Effects of free fatty acids on carbohydrate metabolism and insulin signalling in perfused rat liver

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Abstract
Background  Elevated circulating free fatty acids (FFAs) induce insulin resistance and play a crucial role in the development of type 2 diabetes, in which fasting hepatic glucose production (HGP) is increased. However, direct effects of FFAs on fasting HGP are still unclear because indirect endocrine and metabolic effects contribute to FFA action. Thus, we aimed to investigate acute direct effects of specific FFAs on fasting HGP, lactate uptake, and insulin signalling.Materials and methods  Isolated livers obtained from 20 h fasted rats were perfused with albumin‐bound palmitate or oleate (200 µmol L−1 each) or vehicle (control) for 180 min (n = 5–7/group).Results  Compared to control, hepatic lactate uptake was increased by palmitate and oleate (~+40%; P < 0·05), while HGP from lactate (~3 mmol L−1) and liver glycogen content were similar. Tyrosine phosphorylation (pY) of insulin‐receptor‐substrate‐(IRS)‐2 and p70S6‐kinase phosphorylation were not affected by FFAs. Palmitate decreased insulin‐receptor‐β pY, IRS‐1 pY and phosphoinositol‐3‐kinase expression by 46 ± 16%, 46 ± 11% and 20 ± 9%, respectively (P < 0·03), while oleate reduced Akt phosphorylation by 85 ± 7% (P < 0·006).Conclusions  Isolated liver perfusion with saturated or unsaturated FFAs reduced insulin signalling protein phosphorylation at different sites and increased lactate uptake without affecting HGP or glycogen content. These results suggest that at fasting, both saturated and unsaturated FFAs increase hepatic glucose precursor uptake and may, independently of insulin's presence, accelerate protein dephosphorylation of the insulin signalling cascade at different sites.

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