Abstract
Nutrients often stimulate gut hormone secretion, but the effects of fructose are incompletely understood. We studied the effects of fructose on a number of gut hormones with particular focus on glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In healthy humans, fructose intake caused a rise in blood glucose and plasma insulin and GLP-1, albeit to a lower degree than isocaloric glucose. Cholecystokinin secretion was stimulated similarly by both carbohydrates, but neither peptide YY3–36 nor glucagon secretion was affected by either treatment. Remarkably, while glucose potently stimulated GIP release, fructose was without effect. Similar patterns were found in the mouse and rat, with both fructose and glucose stimulating GLP-1 secretion, whereas only glucose caused GIP secretion. In GLUTag cells, a murine cell line used as model for L cells, fructose was metabolized and stimulated GLP-1 secretion dose-dependently (EC50 = 0.155 mM) by ATP-sensitive potassium channel closure and cell depolarization. Because fructose elicits GLP-1 secretion without simultaneous release of glucagonotropic GIP, the pathways underlying fructose-stimulated GLP-1 release might be useful targets for type 2 diabetes mellitus and obesity drug development.
Highlights
IntroductionWhile it has long been known that the presence of nutrients such as glucose, fat, and protein in the intestinal lumen stimulates secretion of many gut hormones, the effects of fructose are poorly understood
THE GUT IS THE LARGEST hormone-producing organ of the body
Maximum blood glucose concentrations were higher in the glucose group
Summary
While it has long been known that the presence of nutrients such as glucose, fat, and protein in the intestinal lumen stimulates secretion of many gut hormones, the effects of fructose are poorly understood. Increased dietary intake of fructose has been suspected to be partly responsible for the growing rates of obesity and the metabolic syndrome (hypertension, hypertriglyceridemia, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus) [17, 20], possibly due to fructose-induced perturbation of cell signaling and inflammatory reactions in insulin-sensitive tissues [21]. We conducted the present study to investigate the effect of fructose on appetite- and metabolism-regulating hormones from the gut, with a particular focus on the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), since recent expression profiles of some gut endocrine cells suggested expression of the fructose transporter, GLUT5 [14, 19]. Because it turned out that fructose clearly stimulated GLP-1 secretion in humans, we investigated intracellular mechanisms behind fructose-stimulated secretion in the murine L cell model, the GLUTag cell line [4], after confirming that GLP-1 secretion was stimulated in rats and mice
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