Differential metabolic actions of biosynthetic insulin analogues in normal man assessed by stable isotopic tracers

Insulin analogues have been produced with high affinity for the insulin receptor and with affinity lower than that of native insulin, but differences in activity when administered in vivo to man are unconvincing. We have used very low dose insulin (0.005 units kg-1 h-1) to investigate possible differences in effect of these insulin analogues on lipolysis in seven healthy subjects. Only minor effects on blood glucose concentration were observed and glucose turnover measured isotopically with 6,6 2H glucose and leucine turnover measured with 1-13C leucine did not change significantly. Fatty acid levels decreased with insulin (area under curve, median (range) -23 (-41-10) mmol l-1) and with the low affinity analogue (-28 (-42-19) mmol l-1 h,), but the high affinity analogue had no significant effect compared with controls (high affinity analogue -8 (-28-35) mmol l-1 h; control +15 (11-53) mmol l-1). Glycerol production measured isotopically decreased with insulin (-0.54 (-1.50-0.63) mumol kg-1 min-1) and with the low affinity analogue (-0.74 (-1.76-0.72) mumol kg-1 min-1), but the high affinity analogue at these doses had no significant effect on glycerol turnover (-0.19 (-0.74-1.13) mumol kg-1 min-1). Thus at these low infusion rates insulin itself and the low affinity analogue suppressed lipolysis, as assessed by glycerol turnover and by circulating fatty acid concentrations. The high affinity analogue was cleared rapidly from the circulation producing no measurable increase in immunoreactive insulin concentrations, and no effect was observed on lipolysis.