Effect of heart work and insulin on the incorporation of [14C]glucose into hexose phosphates, uridine diphosphate glucose and glycogen in the normal and insulin-deficient perfused rat heart under working and non-working conditions

Abstract

1. The specific radioactivities of glucose 1-phosphate, glucose 6-phosphate, fructose 6-phosphate, UDP-glucose and glycogen, derived from [14C]gluocose, were determined in the normal and insulin-deficient (streptozotocin-diabetic and anti-insulin-serum-treated) perfused non-working and working rat heart. 2. The specific radioactivities of all glucose metabolities reached a plateau after about 10 min, except that for glycogen, which increased slightly but steadily over the whole observation period of 30min. 3. The specific radio-activities of fructose 6-phosphate, UDP-glucose and glycogen were slignificantly lower in the streptozotocin-diabetic heart than in the normal heart. 4. Mechanical work in the normal rat heart increased the specific radioactivities of glucose 1-phosphate, UDP-glucose and glycogen, but had little or no effect on those of gluose 6-phosphate and fructose 6-phosphate. 5. In the normal heart insulin strongly increased the specific radioactivities of all gluocse metabolites under all conditions tested. The maximum values achieved in the normal working heart in the presence of insulin were only about 15-20% above those in the normal non-working heart in the presence of insulin for the phosphorylated intermediates and about 40% above for glycogen. 6. In the streptozotocin-diabetic heart, work restored the specific radioactivities of all glucose metabolities to about normal values. 7. In the streptozotocin-diabetic heart insulin strongly increased the specific radioactivities of the direct glycogen precursors glucose 1-phosphate and UDP-glucose; the effect of insulin on glucose 6-phosphate and fructose 6-phosphate was less marked. These results confirm previous findings that the primary metabolic lesion in diabetic heart muscle is a defect of glycogen synthesis. The specific radioactivity of glycogen itself was increased sixfold. 8. Under all conditions tested the specific radioactivity of glucose 1-phosphate was always found to be higher than that of glucose 6-phosphate. This indicated either compartmentation of a small but metabolically very active pool of glucose 6-phosphate, or the existence of a hitherto unknown pathway of metabolism in which glucose 1-phosphate is the primary reaction product. For a number of reasons the authors prefer the first explanation, which could also account for the observation that in the perfused normal working and non-working heart the specific radioactivity of fructose 6-phosphate was always found to be higher than that of glucose 6-phosphate. This difference disappeared or was reversed in the rat hearts rendered insulin-insufficent by either streptozotocin or anti-insulin treatment.