Context: Growth hormone and other stress hormones stimulate lipolysis which may result in free fatty acid (FFA) mediated insulin resistance. However, there are also indications that FFAs in the very low physiological range have the same effect.

Objective: To systematically address dose-response relations between FFAs and insulin sensitivity.

Design: We therefore examined 8 healthy men for 8 h (6 h basal and 2 h glucose clamp) on 4 occasions.

Intervention: Intralipid was infused at varying rates (0, 3, 6, 12 µl/kg/min), lipolysis was blocked by acipimox, and endogenous GH, insulin, and glucagon secretion was blocked by somatostatin and subsequently replaced at fixed rates.

Results: This resulted in four different FFA levels between 50 and 2000 µmol/liter, with comparable levels of insulin and counter regulatory hormones. Both in the basal state and during insulin stimulation, we saw progressively decreased glucose disposal, non-oxidative glucose disposal and forearm muscle glucose uptake at FFA levels above 500 µmol/l. Apart from forearm glucose uptake the very same parameters were decreased at low FFA levels (50 µmol/liter). FFA rate of disposal was linearly related to the level of FFAs, whereas lipid oxidation reached a max at FFA levels 1000 µmol/l.

Conclusion: In the presence of comparable levels of all major metabolic hormones, insulin sensitivity peaks at physiological levels of FFAs with a gradual decrease at elevated as well as suppressed FFA concentrations. These data constitute comprehensive dose-response curves for FFAs in the full physiological range from close to zero to above 2000 µmol/l.