Lipid-induced insulin resistance is associated with a reduction of IGF1 bioactivity independent of changes in IGFBP-1 and -2 in humans
A. Arafat1,2, S.v.G. Homssi1, M. Weickert3,4, J. Kraatz1, J. Spranger1,5,6, J. Frystyk6, A. Pfeiffer1,2 & M. Mohlig1,2
Objectives: Insulin interacts with the GH insulin-like growth factor (IGF) system by a reciprocal regulation of IGF-binding proteins (IGFBPs) and GH, which in turn interact to regulate insulin sensitivity (IS). We previously showed that IGFBP-2 is involved in the insulin-induced reduction in IGF1 bioactivity. We here address the modulation of IGF1 bioactivity during acute lipid-induced insulin resistance.
Methods: 18 healthy men (30.8±2.6 years; BMI 23.6±0.5 kg/m2) were studied in a controlled, randomized crossover trial using lipid-heparin infusion at a dose inducing physiological elevations of free fatty acids (FFAs), vs saline-heparin infusion as control. IS was quantified by subsequent hyperinsulinemic euglycemic clamps. IGF1 bioactivity was estimated using an IGF1 kinase receptor activation assay (KIRA). Total IGF1, IGFBP-1 and IGFBP-2 were also measured under fasting conditions, during lipid or saline infusions and during the steady state of the subsequent clamps.
Results:: Lipid-infusion significantly reduced IGF1 bioactivity [3.3±0.3 μg/l (baseline) vs 2.5±0.2 (180 min); P<0.01], total IGF1 [135.2±10.8 μg/l (baseline) vs 121.9±9.7 (180 min); P<0.01] and IGFBP-1 [27.1±4 μg/l (baseline) vs 15.2±2.4 (180 min); P<0.01]. This was associated with significant reduction in peripheral glucose-uptake [GIR.kg-1BW: 4.3±0.4 (lipid) vs 6.1±0.5 (saline); P<0.01]. No changes were detected after saline-infusion (P>0.05).
Subsequently, euglycemic hyperinsulinemia induced further reductions in IGF1 bioactivity and in IGFBP-1 levels (P<0.01) in both intervention arms, but did not change total IGF1 levels (P>0.05).
IGFBP-2 levels did not change neither after lipid- nor saline-infusions (P>0.05) but significantly increased during steady state (P<0.05).
Conclusions: We here show that lipid-induced reduction of insulin sensitivity was associated with reduction in IGF1 bioactivity. The impact of elevated free fatty acids/triglycerides on IGF1 bioactivity was not mediated by changes in IGFBPs, but may relate to the concomitant suppression of total IGF1.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.