. Upregulation is restricted to cytosolic utilization pathways, however (glycolysis and glycogen synthesis), and fat continues to be the major source of mitochondrial oxidative substrate.
McNulty
P H
PH
Department of Internal Medicine, VA Connecticut Medical Center, New Haven, 06520, USA.
Sinusas
A J
AJ
Shi
C Q
CQ
Dione
D
D
Young
L H
LH
Cline
G C
GC
Shulman
G I
GI
D000409:Alanine / Q000032:analysis; D000818:Animals; D003327:Coronary Disease / Q000378:metabolism*; D003331:Coronary Vessels / Q000502:physiology*; D004195:Disease Models, Animal; D004285:Dogs; D004699:Endocardium / Q000737:chemistry; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000032:analysis; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D010084:Oxidation-Reduction; D010496:Pericardium / Q000737:chemistry; D012039:Regional Blood Flow
D005230:Fatty Acids, Nonesterified; D018698:Glutamic Acid; D006003:Glycogen; D005947:Glucose; D000409:Alanine