The effects of starvation and of acute and chronic alloxan diabetes on myocardial substrate levels and on liver glycogen in the rat in vivo.

Abstract

Cardiac levels of ATP, glycogen, glucose, glucose 6‐phosphate, fructose 6‐phosphate, fructose 1,6‐diphosphate, triose phosphates, glycerol 3‐phosphate, pyruvate, lactate, citrate, 2‐oxoglutarate, malate, acetoacetate, 3‐hydroxybutyrate and free fatty acids, as well as the liver glycogen content were determined simultaneously by instant deep‐freezing of the tissues in situ in urethanechloralose anaesthetized, normal and alloxan‐diabetic rats. In comparison to the mean values obtained in fed, normal rats the following changes in the pattern of substrate levels were found to be typical of:a) Starvation in normal rats: significant increases in citric acid cycle intermediates, in ketone bodies and in cardiac glycogen; an increase in the levels of hexose monophosphates and a decrease in fructose diphosphate, indicating inhibition of phosphofructokinase activity, and also a decrease in glycerol 3‐phosphate and triose phosphates; increase in malate/pyruvate ratio; no change in free fatty acids, ATP and pyruvate; and a most marked decrease in liver glycogen content.b) Acute alloxan diabetes: in general, changes similar to, but greater in magnitude than found in starved, normal rats, except for an unchanged 2‐oxoglutarate level; moreover, significant increases in lactate/pyruvate and 3‐hydroxybutyrate/acetoacetate ratios and a concomitant decrease in ATP were recorded. On starvation of acute diabetic rats the changes were attenuated, most significantly in regard to ketone bodies and ATP; the effect of starvation was exactly the opposite of that seen on starvation of normal rats.c) Chronic alloxan diabetes: no significant alterations except for a somewhat raised citrate level, a lowered FDP level with an associated decrease in phosphofructokinase activity, also decreased glycerol 3‐phosphate and ATP levels; liver glycogen content reduced. Starvation produced a picture of general substrate exhaustion, in which citrate, malate and the intermediates of glycolysis reached very low levels although phosphofructokinase activity was high, in association with low acetoacetate values and a decrease in even cardiac glycogen and FFA levels; liver glycogen stores were depleted.Regression analyses were carried out on the above data and it was established that the FDP/F6P ratio showed a highly significant negative correlation to cardiac citrate, but not to ATP levels, under all conditions. Furthermore, ketone‐body levels and also the lactate/pyruvate ratio showed a steep positive correlation to citrate above a critical level of 60–70 μmoles/100 g citrate, whilst the 3‐hydroxybutyrate/acetoacetate ratio was positively correlated to citrate over the entire range of concentrations. A further aspect was the demonstration of a highly significant negative correlation between cardiac citrate and liver glycogen in normal and in acute diabetic rats, and between cardiac ketone bodies and liver glycogen under all conditions; cardiac ketone bodies did not accumulate until the liver glycogen stores were depleted below a critical level of about 2000 μmoles/100 g, but then increased very steeply.