Gut glucose assimilation governs glucose homeostasis through reciprocal interaction between glucose and amino acid transporter.

Glucose homeostasis is orchestrated through the integrated actions of pancreatic insulin secretion, hepatic glucose production, and peripheral glucose utilization. However, the mechanism governing gut glucose metabolism remains incompletely characterized. We employed positron emission tomography coupled with metabolomic profiling to demonstrate that the rodent small intestine possesses a remarkable capacity to sequester and catabolize circulating fasting glucose. Notably, these effects were consistent across sexes and various physiological conditions. Mechanistic studies revealed that gut glucose assimilation during fasting is mediated by basolateral GLUT1, which is modulated through reciprocal regulation by apical angiotensin-converting enzyme 2 (ACE2) and the neutral amino acid transporter SLC6A19. Impaired gut glucose assimilation contributes to hyperglycemia in both rodent models and type 2 diabetic patients, which is associated with inhibition of SLC6A19 and disruption of ACE2/GLUT1 interaction yet ameliorated by SGLT2 inhibitors. We highlight that the small intestine harnesses glucose homeostasis through reciprocal interactions between glucose and amino acid transporters.