Emerging evidence suggests the gastrointestinal tract plays an important glucoregulatory role. In this perspective, we first review how the intestine senses ingested nutrients, initiating crucial negative feedback mechanisms through a gut-brain neuronal axis to regulate glycemia, mainly via reduction in hepatic glucose production. We then highlight how intestinal energy sensory mechanisms are responsible for the glucose-lowering effects of bariatric surgery, specifically duodenal-jejunal bypass, and the antidiabetic agents metformin and resveratrol. A better understanding of these pathways lays the groundwork for intestinally targeted drug therapy for the treatment of diabetes.