Fasting and lactate unmask insulin responsiveness in the isolated working rat heart

We have previously reported that the nutritional state in vivo results in differential insulin responses by the perfused heart in vitro. To further assess the effects of insulin on glucose uptake at physiological work loads, hearts from fed and fasted (16-20 h) rats were perfused with buffer containing 2-[18F]fluoro-2-deoxy-D-glucose (2-FDG) and glucose (10 mM) alone or plus lactate (10 mM) as a competing substrate, with insulin (10 mU/ml) added after a control period. When glucose was the only substrate, the addition of insulin decreased the fractional rate of 2-FDG uptake in hearts from either fed or fasted rats. The effect of insulin on increasing myocardial 2-FDG uptake was immediate and sustained only in hearts from fasted rats in the presence of lactate, despite no change in cardiac work. At the same time, the increase in 2-FDG uptake and phosphorylation was associated with an increase in the tissue content of glycogen in hearts from fasted rats. We conclude that lactate unmasks insulin sensitivity in heart muscle at physiological work loads but that this unmasking of insulin-mediated glucose uptake is dependent on the nutritional state of the animal. The glucose up as a result of insulin stimulation is preferentially utilized for glycogen repletion and does not enter the glycolytic pathway. This observation also suggests that myocardial glycogen synthesis in vitro is affected by the nutritional state in vivo and that lactate provides a substrate for oxidative phosphorylation while glucose is preferentially utilized for glycogen synthesis.