Tu1451 Retrograde Axonal Transport of Fluorogold Was Reduced in Gastric Ascending, but Not Descending, Enteric Neurons in Type 2 Diabetic Kkay as Compared to Control Kk Mice

Abstract

Retrograde axonal transport was impaired in the gastric branch of the vagus nerve in animals with type 1 diabetes mellitus (DM). These studies evaluated active, retrograde axonal transport of the neural tracer fluorogold (FG) in gastric enteric neurons in KKAy mice 4 weeks prior to and at the onset of type 2 DM, and after 8, 16, and 24 weeks of uncontrolled DM. We hypothesized that the number of FG-labeled enteric neurons would progressively decrease with increasing durations of uncontrolled DM as compared to control KK mice. Under anesthesia, FG was injected into the ventral fundus or antrum. After 5-6 days, the stomach was removed and the numbers of FG-labeled enteric neurons with cell bodies in 2.8 mm2 of fundus, 1.7 mm2 of corpus, and 1.7 mm2 of antrum were counted. The total number of FG-labeled neurons in ascending pathways (cell bodies in corpus or antrum with nerve terminals in fundus), descending pathways (cell bodies in the fundus or corpus with nerve terminals in antrum), the local fundic pathway (cell body and nerve terminals in fundus), and the local antral pathway (cell body and nerve terminals in antrum) were compared in control and diabetic mice of different ages by 2-way ANOVA. Only main effects were significant; no interactions were significant. Data are mean±SEM with n representing the number of mice. In the ascending pathway, fewer FG-labeled neurons were observed in diabetic as compared to control mice [F(1,116)=10.668; control (n=68), 179±11; diabetic (n= 58), 145±11*; *p<0.05]. In contrast, similar numbers of FG-labeled neurons were observed in descending pathways [F(1,124)=0.489; p=0.486], local fundic pathways [F(1,53)=2.464; p=0.122], and local antral pathways [F(1,57)=0.728; p=0.397] of control and diabetic mice. Overall, the number of FG-labeled neurons decreased significantly with age in all pathways [ascending: F(4,116)=42.862; descending: F(4,124)=2.456; local fundic: F(4,53)=5.195; local antral: F(4,57)=8.920]. In the ascending pathway, the number of FG-labeled neurons was significantly less at 16 weeks of age [n=28, 146±12] as compared to 4 weeks [n=24, 246±8] or 8 weeks [n=28, 229±12] of age, reaching its lowest value at 24 weeks of age [n= 24, 80±10]. In conclusion, DM did not uniformly impair active tracer transport in all gastric enteric neurons suggesting specific axonal targets in ascending enteric neurons rendering them more susceptible to hyperglycemia and low effective insulin. Supported by ORSP at MWU.