Denervation and hyperinnervation in the nervous system of diabetic animals. I. The autonomic neuronal dystrophy of the gut

Abstract

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.

Diabetic neuropathy in the rat: 1. Alcar augments the reduced levels and axoplasmic transport of substance P

“…Substance P is supplied to the gastrointestinal tract mainly by intrinsic innervation arising from myenteric and submucosal plexi (Pernow, 1983). Our data confirm previous suggestions of enteric nerve pathology in the gut of diabetic animals (Lincoln et al, 1984;Di Giulio et al, 1989a). The protective effects of ALCAR treatment reported in this paper confirm previous results suggesting a remarkable effect of such a pharmacological treatment upon peptide alterations observed in the gut of diabetic rats.…”

Progressive and selective changes in neurotrophic factor expression and substance p axonal transport induced by perinatal diabetes: Protective action of antioxidant treatment

“…In more chronic diabetes, the nerve content of substance P is also reduced (Robinson et al, 1987). The peptidergic loss also occurs in the gastrointestinal system, where the content of metenkephalin, calcitonin gene-related peptide (CGRP), and substance P progressively decreases in diabetic rats (Gorio et al, 1992;Di Giulio et al, 1989;Belai et al, 1987). It has also been reported that in skin biopsies of chronic diabetic patients affected by sensory loss and hypo-aesthesia, there is a reduction in the density of substance P immunocytochemically stained nerve fibers (Levy et al, 1992).…”

Denervation and hyperinnervation in the nervous system of diabetic animals: III. Functional alterations of G proteins in diabetic encephalopathy

“…There are indeed good correlations between biochemical changes of axonal transport and morpho-functional alterations, e.g., axonal atrophy and changes of conduction velocity (Vitadello et a]., 1983(Vitadello et a]., , 1985Gorio et al, 1984;Norido et al, 1984). The innervation of the gut is also deeply affected by diabetcs with specific changes in peptidergic and monoaminergic levels (Di Giulio et al, 1989a). We have also shown that the central nervous system may also be affected in diabetic animals (Di Giulio et al, 1989b).…”

“…Substance P (SP), vaso-active intestinal peptide (VIP), and met-enkephalin (ME) levels were determined with radioimmunoassay (RIA) as previously reported (Di Giulio et al, 1989a).…”