Delayed gastric emptying (GE) in non-obese diabetic (NOD) mice occurs in a subset of diabetic mice that fail to sustain elevated heme oxygenase-1 (HO1) expression in alternatively activated M2 macrophages (1). We demonstrated that mice with delayed GE and low HO1 expression have increased oxidative stress and loss of interstitial cells of Cajal (ICC). Induction of HO1 by treatment with hemin reverses delayed GE (2,3). Similar results were seen with interleukin-10 (IL-10) treatment. The aim of this study was to examine ICC morphology and function in IL-10 -treated mice. Methods: Mice were included if they developed delayed GE (T½ >118 min) within 10 weeks of start of hyperglycemia (glucose>250mg/dl). GE was measured every week. Mice with delayed GE were treated with vehicle (n = 5) or IL-10 (1 µg ip twice daily, n = 5). Smooth muscle membrane potential and electrical slow waves were recorded from circular muscle of the stomach at 12 regions distributed from the proximal body to distal antrum. After recording, tissues were doubly immunolabeled for HO1 and for Kit to identify ICC. Confocal images were also collected at 12 places distributed across the tissue. ICC and HO1 labeling were scored by 2 independent investigators blinded to the image source. Results: Prior to treatment, mean T½ value were 180±19 min (n = 8, all delayed). While GE remained delayed in mice treated with vehicle (T1/2 = 157±11 min, n = 5), GE returned to normal after 3.1 ± 0.9 weeks in IL-10-treated mice (T1/2 = 106 ± 4 min, n=5). There were significant abnormalities in the electrical slow wave of all vehicle treated mice; abnormalities were not observed in IL-10 treated mice. Slow waves had a higher frequency, the rise time was faster and the events were broader in IL-10 treated mice than in vehicle-treated mice (p < 0.05, paired sign test). The parameters in IL-10 treated mice were similar to previously recorded slow waves from mice with normal GE. The most pronounced differences were seen in the distal antrum where slow waves in IL-10 treated mice had a faster frequency (Veh: 0.04±0.01, IL-10: 0.07±0.02 Hz, Mean±SEM, p<0.05, ttest) and lower variation in peak amplitude than in vehicle treated mice (Veh: 3.85±0.71, IL-10: 0.58±0.41, Mean±SEM, p<0.05 ttest). HO1 expression was significantly higher in tissues from IL-10 treated mice. ICC networks in vehicle-treated mice had patchy damage and were scored as significantly less intact than networks from IL-10 treated mice. Conclusions: Uneven damage to ICC networks likely underlies electrical abnormalities in the stomachs of diabetic mice with delayed GE. Treatment of delayed GE with IL-10 normalizes delayed GE, changes to ICC networks and slow wave abnormalities.