Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing.

High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive. Here we show that acute administration of casein hydrolysate directly into the upper small intestine increases glucose tolerance and inhibits glucose production in rats, independently of changes in plasma amino acids, insulin levels, and food intake. Inhibition of upper small intestinal peptide transporter 1 (PepT1), the primary oligopeptide transporter in the small intestine, reverses the preabsorptive ability of upper small intestinal casein infusion to increase glucose tolerance and suppress glucose production.

Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota.

Despite significant progress in understanding the homeostatic regulation of energy balance, successful therapeutic options for curbing obesity remain elusive. One potential target for the treatment of obesity is via manipulation of the gut-brain axis, a complex bidirectional communication system that is crucial in maintaining energy homeostasis. Indeed, ingested nutrients induce secretion of gut peptides that act either via paracrine signaling through vagal and non-vagal neuronal relays, or in an endocrine fashion via entry into circulation, to ultimately signal to the central nervous system where appropriate responses are generated.

Glucoregulatory Relevance of Small Intestinal Nutrient Sensing in Physiology, Bariatric Surgery, and Pharmacology.

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.

Does nutrient sensing determine how we "see" food?

The ability to "see" both incoming and circulating nutrients plays an essential role in the maintenance of energy homeostasis. As such, nutrient-sensing mechanisms in both the gastrointestinal tract and the brain have been implicated in the regulation of energy intake and glucose homeostasis. The intestinal wall is able to differentiate individual nutrients through sensory machinery expressed in the mucosa and provide feedback signals, via local gut peptide action, to maintain energy balance.