Differential Regulation of NHE3 Expression in Type 1 and Type 2 Diabetic Intestine: Impaired Endosomal Regulation of...

Chronic diarrhea is a frequent gastrointestinal complication in both type 1 (T1D) and type 2 diabetes (T2D), though the underlying mechanisms differ: T1D is linked to autonomic neuropathy and disrupted transporter regulation, while T2D is often linked to medications and intestinal inflammation. Using streptozotocin-induced mouse models of T1D and T2D, we observed increased luminal fluid in the small intestine of both. Given the role of Na⁺/H⁺ exchanger 3 (NHE3) in fluid absorption and its loss in most diarrheal diseases, we examined NHE3 expression across intestinal segments. In T1D, NHE3 protein was significantly reduced in the duodenum and jejunum without changes in mRNA, suggesting post-transcriptional regulation. In contrast, T2D mice exhibited reduced NHE3 protein and mRNA, restricted to the proximal colon. To investigate mechanisms underlying NHE3 loss in T1D, we evaluated endosomal scaffolding proteins involved in NHE3 trafficking. While our previous work showed that the Sorting Nexin-27 (SNX27)-retromer complex does not regulate NHE3 protein stability, we found that SNX17 was significantly decreased in the small intestine of T1D mice but unchanged in T2D. SNX17 knockdown in SK-CO15 cells reduced NHE3 activity and stability. A GST pull-down assay showed that SNX17 interacts with the C-terminus of NHE3. Mutation of the NHE3 distal NPxY motif disrupted this interaction, leading to reduced NHE3 expression and increased degradation. These findings reveal segment-specific and mechanistically distinct causes of diabetic diarrhea in T1D versus T2D, and identify SNX17 loss as a contributor to reduced NHE3 stability and activity in T1D, likely promoting diabetic diarrhea.