Glucose-induced insulin secretion in vivo is known to be severely blunted in the rat as a consequence of protein-energy restriction starting early in life. We have recently reported in such malnourished rats (M rats) that the release of the counterregulatory hormones that defend against hypoglycemia was severely disturbed, and their plasma levels of epinephrine and norepinephrine were prominently increased. Knowing that the autonomic nervous system has the potential to play a major role in the control of insulin secretion in response to glucose in vivo, we therefore determined whether protein-energy restriction starting after weaning could alter sympathetic and/or parasympathetic nerve activities, and whether these changes could be responsible for the lack of response to glucose of their beta-cells in vivo. When tested in the basal postabsorptive state, the malnourished rats exhibited profound alterations of both parasympathetic and sympathetic nerve activities; the firing rates of the vagus nerve and the superior cervical ganglion were dramatically decreased and increased, respectively. Under the same conditions, insulin secretion in vivo in response to a glucose load (deltaI/deltaG) was severely decreased in M rats compared with that in control (C) rats. When evaluated after administration of acetylcholine, deltaI was amplified to the same extent in M rats as in C rats. After administration of the alpha2A-adrenergic agonist oxymetazoline, glucose-induced insulin release in M rats was not significantly affected, whereas it was sharply decreased in C rats. Finally, administration of yohimbine, an alpha2-adrenergic antagonist, partially restored the lack of reactivity of the beta-cells to glucose in the M rats, as deltaI/deltaG was amplified by 6-fold in the M group and by 3.3-fold in the C group. We conclude that protein-energy restriction starting early in life in rats brings about changes in the overall activity of the autonomic nervous system that, in turn, are responsible at least in part for the acquisition/maintenance of decreased beta-cell reactivity to glucose in vivo.