Insulin resistance caused by hepatic cholinergic interruption and reversed by acetylcholine administration

The role of hepatic parasympathetic nerves in insulin effectiveness was evaluated in fed anesthetized rats. Insulin sensitivity was assessed using a modified euglycemic clamp to quantitate the amount of glucose required to maintain euglycemia over 60 min after administration of insulin (50 mU/kg). With normal innervation, intraportal infusions of acetylcholine (ACh, 2.5 micrograms.kg-1.min-1) did not alter insulin sensitivity, but intraportal venous atropine (3 mg/kg) reduced insulin sensitivity (49.4 +/- 5.8%, P < 0.001, n = 7). Liver denervation resulted in reduction of insulin responsiveness by 70.8 +/- 5.8% (P < 0.001, n = 8), which was fully (96.8 +/- 12.5%) reversed by ACh. ACh into the portal vein reversed insulin resistance produced by denervation, but intravenous ACh was without effect, thus showing that the liver was the site of ACh action. Regression analysis suggests that some component of insulin response is not dependent on hepatic cholinergic nerve effects but that virtually all of the variability in response to insulin in normal fed rats tested under these conditions could be accounted for by variability in the hepatic parasympathetic-dependent insulin sensitivity. These data suggest a major role for hepatic parasympathetic nerves in regulation of whole body clearance of glucose in response to insulin.