Peripheral neuropathy is a correlate of experimental diabetes induced in rats by means of a single injection of alloxan. The autonomic and enteric innervation of the gut are profoundly affected in the small intestine of such animals. A complex process of denervation and hyperinnervation of the gut wall of diabetic animals is observed. It was previously reported that the cholinergic parasympathetic innervation of the intestine is markedly reduced. We have found that noradrenergic sympathetic axons hyperinnervate the duodenum of diabetic rats, whereas noradrenaline levels are significantly reduced in the jejunum. The putative enteric neurotransmitter dopamine is also present in higher levels in the duodenum. The intrinsic peptidergic neurons of the gut are deeply affected as well in diabetic rats. Substance P and met-enkephalin content are remarkably reduced throughout the small intestine, whereas vasoactive intestinal polypeptide levels (VIP) are significantly increased in the duodenum. Indeed, immunocytochemical staining of the ileum did reveal hypertrophy of VIP-positive axons in diabetic rats. The intrinsic serotoninergic innervation of the gut is apparently unaffected. Our results indicate that the changes of gut innervation observed in experimental diabetes are consistent with increased content and also likely with hyperinnervation by the neuronal systems involved in smooth muscle relaxation and decreased content and with denervation by those systems with smooth muscle contraction properties. Such a perturbed gut innervation may be responsible of the gastrointestinal dysfunctions that are among the most common complications of diabetes.

The monoaminergic innervation of the central nervous system (CNS) is characterized by long and short projecting neurons. The neurological correlates of diabetes are usually referred to as processes of degenerative atrophy affecting motor and sensory peripheral nerves. We have found that the long serotoninergic axons innervating the spinal cord and the cerebral cortex are unaffected in diabetic animals and that the noradrenergic innervation of the cortex is normal as well. The serotonin content is doubled in the hypothalamus with no apparent alteration of 5-HIAA levels, suggesting a supernumerary innervation that is accompanied by a reduced release. In pons medulla oblongata, serotonin and dopamine with the relative metabolites 5-HIAA and DOPAC are significantly reduced, whereas noradrenaline is markedly increased. In the hippocampus, there is a reduction of serotonin content. The serotoninergic alterations are peculiar as suggested by the sparing of the most distal projections that is accompanied by hyperinnervation of the hypothalamus and the loss of shorter collaterals in the pons medulla oblongata. In the hypothalamus and in the striatum of diabetic rats, there are significant higher levels of substance P and met-enkephalin, respectively. The abundance of proenkephalin A mRNA is also increased in the striatum. Conversely, in the lumbar cord of diabetic animals, the levels of substance P and met-enkephalin are significantly reduced. Such alterations likely reflect retrograde degeneration of the peripheral sensory input. The CNS changes are unlikely due to vascular abnormalities in the brain of diabetic rats; rather, we suggest that the persistent lack of insulin is the major factor involved as a trigger of the monoaminergic changes in the diabetic brain.

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