Effect of nerve blockade on pulsatile insulin and glucagon secretion in vitro

We recently reported that the secretion of insulin and glucagon by isolated murine islets is pulsatile and suggested that the pacemaker controlling these hormone oscillations is present in the islet. In the present study, we tested the hypothesis of an intrinsic islet neural controlling mechanism for the observed hormone pulsatility. Nerve blockade was attempted by infusion of tetrodotoxin (TTX) on a background of combined adrenergic and cholinergic blockade with atropine, propranolol, and phentolamine, (ATX). Because TTX acts by blocking Na+ channels, we also studied the effects of other cationic channel manipulations on the amplitude and frequency of the oscillations. The normal frequency and amplitude of glucagon and insulin oscillations were not affected by ATX. In contrast, TTX infusion increased the amplitude of insulin (198.6 +/- 20.9 vs. 507.2 +/- 62.8 pg/min, p less than 0.05, n = 4) and shortened the period from 5.03 +/- 0.26 to 3.33 +/- 0.0 min without affecting glucagon cycles. Whereas the Ca2+ ionophore A23187 had no effect on either hormone oscillation, the ATP-sensitive K+ channel blocker glyburide only increased the amplitude of insulin and decreased the amplitude of glucagon, without altering the frequencies. These data suggest that an intrinsic autonomously functioning islet nervous system is the pacemaker for the insulin oscillations and that the control of glucagon cycles differs from that of insulin.