Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin‐induced diabetes

Abstract

Interstitial cells of Cajal (ICC) are associated with afferent innervation and peristalsis of the stomach suggestive of a key role in the pathophysiology of gastroparesis. We studied changes in the density and ultrastructure of ICC and enteric nerves in the streptozotocin-induced diabetes mellitus (STZ-DM) in Wistar rats using immunohistochemistry and electron microscopy. Gastric emptying was studied in vivo by single-photon emission computed tomography. In the STZ-DM antrum, a marked reduction was observed in the density of the intramuscular ICC (ICC-IM) and ICC located at the submucosal border of the circular muscle layer of the antrum (ICC-SM). The surviving ICC showed lamellar bodies and partial vacuolation of the cytoplasm content, loss of connections between ICC-IM and nerves; it appeared that injured ICC-IM developed into fibroblast-like ICC. ICC associated with Auerbach's plexus (ICC-AP) in the antrum and ICC in the fundus were not affected significantly except for a loss of connections with nerve structures. Marked reduction in nerve tissue (Protein Gene Product-9.5 positivity) was also restricted to the muscle layers including nitrergic nerves (neuronal nitric oxide synthase positivity). In vivo assessed gastric emptying was markedly reduced in STZ-DM rats. Our data demonstrate in the STZ-DM rat stomach a decreased density of ICC limited to the antrum and to ICC-IM and ICC-SM, and structural degeneration in ICC-IM and associated nerves with a special emphasis on loss of synaptic connections, accompanied by a decrease in gastric emptying. Hence, in this model of gastroparetic diabetes, regional injury to subsets of ICC and nerves are associated with gastric motor dysfunction.