Meal-induced peripheral insulin sensitization is regulated by hepatic parasympathetic nerves

W. Wayne Lautt and Joshua Schafer, Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, R3E 0T6.

The glucose disposal effect of administered insulin is approximately doubled in response to a meal. The insulin sensitization is proposed to result from insulin acting on the liver in the presence of a parasympathetic feeding signal to cause the release of a putative hepatic insulin sensitizing substance (HISS) which acts selectively on skeletal muscle to stimulate glucose uptake and glycogen storage. Elimination of the parasympathetic feeding signal to the liver through either surgical denervation or atropine to block hepatic muscarinic receptors eliminates the HISS response thereby decreasing the response to insulin by 55% in the fed state. The parasympathetic permissive signal can be restored in the denervated liver by intraportal infusion of acetylcholine. The cholinergic agonist does not produce a direct effect on glucose dynamics but restores the postprandial insulin sensitization in fed but not fasted animals. Insulin action, as determined using a rapidly sampled transient euglycemic clamp in response to 50 mU/kg insulin is decreased in a dose-dependent manner by atropine. Using a model of 75% atropine induced HISS-dependent insulin resistance, potentiation of the remaining parasympathetic effect through the use of neostigmine, an acetylcholinesterase antagonist, restores the postprandial insulin sensitization.

The data suggest the use of either direct or indirect acting cholinergic agonists for the treatment of impaired postprandial insulin sensitization.