INDUCTION OF INSULIN-RESISTANCE BY CHOLINERGIC BLOCKADE WITH ATROPINEIN THE CAT

1 Insulin sensitivity was quantified using a modified euglycaemic tech nique after hepatic cholinergic blockade with atropine and compared wi th that after surgical denervation. 2 Intraportal administration of at ropine produced dose-dependent inhibition of insulin sensitivity in gl ucose metabolism. ED(50) of atropine was 0.99 mg kg(-1) (1 mg = 1.5 mu M) with maximum inhibition of 40.3 +/- 11.6%. 3 Atropine (3 mg kg(-1) ) reduced insulin sensitivity by a similar amount (33.6 +/- 3.4%) to t hat produced by hepatic surgical denervation (37.8 +/- 9.8%). Doses gr eater than 3 mg kg(-1) failed to further alter the insulin resistance produced by surgical denervation or atropine (3 mg kg(-1)) administrat ion, suggesting that activation of hepatic parasympathetic nerves is n ecessary to fully express the insulin effect. 4 Atropine reduced insul in sensitivity without changes in plasma concentrations of glucagon or insulin. The temporal response to insulin in this euglycaemic study w as not changed after atropine administration or after surgical hepatic denervation. 5 It is suggested that hepatic parasympathetic nerves sh ow a synergistic effect with insulin. Disease states that result in he patic parasympathetic neuropathy would be expected to produce an insul in resistant liver. 6 The modified euglycaemic clamp method for assess ing insulin responses was shown to be reproducible up to four times in the same animal and was sufficiently sensitive and quantitative to be able to generate a dose-response curve in each animal for atropine-in duced insulin resistance.