Abstract
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. The glucoregulatory role of PepT1 in the upper small intestine of healthy rats is further demonstrated by glucose homeostasis disruption following high protein feeding when PepT1 is inhibited. PepT1-mediated protein-sensing mechanisms also improve glucose homeostasis in models of early-onset insulin resistance and obesity. We demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by PepT1 have beneficial effects on whole-body glucose homeostasis.
Highlights
High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive
We first investigated the potential glucoregulatory role of upper small intestinal protein sensing on whole-body glucose homeostasis under physiological conditions
As previous studies have highlighted the role of peptide transporter 1 (PepT1) activation in the stimulation of glucagon-like peptide-1 (GLP-1) release[25,35] and GLP-1 release is associated with beneficial effects on glucose production (GP) and tolerance, we investigated whether the influence of upper small intestinal casein infusion on GP relies on the action of GLP-1 signaling
Summary
High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive. 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. As hyperglycemia contributes to the development of diabetic-related complications such as blindness, renal failure, cardiovascular disease, and stroke, there is an increasingly urgent need to identify novel therapeutic strategies to restore glucose homeostasis and/or reduce blood glucose levels in diabetic individuals In this regard, exhaustive studies conducted in rodents and humans have demonstrated that high protein (HP) diets improve glucose homeostasis. While the demonstrated improvements in glucose homeostasis might result secondary to decreased food intake and weight loss, 5 weeks of HP feeding in diabetic patients improved glucose tolerance even when individuals maintained a stable weight[7] and pair-feeding to match energy intake and body weight improved glucose homeostasis in rats fed a HP diet[8]. Statistical significance was determined using an unpaired, two-tailed t-test (two groups) or ANOVA with Tukey post-hoc test (3+ groups)
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