Glycogen is an important energy source for the heart, particularly at times when the oxygen supply is limited. In addition to oxygen availability, myocardial glycogen metabolism is regulated by other factors including the hormones insulin, glucagon and catecholamines. In hearts from diabetic animals, the activity of glycogen synthase is depressed and phosphorylase displays an increased sensitivity to activation by glucagon and catecholamines. In addition, the ability of insulin to stimulate glycogen synthesis is impaired in perfused hearts from diabetic animals. It has been difficult, however, to relate the impact of the alterations in the activity of enzymes involved in glycogen metabolism measured in vitro to either a quantitative understanding of the control of glycogen metabolism in vivo in the normal and diabetic heart or to assess the effect of alterations of glycogen metabolism which accompany diabetes upon the ability of the diabetic hearts to generate energy anaerobically. To understand more fully the control of glycogen metabolism as it occurs in vivo we propose a series of studies using 13C-NMR spectroscopic methods which once fully validated will allow quantitation of the in vivo rates of hearts glycogen synthesis and breakdown in both normal and diabetic animals. Using these spectroscopic measurements, together with conventional measurements of the activity of glycogen synthase and phosphorylase, we will assess the dose-response relationship between plasma insulin and stimulation of glycogen synthesis and determine if it is altered by diabetes. In additional studies, the role of pre-existing myocardial glycogen content on heart glycogen synthesis will be assessed, and perhaps of most pathophysiologic interest the ability of the diabetic versus normal heart to use glycogen and circulating glucose to generate energy anaerobically will be measured using combined techniques of 31P and 13C-NMR. Efforts will also be directed at development of proton NMR spectroscopic methods applicable to measurement of heart lactate content in the belief that the greater intrinsic sensitivity of the proton will result in improved signal strength and may in the future allow extension of NMR-spectroscopic methods to study of myocardial metabolism in man.
| Laughlin, M R; Morgan, C; Barrett, E J (1991) Hypoxemic stimulation of heart glycogen synthase and synthesis. Effects of insulin and diabetes mellitus. Diabetes 40:385-90 |
| David, M; Petit, W A; Laughlin, M R et al. (1990) Simultaneous synthesis and degradation of rat liver glycogen. An in vivo nuclear magnetic resonance spectroscopic study. J Clin Invest 86:612-7 |
| Shulman, G I; Rothman, D L; Chung, Y et al. (1988) 13C NMR studies of glycogen turnover in the perfused rat liver. J Biol Chem 263:5027-9 |
| Laughlin, M R; Petit Jr, W A; Dizon, J M et al. (1988) NMR measurements of in vivo myocardial glycogen metabolism. J Biol Chem 263:2285-91 |
| Barrett, E J; Petit, W A; Laughlin, M R (1987) In vivo NMR studies of glycogen metabolism: a new look at a time honored problem. Ann N Y Acad Sci 508:251-64 |
