Effects of FFAs on Hepatic Insulin Clearance

An elevation of circulating FFA experimentally induced by an Intralipid + heparin infusion decreases hepatic insulin extraction in vivo in dogs (162). Hennes et al. (171) showed in humans that Intralipid + heparin decreased whole body insulin clearance (which includes both hepatic and peripheral insulin extraction) during hyperglycemic clamps. We have obtained similar findings in humans (172) but only after prolonged Intralipid + heparin infusion. On the contrary, others failed to show changes in hepatic insulin extraction after 48 h of Intralipid + heparin infusion performed during a 48 h hyperglycemic clamp (173), possibly because of different experimental protocols. The mechanism underlying the effect of FFAs on insulin clearance may involve an increase in insulin receptor internalization and decreased insulin binding via a progressive increase in PKC8 translocation (174,175). The FFA-mediated reduction in hepatic insulin extraction may be viewed as an adaptive mechanism to generate peripheral hyperinsulinemia, and thus partially overcome the peripheral insulin resistance induced by FFAs. This adaptive mechanism could relieve, in part, the stress on pancreatic ^-cells imposed by insulin resistance (176). This is another example of co-ordinated regulation of insulin secretion, insulin clearance, and insulin action to maintain glucose homeostasis, although the mechanisms of this cross organ communication are not currently known.

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