Upper Small Intestinal Protein Sensing Improves Glucose Tolerance Through Suppression of Hepatic Glucose Production

Intestinal lipid-sensing initiates a neuronal gut-brain-liver negative feedback pathway to lower glucose production (GP) and maintain glucose homeostasis in vivo. However, whether intestinal protein-sensing regulates GP and consequently glucose tolerance via a neuronal network remains unknown, despite the ability of high-protein feeding to improve hyperglycemia and glucose tolerance in healthy and diabetic rodents and humans. Thus, we investigated the effects of upper small intestinal protein-sensing on glucose homeostasis by first infusing intraduodenal 10% w/v casein hydrolysate (CH) during an intravenous glucose tolerance test (IVGTT) in healthy rats. Intestinal infusion of CH for 50 min improved glucose tolerance as compared to saline (AUC saline: 1186.4±106.8 vs. CH: 340.29±128.96, n=8, p<0.05), independent of a rise in plasma amino acids. Thus, this protein-induced glucose-lowering effect was preabsorptive. To assess whether intestinal protein-sensing improves glucose tolerance by directly lowering GP or increasing glucose uptake (GU) independent of changes in circulating glucoregulatory hormones, we infused intestinal CH during a pancreatic (basal-insulin) euglycemic clamp and evaluated changes in glucose kinetics using tracer-dilution methodology. Intestinal CH lowered GP (% suppression from basal; saline: -18.2±4.9% vs. CH: 46±3.2%, n=8, p<0.05) compared to saline-treated rats, while GU remained unchanged (basal GU: 13.2±0.7 mgkg-1min-1 vs. CH GU: 12.6±0.7 mgkg-1min-1, n=8, p>0.05). These findings collectively suggest that upper small intestinal protein-sensing improves glucose tolerance by lowering GP in healthy rodents. Future studies will address the underlying preabsorptive signaling mechanisms, the potential involvement of a neuronal gut-brain-liver axis, and the capacity of intestinal protein-sensing in models of obesity and diabetes.