In vivo dose response curves of insulin action in heart: anomalous effects at high insulin doses.

The euglycaemic hyperinsulaemic clamp technique in conscious unrestrained rats was used to compile insulin dose response curves of glucose metabolism in the heart in vivo. An estimate of heart glucose uptake (Rg') was obtained using [3H]-2-deoxyglucose and glucose disposal was examined by measuring cardiac glycogen content. Elevation of insulin from 29 to 54 mU/l resulted in a significant increase in Rg' in heart from 41 +/- 6 to 77 +/- 4 mumol/100 g/min (P less than 0.01) with no effect on glycogen content. This is consistent with increased glucose oxidation. At 150 mU/l of insulin both Rg' and glycogen synthesis were increased. Glycogen content increased from 18.5 +/- 1.7 mumol/g under basal conditions to 27.9 +/- 1.6 mumol/g with insulin. However, at subsequent insulin doses producing plasma levels exceeding 600 mU/l there was an anomalous reversal of Rg' back to basal levels while glycogen content was significantly elevated (2.4-fold, P less than 0.01). This effect may be related to feedback inhibition of tissue glycogen on glucose transport or to accumulation of tissue metabolites such as glucose-6-phosphate. The dose response curve for insulin stimulated Rg' in heart does not resemble either the whole body glucose utilization curve or that in individual skeletal muscles.